What are the causes of overdose in a patient taking Vyvanse (lisdexamfetamine) for Attention Deficit Hyperactivity Disorder (ADHD), particularly in those with a history of substance abuse or taking interacting medications?

Causes of Vyvanse (Lisdexamfetamine) Overdose

The primary causes of lisdexamfetamine overdose include intentional ingestion of excessive doses (whether for abuse, suicide attempt, or seeking psychoactive effects), accidental ingestion (particularly medication errors in children), and drug interactions that potentiate sympathomimetic effects, with the most dangerous being concurrent use of other serotonergic medications. 1, 2

Intentional Overdose Mechanisms

Abuse and misuse represent major overdose risks, as lisdexamfetamine has high potential for abuse despite being a prodrug of dextroamphetamine. 1

• Patients may intentionally take excessive doses seeking euphoric or psychostimulant effects, with abuse occurring through approved oral routes or unapproved methods like crushing and snorting (though this is less effective with the prodrug formulation). 1
• Suicide attempts account for a significant proportion of intentional overdoses, particularly in patients with depression or psychiatric comorbidities. 2
• Approximately 7% of overdose patients take stimulants "for kicks" seeking psychological effects and inadvertently overdose. 3

Accidental Overdose Scenarios

Medication errors are common, especially in pediatric populations, where children may access medications or take the wrong prescription. 4, 5

• A documented case involved an 8-year-old who mistakenly took his brother's 36-mg methylphenidate instead of his prescribed 20-mg lisdexamfetamine, resulting in severe hyponatremia and status epilepticus. 5
• Another case described a 6-year-old girl with accidental lisdexamfetamine ingestion leading to serotonin syndrome requiring dexmedetomidine after benzodiazepines failed. 4
• Iatrogenic overdose occurs when prescribers fail to account for renal impairment, as the FDA label specifies maximum doses of 50 mg/day for severe renal impairment (GFR 15-30) and 30 mg/day for ESRD. 1

Drug Interactions That Precipitate Overdose

Concurrent use of serotonergic medications dramatically increases overdose risk and severity. 1

• MAOIs are absolutely contraindicated and can cause hypertensive crisis and serotonin syndrome when combined with lisdexamfetamine. 1
• SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and St. John's Wort all increase risk of serotonin syndrome when combined with lisdexamfetamine. 1
• Drugs that impair serotonin metabolism, including linezolid, pose particular danger. 1

While the evidence provided focuses heavily on opioid interactions 6, 7, these are not directly relevant to lisdexamfetamine overdose mechanisms, as lisdexamfetamine is a stimulant, not an opioid.

High-Risk Patient Populations

Patients with substance use disorder history are at markedly elevated risk for both intentional overdose and developing tolerance requiring escalating doses. 2

• History of prior overdose increases future overdose risk, a pattern documented extensively in opioid literature that likely applies to stimulants. 6
• Psychiatric comorbidities, particularly depression and bipolar disorder, increase risk of intentional overdose and suicide attempts. 1, 2
• Patients with renal or hepatic dysfunction experience reduced drug clearance, leading to higher and longer-lasting blood levels at standard doses. 1

Tolerance and Dose Escalation

Daily use without medication breaks can lead to tolerance, requiring increasing doses that approach toxic levels. 8

• Lisdexamfetamine can produce tolerance after prolonged use, even when taken as prescribed, which is a physiological state requiring higher doses to achieve the same therapeutic effect. 1
• The maximum FDA-approved dose is 70 mg/day, and exceeding this significantly increases overdose risk. 6, 1

Critical Clinical Pitfall

The most dangerous oversight is failing to recognize that lisdexamfetamine is converted to dextroamphetamine, meaning all amphetamine-related drug interactions and contraindications apply. 6 Prescribers must screen for serotonergic medications, MAOIs, and substance use history before initiating therapy, and patients require education about the absolute necessity of taking only prescribed doses and avoiding medication sharing. 1, 2