Stimulants: Methylphenidates

Table of Contents

What are Stimulants?

The term “stimulant” is a bit nebulous. Generally, stimulants refer to medications that promote attention and arousal. They include medications used to treat narcolepsy, daytime fatigue, and attention deficit hyperactivity disorder. 

The stimulants include the amphetamines (dextroamphetamine, amphetamine mixed salts, lisdexamfetamine, methamphetamine), methylphenidates (ritalin, concerta), modafinil (Provigil) and armodafinil (Nuvigil). 

Amphetamine and methylphenidate primarily promote dopamine and norephinephrine neurotransmission in specific areas of the brain whereas modafinil and armodafinil primarily promote histamine release.

Overview of Methylphenidate

Methylphenidate was first synthesized in 1944 by the CIBA Pharmaceutical company’s chemist Leandro Panizzon. Panizzon’s wife, Rita, used it for her chronic low blood pressure and therefore Panizzon named the drug “Ritaline” after his wife. 

In the 1960s and 1970s, Methylphenidate was first marketed for “hyperkinetic syndrome” (now known as ADHD), narcolepsy, and depression. Methylphenidate is primarily used to treat Attention Deficit Hyperactivity Disorder, Narcolepsy, Depression, and Chronic Fatigue. Methylphenidate comes in a number of formulations with different durations of action. Brand names for methylphenidate-based medications include Focalin, Ritalin, Metadate, Concerta, Daytrana, and Methylin.

Clinical Information

Methylphenidate (Ritalin, Concerta)

Generic NameBrand NameUsual Starting DoseTypical Daily Dose Range
Long-acting MPHRitalin SR20mg QAM10-140mg
Ritalin LA20mg QAM20-120mg
Concerta18mg QAM18-144mg
Metadate CD10-20mg QAM10-120mg
Short-acting MPHMethylphenidate 10mg q4hrs10-140mg
Methylin10mg q4hrs10-140mg
Ritalin10mg q4hrs10-140mg
D-methylphenidate Focalin5mg q4-6hrs10-80mg
Focalin XR5-10mg QAM10-80mg
MPH, Methylphenidate; XR, Extended Release; SR, Sustained Release; LA, Long-Acting

HALF-LIFE: 2-4 hours

PROTEIN BINDING: Low (15%)

TIME TO EFFECT: IR ~15-30min | Concerta/LA/SR ~1-2 hours

PEAK IN PLASMA: IR 1-2 hours | Concerta/LA/SR ~5-8 hours

DURATION OF CLINICAL ACTION: IR 4-5 hours |Concerta/LA/SR ~ 8-12 hours

METABOLISM: Primarily Hepatic (liver) via carboxylesterase CES1A1 (not CYP mediated) and gut

WITH/WITHOUT FOOD: Methylphenidate is absorbed at a faster rate in the presence of food

STARTING DOSE: (See Table Above)

TARGET DOSING RANGE: (See Table Above)

BEST TIME TO DOSE: Morning

PREGNANCY: Avoid if possible (discuss with a medical professional)

BREASTFEEDING: Avoid if possible (discuss with a medical professional)

Mechanism of Action

Methylphenidate, like cocaine, binds to and inhibits both the norepinephrine transporter (NET) and the dopamine transporter (DAT) on noradrenergic neurons and dopaminergic neurons in the brain, respectively. Inhibition of NET and DAT increases extracellular levels of norepinephrine (NE) and dopamine (DA), respectively, in specific areas of the brain. Methylphenidate, unlike amphetamines, does not facilitate release of dopamine and norepinephrine by reversing the mechanism of the dopamine and norepinephrine transporters. 

Notable Interactions

  • Desipramine should be used with extreme caution if used with methylphenidate
  • Antacids increase absorption of methylphenidate
  • Dopamine antagonists such as haloperidol and chlorpromazine as well as lithium may inhibit stimulant effects
  • Avoid using with monoamine oxidase inhibitors (MAOIs) due to risk of hypertensive crises and malignant hyperthermia

Notable Side Effects

  • Insomnia
  • Headache
  • Anxiety/Nervousness
  • Abdominal Pain
  • Anorexia
  • Nausea
  • Vomiting
  • Dry Mouth
  • Weight loss
  • Seizures (rarely with PO)
  • Psychosis (rarely with PO)
  • Elevated Blood Pressure
  • Tachycardia
  • Sudden death has been reported in patients with preexisting cardiac structural abnormalities

FDA Indications

  1. Attention Deficit Hyperactivity Disorder in children and adults
  2. Narcolepsy (Ritalin, Concerta, Ritalin-SR, Ritalin-LA)

Additional Information

  • Methylphenidate has four (4) possible stereoisomers because it has two (2) stereoactive centers.
  • Dexmethylphenidate (brand name Focalin) is the most biologically active form and is also twice as potent as methylphenidate. Methylphenidate generally has fewer adverse effects compared to amphetamine but may not be as effective.

References

  1. Schatzberg, A. F., & DeBattista, C. (2015). Manual of clinical psychopharmacology. Washington, DC: American Psychiatric Publishing.
  2. Schatzberg, A. F., & Nemeroff, C. B. (2017). The American Psychiatric Association Publishing textbook of psychopharmacology. Arlington, VA: American Psychiatric Association Publishing.
  3. Stahl, S. M. (2013). Stahl’s essential psychopharmacology: Neuroscientific basis and practical applications (4th ed.). New York, NY, US: Cambridge University Press.
  4. Cooper, J. R., Bloom, F. E., & Roth, R. H. (2003). The biochemical basis of neuropharmacology (8th ed.). New York, NY, US: Oxford University Press.
  5. Iversen, L. L., Iversen, S. D., Bloom, F. E., & Roth, R. H. (2009). Introduction to neuropsychopharmacology. Oxford: Oxford University Press.
  6. Puzantian, T., & Carlat, D. J. (2016). Medication fact book: for psychiatric practice. Newburyport, MA: Carlat Publishing, LLC.
  7. Ebenezer, Ivor. Neuropsychopharmacology and Therapeutics. John Wiley & Sons, Ltd. 2015.