Do cannabinoids interact with Vyvanse (lisdexamfetamine)?

Cannabinoid-Vyvanse Interactions: Clinical Considerations

There is substantial reason to believe cannabinoids can interfere with Vyvanse (lisdexamfetamine) through both pharmacokinetic enzyme inhibition and additive central nervous system effects, requiring caution and close monitoring if used concurrently.

Pharmacokinetic Interaction Mechanisms

Cannabinoids inhibit multiple cytochrome P450 enzymes that may affect amphetamine metabolism, potentially increasing drug levels unpredictably. 1, 2

• CBD demonstrates potent inhibition of CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes, with binding-corrected IC50 values ranging from 0.17 to 0.95 µM, indicating moderate to strong interaction potential 2
• THC shows even more potent inhibition of CYP1A2 and CYP2C9 (IC50,u of 0.06 and 0.012 µM respectively), which are involved in amphetamine metabolism 2
• Lisdexamfetamine is a prodrug that requires hydrolysis to release active d-amphetamine, which is then metabolized hepatically 3
• The variable THC and CBD content in cannabis products makes drug interactions highly unpredictable, as enzyme inhibition is dose-dependent 1, 4

Additive Central Nervous System Effects

Both cannabinoids and amphetamines cause overlapping CNS effects that compound when used together, creating significant safety concerns. 1, 5

• Cannabis causes dizziness, confusion, dry mouth, fatigue, tachycardia, and orthostatic hypotension—effects that overlap substantially with amphetamine side effects 1, 4
• The combination may result in enhanced cardiovascular stimulation (additive tachycardia and blood pressure effects) or paradoxically increased sedation and cognitive impairment 1, 5
• Older adults face particularly high risk for confusion, falls, and cardiovascular events (myocardial ischemia/infarction) when combining these substances 1

Psychiatric Disorder Exacerbation Risk

Cannabis use is associated with worsening psychiatric symptoms that may counteract ADHD treatment benefits. 1, 4

• Cannabis associates with major depression, suicidal ideation, and elevated risk for psychotic disorders, potentially undermining the therapeutic goals of ADHD treatment 1
• Patients with pre-existing psychiatric disorders should exercise extreme caution, as cannabis may destabilize their conditions 1
• THC has been associated with psychotic symptoms in some individuals, which could complicate ADHD management 5

Clinical Management Algorithm

If a patient chooses to use cannabis while taking Vyvanse, implement the following monitoring strategy: 1, 4

1. Start with the lowest possible cannabis dose and titrate slowly over 1-2 weeks, allowing sufficient time between doses to gauge effects 1, 6
2. Monitor for signs of amphetamine toxicity: excessive stimulation, anxiety, tremors, hypertension, tachycardia, and diaphoresis 1, 4
3. Check liver function tests when using CBD products, especially at doses ≥300 mg/day, as reversible transaminase elevations can occur 7, 4
4. Avoid high-fat meals when taking oral cannabis, as this significantly increases cannabinoid absorption and may exacerbate drug interactions 1, 4, 5
5. Consider dose reduction of Vyvanse if signs of increased amphetamine effects emerge 1

Critical Safety Warnings

Cannabis impairs reaction time and coordination for up to 12 hours depending on product type, and drivers testing positive for cannabis are more than twice as likely to be involved in motor vehicle crashes. 1, 4

• Patients must avoid driving or operating heavy machinery for 5-8 hours after cannabis use (longer for edible formulations) 5
• Store cannabis separately from other medications in locked, child-resistant containers, as pediatric cannabis exposures increased from 207 in 2017 to 3,054 in 2021 1

High-Risk Populations Requiring Absolute Caution

The following patients should avoid this combination entirely: 1, 4

• Pregnant and breastfeeding individuals must avoid cannabis due to fetal brain development risks and premature birth 1
• Patients with history of psychotic disorders should not use cannabis, as it may trigger psychotic episodes 1, 5
• Those with substance use disorder history face higher risk of developing cannabis use disorder 1
• Patients with cardiovascular conditions require additional monitoring as both substances affect heart rate and blood pressure 5

Common Pitfalls to Avoid

• Do not assume "medical marijuana" is safer than recreational products—both contain variable cannabinoid concentrations that affect interaction potential 1, 4
• Do not rely on patient-reported cannabis dosing—most patients cannot accurately quantify their THC/CBD intake 1
• Do not ignore the delayed onset of edible cannabis products (up to 2 hours), which may lead to repeated dosing and excessive drug exposure 5, 6