What are the potential interactions between marijuana and medications such as buspirone, Lamictal (lamotrigine), mirtazapine, and Rexulti (brexpiprazole)?

Marijuana Interactions with Buspirone, Lamotrigine, Mirtazapine, and Brexpiprazole

Cannabis inhibits multiple cytochrome P450 enzymes (CYP3A4, CYP2C19) that metabolize these psychiatric medications, potentially increasing their blood levels and adverse effects, requiring dose reduction and close monitoring when used concurrently. 1

Pharmacokinetic Interaction Mechanisms

Cannabis-mediated enzyme inhibition affects drug metabolism:

• Cannabis and cannabinoids inhibit CYP3A4 and CYP2C19 enzymes responsible for metabolizing buspirone, lamotrigine, mirtazapine, and brexpiprazole 1
• This inhibition increases medication blood levels unpredictably, particularly because cannabis products have highly variable THC and CBD content 1
• CBD at doses >300 mg/day causes dose-related, reversible hepatotoxicity with transaminase elevations, which may further impair drug metabolism 1
• High-fat meals significantly increase oral cannabinoid absorption, exacerbating drug interactions 1

Medication-Specific Risks

Buspirone with marijuana:

• Increased buspirone levels may enhance serotonergic effects, theoretically raising serotonin syndrome risk 1, 2
• Historical data show buspirone has minimal interaction with other medications, but cannabis was not specifically studied 3

Lamotrigine (Lamictal) with marijuana:

• Elevated lamotrigine levels increase seizure risk paradoxically, as seen in overdose cases where lamotrigine caused status epilepticus 4
• Cannabis may exacerbate psychiatric disorders in vulnerable individuals, potentially counteracting lamotrigine's mood-stabilizing effects 1

Mirtazapine with marijuana:

• Both substances cause sedation through H1 receptor antagonism; combined use compounds drowsiness, dizziness, and confusion 1, 5
• Mirtazapine increases appetite and weight gain; cannabis similarly stimulates appetite, potentially causing excessive weight gain 5
• Research shows mirtazapine did not reduce marijuana withdrawal symptoms or relapse, suggesting no therapeutic synergy 6

Brexpiprazole (Rexulti) with marijuana:

• Increased brexpiprazole levels may enhance dopamine blockade, worsening extrapyramidal symptoms and sedation 1
• Cannabis may worsen psychotic symptoms in vulnerable patients, directly opposing brexpiprazole's antipsychotic effects 7

Additive Central Nervous System Effects

Overlapping adverse effects create compounded risks:

• Cannabis causes dizziness, confusion, dry mouth, fatigue, tachycardia, orthostatic hypotension, severe confusion, and paranoia 1
• These effects overlap with side effects from all four psychiatric medications, particularly sedation and cognitive impairment 1, 5
• Older adults face higher risk of confusion, falls, and cardiovascular events (myocardial ischemia/infarction) when combining these substances 7, 1

Psychiatric Disorder Exacerbation

Cannabis worsens underlying mental health conditions:

• Cannabis use associates with major depression, suicidal ideation, and elevated risk for psychotic disorders 7
• Patients with pre-existing psychiatric disorders should exercise extreme caution, as cannabis may destabilize their conditions 1
• Cannabis use disorder (CUD) risk increases with regular use, causing withdrawal symptoms including irritability, insomnia, and headaches 7

Clinical Management Algorithm

Start with the lowest cannabis dose and titrate slowly:

• Begin cannabis at minimal doses with sufficient time (days to weeks) between increases to assess effects 1
• Monitor for serotonin syndrome signs: confusion, agitation, anxiety, tremors, hyperreflexia, muscle rigidity, hypertension, tachycardia, diaphoresis 1, 2
• Check liver function tests when using CBD products, especially at doses >300 mg/day 1
• Avoid high-fat meals when taking oral cannabis to prevent excessive absorption 1

Adjust psychiatric medication doses downward:

• Consider reducing buspirone, lamotrigine, mirtazapine, or brexpiprazole doses by 25-50% when initiating cannabis to prevent toxicity 1
• Elderly patients and those with hepatic impairment require more aggressive dose reductions due to reduced drug clearance 1

Critical Safety Warnings

Avoid driving and safety-sensitive activities:

• Cannabis impairs reaction time and coordination for up to 12 hours depending on product type 7
• Drivers testing positive for cannabis are more than twice as likely to be involved in motor vehicle crashes 1
• Combined sedative effects from these medications further impair driving ability 7, 1

Storage and accidental exposure prevention:

• Store cannabis separately from other foods in locked, child-resistant containers out of reach of children and pets 7
• Pediatric cannabis exposures increased from 207 in 2017 to 3,054 in 2021, causing CNS depression, vomiting, and tachycardia 7

Contraindications and High-Risk Scenarios

Absolute caution in specific populations:

• Pregnant and breastfeeding individuals must avoid cannabis due to fetal brain development risks and premature birth 7
• Patients with history of psychotic disorders should not use cannabis, as it may trigger psychotic episodes 7, 1
• Those with substance use disorder history face higher risk of developing cannabis use disorder 7