What are Stimulants?

The term “stimulant” is a bit nebulous. In neuropsychopharmacology (and for our purposes) 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 the nucleus accumbens and prefrontal cortex whereas modafinil and armodafinil primarily promote histamine release from hypothalamic nuclei.

 

Below is a brief review of the amphetamine-based stimulants. 

Overview of Amphetamines

Amphetamine is phenylisopropylamine

 

Alterations of the three main parts of the phenylisopropylamine backbone ultimately determines its pharmacological effects

  • Amine Group: Most common alteration is at the amine group, which is thought to alter the stimulant like properties of amphetamines
  • Isopropyl Group: Needed to maintain potency
  • Phenyl Group: Changes are associated with decrease in amphetamine properties (methoxy alterations are associated with hallucinogenic properties)

 

Stereospecificity (D,L – stereoisomers)

  • Amphetamine mixed salts are typically a mixture of dextroamphetamine (D-amphetamine) and levoamphetamine (L-amphetamine). 
  • D-amphetamine is almost twice as potent as the levo form in promoting wakefulness
  • D and L are of equal potency in reducing cataplexy and REM sleep
  • Stereospecificity also determines the degree of dopamine reuptake inhibition (in rat models)
  • D-amphetamine is four times more potent than the L-isomer in promoting lever pressing in rats (model of reinforcement)

 

Mechanism of Action

  • Amphetamine rapidly diffuses directly into neuron terminals and enters neuronal vesicles which causes release of dopamine and norepinephrine
  • Amphetamine also inhibits reuptake of these catecholamines by inhibition of the their respective reuptake transporters

 

Pharmacokinetics

  • Amphetamine is lipid soluble, distributes rapidly into tissues, and readily crosses the blood brain barrier.
  • Amphetamine reaches peak levels in ~2 hours
  • Half life of amphetamine is approximately 16-30 hours.
  • 30% of amphetamine is excreted unchanged

 

Side Effects

  • Nervousness
  • Agitation
  • Decreased sleep
  • Diaphoresis (sweating)
  • Anorexia
  • Psychosis (rare with oral formulations) 

 

Methamphetamine

  • Methamphetamine is more potent but also more toxic than amphetamine
  • Methamphetamine can cause destruction of dopaminergic neurons in the basal ganglia (increased likelihood of future parkinsonism?)
  • Psychosis, rhabdomyolysis, convulsions, arrhythmia, hyperpyrexia, and death may result from inhaled or injected methamphetamine
  • MDMA “Ecstasy” is toxic to both serotonergic and dopaminergic neurons

(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

 

PROTEIN BINDING: ~20%

 

METABOLISM: CYP2D6 (partially)

 

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)

 

HOW TO DOSE:

  • 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 stimulant effects of amphetamines
  • Amphetamines increase the analgesic effects of meperidine
  • Avoid using with monoamine oxidase inhibitors due to risk of hypertensive crises and malignant hyperthermia

 

NOTABLE SIDE EFFECTS:

  • Insomnia
  • Headache
  • Anxiety
  • Tremor
  • Anorexia
  • 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

 

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

 

PROTEIN BINDING: ~20%

 

METABOLISM: CYP2D6 (partially)

 

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)

 

HOW TO DOSE:

  • 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:

  • 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 stimulant effects of amphetamines
  • Amphetamines increase the analgesic effects of meperidine
  • Avoid using with monoamine oxidase inhibitors due to risk of hypertensive crises and malignant hyperthermia

 

NOTABLE SIDE EFFECTS:

  • Insomnia
  • Headache
  • Anxiety
  • Tremor
  • Anorexia
  • 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

 

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 
  • Anecdotally, patients experience less peripheral sympathetic side effects and anxiety with D-Amphetamine compared to D,L-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

 

METABOLISM: Minimal CYP450 involvement

 

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 

 

HOW TO DOSE:

  • 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:

  • 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 stimulant effects of amphetamines
  • Amphetamines increase the analgesic effects of meperidine
  • Avoid using with monoamine oxidase inhibitors due to risk of hypertensive crises and malignant hyperthermia

 

NOTABLE SIDE EFFECTS:

  • Insomnia
  • Headache
  • Anxiety
  • Tremor
  • Anorexia
  • 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

 

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 (i.e., dextroamphetamine attached to a lysine amino acid). This means that is needs to be metabolized in order for it to be active.
  • Lisdexamfetamine is metabolized primarily by gastrointestinal 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.

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