What is Methylphenidate (Central Nervous System Stimulant)?

What is Methylphenidate?

Methylphenidate is an FDA Schedule II central nervous system (CNS) stimulant that blocks dopamine and norepinephrine reuptake transporters, primarily indicated for treating ADHD in patients 6 years and older and narcolepsy. 1

Drug Classification and Regulatory Status

• Methylphenidate is classified as a federally controlled Schedule II substance due to its high potential for abuse, misuse, and addiction, which can lead to substance use disorder 1, 2
• The FDA black box warning emphasizes that misuse and abuse can result in overdose and death 1
• It carries a black box warning specifically cautioning use in patients with history of drug dependence or alcoholism 2

Mechanism of Action

Methylphenidate enhances catecholaminergic neurotransmission through multiple pathways 3, 1:

• Blocks dopamine and norepinephrine reuptake transporters, increasing synaptic concentrations of these neurotransmitters in the prefrontal cortex and striatum 3, 1
• Amplifies dopamine response duration and disinhibits dopamine D2 autoreceptors 3
• Activates D1 receptors on postsynaptic neurons 3
• Acts as an agonist at serotonin type 1A receptors and redistributes vesicular monoamine transporter 2 3

The d-threo enantiomer is the pharmacologically active component, being more potent than the l-threo enantiomer 1

FDA-Approved Indications

Methylphenidate is indicated for 1:

• Attention Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years of age and older
• Narcolepsy (conditional recommendation with very low quality evidence, primarily improving disease severity) 2

Pharmacokinetic Profile

• Peak plasma concentration occurs 1-3 hours after oral administration 4, 1
• Half-life is 2-3 hours, making it a short-acting stimulant 4, 1
• Duration of action for immediate-release formulations is 4-6 hours 5
• Plasma protein binding is 10-33% 1
• Metabolized primarily by deesterification to ritalinic acid (inactive metabolite), with 90% of radioactivity recovered in urine 1

Available Formulations

Immediate-Release Formulations

• Provide 4-6 hours of clinical action with onset at 30 minutes 5
• Require multiple daily doses to maintain symptom control throughout the day 5
• Create predictable plasma concentration troughs at unstructured times 5

Extended-Release Formulations

• Newer extended-release formulations with early peak followed by 8-12 hours of action are superior to older sustained-release preparations 5
• OROS-methylphenidate (Concerta) provides the longest duration at 12 hours of coverage 5
• Long-acting formulations are associated with better medication adherence and probably lower risk of rebound effects 5
• Microbead capsule formulations can be sprinkled for patients who cannot swallow tablets 5

Clinical Efficacy

• Produces effect sizes of approximately 1.0 for ADHD treatment, significantly higher than non-stimulant alternatives 4
• In advanced cancer patients, methylphenidate significantly decreases fatigue severity, with 41% experiencing clinically significant improvement versus 15% with placebo 4
• Methylphenidate is recommended as first-line pharmacologic treatment for preschool children (ages 4-5 years) with moderate-to-severe ADHD, though this remains off-label use 2

Contraindications

Methylphenidate is contraindicated in 1, 4:

• Known hypersensitivity to methylphenidate or its components
• Concurrent treatment with MAOIs or use within 14 days of MAOI discontinuation
• Uncontrolled hypertension
• Underlying coronary artery disease
• Tachyarrhythmias

Serious Warnings and Precautions

Cardiovascular Risks

• Avoid use in patients with known structural cardiac abnormalities, cardiomyopathy, serious cardiac arrhythmias, coronary artery disease, or other serious cardiac disease 1
• Measure blood pressure and heart rate before initiating treatment and at each follow-up visit 4, 1

Psychiatric Adverse Reactions

• Screen patients for risk factors for developing manic episodes prior to initiation 1
• If new psychotic or manic symptoms occur, consider discontinuing methylphenidate 1

Growth Suppression in Pediatric Patients

• Closely monitor height and weight in pediatric patients 4, 1
• Pediatric patients not growing or gaining height/weight as expected may need treatment interruption 1

Ophthalmologic Concerns

• Can cause acute angle closure glaucoma in at-risk patients (e.g., significant hyperopia) 1
• Prescribe cautiously to patients with open-angle glaucoma or abnormally increased intraocular pressure 1

Other Serious Risks

• Priapism: Patients should seek immediate medical attention for abnormally sustained or frequent painful erections 1
• Peripheral vasculopathy including Raynaud's phenomenon: Careful observation for digital changes is necessary 1
• Motor and verbal tics: Assess family history and clinically evaluate for tics or Tourette's syndrome before initiating treatment 1

Common Adverse Effects

The most frequently reported adverse reactions include 1, 2:

• Tachycardia and palpitations
• Headache
• Insomnia
• Anxiety
• Hyperhidrosis (excessive sweating)
• Weight loss and decreased appetite
• Dry mouth
• Nausea and abdominal pain
• Stomach discomfort

Dosing Considerations

Pediatric Patients (6 years and older)

• Starting dose is 5 mg twice daily (before breakfast and lunch) 1
• Increase dose by 5-10 mg weekly 1
• Daily dosage above 60 mg is not recommended 1

Adults

• Administer in divided doses 2-3 times daily, preferably 30-45 minutes before meals 1
• Average dosage is 20-30 mg daily 1
• Maximum recommended daily dosage is 60 mg 1

Special Populations

Pregnancy and Breastfeeding

• Based on animal data, methylphenidate may cause fetal harm 2
• Human data are insufficient to determine risk 2
• The balance of risks and harms is likely different for pregnant and breastfeeding women 2

Adolescents

• Assess for symptoms of substance use before beginning treatment 2
• Monitor for signs of misuse or diversion of medication, including by parents, classmates, or other acquaintances 2
• Most states require prescriber participation in prescription drug monitoring programs 2

Abuse Potential and Monitoring

• Methylphenidate has a high potential for abuse and misuse, particularly among older teens and emerging adults 6
• Intranasal abuse produces effects rapidly that are similar to cocaine in both onset and type 7
• Before prescribing, assess each patient's risk for abuse, misuse, and addiction 1
• Throughout treatment, reassess risk and frequently monitor for signs and symptoms of abuse, misuse, and addiction 1
• Educate patients and families about proper storage and disposal of unused medication 1