Stimulants: Amphetamines

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 Amphetamines

Amphetamine has two forms

  • Amphetamine is a molecule that exists in two forms called stereoisomers, which are mirror images of each other. They are labeled D- and L-amphetamine for Dextro and Levoamphetamine, respectively. 
  • Amphetamine mixed salts are typically a mixture of dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine). 
  • Dextroamphetamine is almost twice as potent as the levo form in promoting wakefulness
  • Methamphetamine is amphetamine with a methyl group (-CH3) attached to it, making it more potent but also more toxic than amphetamine
  • Methamphetamine, at high doses, can cause destruction of dopaminergic neurons in the basal ganglia
  • Psychosis, rhabdomyolysis, convulsions, arrhythmia, hyperpyrexia, and death may result from inhaled or injected methamphetamine

Mechanism of Action

  • Amphetamine enhances two important neurotransmitters, dopamine and norepinephrine, in the brain. 
  • Dopamine and norepinephrine have been implicated in working memory, mood regulation, reinforcement, motivation, hedonic drive, and initiation of movement

Interesting Characteristics

  • Amphetamine is lipid soluble, distributes rapidly into tissues, and readily crosses the blood brain barrier.
  • Amphetamine reaches peak blood levels in about 2 hours
  • The Half life of amphetamine (amount of time for half of the drug to be eliminated) is approximately 16-30 hours.
  • About 30% of amphetamine is excreted unchanged

Side Effects

  • Nervousness
  • Agitation
  • Decreased sleep
  • Diaphoresis (sweating)
  • Anorexia
  • Psychosis, especially at very high doses via smoking, injecting or snorting (rare with oral formulations) 

(D,L) Amphetamine (Adderall)

*IR (Instant Release) | XR (Extended Release)

HALF-LIFE: 9-14 hours

TIME TO EFFECT: IR ~1 hour | XR ~1-2 hours

PEAK IN PLASMA: IR 3 hours | XR 7 hours

DURATION OF CLINICAL ACTION: IR 6-9 hours | XR 6-10 hours

WITH/WITHOUT FOOD (PO): Taking with food may delay peak actions. pH of food alters absorption and elimination of amphetamines. GI and urinary Acidifying agents decrease plasma levels of amphetamines. GI and urinary alkalinizing agents increase plasma levels of amphetamines. 

STARTING DOSE: 5mg-10mg

TARGET DOSING RANGE: 10mg-60mg per day

BEST TIME TO DOSE: Morning (but depends on formulation)

TYPICAL DOSING:

  • IR: Initial 5mg twice daily. Increase dose by 5mg-10mg per day each week based on response and tolerability. Typically dose every 4-6 hours. Maximum daily dose generally 40mg-60mg. Some patients may require higher dosages.
  • XR: Initial 10mg every morning. Increase dose by 5mg-10mg at weekly intervals based on response and tolerability. Maximum daily dose generally 30mg-60mg. Some patients may require higher dosages.

NOTABLE INTERACTIONS:

  • GI/Urinary Acidifying agents decrease plasma levels of amphetamine
  • GI/Urinary Alkalinizing agents increase plasma levels of amphetamine
  • Desipramine should be used with extreme caution if used with amphetamine
  • Dopamine antagonists such as haloperidol and chlorpromazine as well as lithium may inhibit the stimulant effects of amphetamines
  • Amphetamines increase the pain relieving effects of meperidine
  • Avoid using with monoamine oxidase inhibitors (MAOIs) due to risk of hypertensive crises (extremely high blood pressures) and malignant hyperthermia (extremely high body temperatures)

NOTABLE SIDE EFFECTS:

  • Insomnia
  • Headache
  • Anxiety
  • Tremor
  • Anorexia (Decreased appetite)
  • Dry Mouth
  • Weight loss
  • Seizures (rare)
  • Psychosis (rare)
  • Elevated Blood Pressure (~5 mmHg)
  • Tachycardia
  • Sudden death has been reported in patients with preexisting cardiac structural abnormalities

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

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

FDA INDICATIONS:
1) Attention Deficit Hyperactivity Disorder in children and adults

2) Narcolepsy

3) Exogenous obesity

ADDITIONAL INFORMATION

  • Adderall is a mixture of the two isomeric forms of amphetamine (D and L Amphetamine) in a ratio of 3 to 1 (D to L)

(D) Amphetamine (Dexedrine)

*IR (Instant Release) | ER (Extended Release)

HALF-LIFE: 10-12 hours

TIME TO EFFECT: IR ~1 hour | ER ~1-2 hours

PEAK IN PLASMA: IR 3 hours | ER 7 hours

DURATION OF CLINICAL ACTION: IR 3-9 hours | ER 6-10 hours

WITH/WITHOUT FOOD (PO): Taking with food may delay peak actions. pH of food alters absorption and elimination of amphetamines. GI and urinary Acidifying agents decrease plasma levels of amphetamines. GI and urinary alkalinizing agents increase plasma levels of amphetamines. 

STARTING DOSE: 5mg-10mg

TARGET DOSING RANGE: 5mg-40mg per day

BEST TIME TO DOSE: Morning (but depends on formulation)

TYPICAL DOSING:

  • IR: Initial 5mg twice daily. Increase dose by 5mg-10mg per day each week based on response and tolerability. Typically dose every 4-6 hours. Maximum daily dose generally 40mg-60mg. Some patients may require higher dosages.
  • ER: Initial 5mg-10mg every morning. Increase dose by 5mg-10mg at weekly intervals based on response and tolerability. Maximum daily dose generally 20mg-40mg. Some patients may require higher dosages.

NOTABLE INTERACTIONS:

  • Same as Adderall

NOTABLE SIDE EFFECTS:

  • Same as Adderall
  • Anecdotally, patients experience less peripheral sympathetic side effects (anxiety, tachycardia, tremors) with dextroamphetamine compared to Adderall (also less irritability at the end of the day)

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

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

FDA INDICATIONS:
1) Attention Deficit Hyperactivity Disorder in children and adults

2) Narcolepsy

ADDITIONAL INFORMATION

  • Dexedrine contains ONLY the dextro isomer of amphetamine 

Lisdexamfetamine (Vyvanse)

HALF-LIFE: lisdexamfetamine (prodrug): <1 hour | dextroamphetamine (active metabolite): 10-13 hours (dextroamphetamine)

TIME TO EFFECT: Variable. But generally longer than other amphetamine formulations

DURATION OF CLINICAL ACTION: Variable

WITH/WITHOUT FOOD (PO): Food does not affect absorption of lisdexamfetamine, but like other amphetamines, acidification of the urine or GI tract results in more rapid clearance. 

STARTING DOSE: 20mg-30mg

TARGET DOSING RANGE: 20mg-70mg per day

BEST TIME TO DOSE: Morning 

TYPICAL DOSING:

  • Initial 20mg-30mg every morning. Increase dose by 10mg-20mg at weekly intervals based on response and tolerability. Maximum daily dose generally 70mg. Some patients may require higher dosages.

NOTABLE INTERACTIONS:

  • Same as other amphetamines

NOTABLE SIDE EFFECTS:

  • Same as other amphetamines 

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

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

FDA INDICATIONS:
1) Attention Deficit Hyperactivity Disorder in children and adults

2) Binge Eating Disorder

ADDITIONAL INFORMATION

  • Lisdexamfetamine is an inactive prodrug, which means it needs to be metabolized in order for it to be active
  • Lisdexamfetamine is metabolized primarily by gastrointestinal (gut) enzymes to the active metabolite dextroamphetamine.
  • Snorting or injecting lisdexamfetamine will not result in “highs” and therefore there is less abuse potential overall
  • Anecdotally, patients experience less peripheral sympathetic side effects and anxiety with lisdexamfetamine (likely related to slower onset/offset of action but may also be due to stereospecificity of dextroamphetamine (active metabolite). 
  • Lisdexamfetamine 70mg is approximately equivalent to 30mg of D,L-Amphetamine (Adderall)
  • Some evidence suggests lisdexamfetamine may be beneficial for residual depressive symptoms (but controversial as RCTs failed to show separation from placebo in treatment resistant depression)

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. Whalen, K., Finkel, R., & Panavelil, T. A. (2015). Lippincotts illustrated reviews: pharmacology. Philadelphia, PA: Wolters Kluwer.
  8. Hales et al. The American Psychiatric Association Publishing Textbook of Psychiatry. 6th Ed.
  9. Goldberg & Ernst. Managing Side Effects of Psychotropic Medications. 1st Ed. 2012. APP.