Medications and Marijuana: Potential Drug Interactions
Direct Answer
Cannabis and cannabinoids interact with numerous medications primarily through inhibition of cytochrome P450 enzymes (CYP3A4, CYP2C9, CYP2C19) and drug transporters (P-glycoprotein, BCRP), with the most clinically significant interactions occurring with warfarin, immunotherapies, tacrolimus, and buprenorphine. 1, 2
High-Risk Medication Interactions
Very High Risk: Warfarin
- Cannabis is classified as very high risk when combined with warfarin 1
- The FDA warfarin label explicitly warns about botanicals including cannabis causing increased PT/INR responses 3
- Monitor PT/INR more frequently when initiating or discontinuing cannabis in warfarin users 3
- Bleeding events are the primary concern 2
High Risk Medications
- Buprenorphine and tacrolimus are classified as high-risk interactions 1
- Tacrolimus interactions were among the most widely reported, with altered serum levels and potential for toxicity 2
- Sirolimus also showed frequent interaction reports 2
Immunotherapy Concerns
- Patients on cancer immunotherapy should avoid cannabis use 1
- Preliminary data suggest poorer clinical outcomes when cannabis is combined with immunotherapies 1
- This represents a critical safety concern given the narrow therapeutic window of these agents 1
Mechanism of Interactions
Cytochrome P450 Enzyme Effects
- Cannabis inhibits CYP3A4, CYP2C9, CYP2C19, CYP1A2, CYP2B6, and CYP2C8 1
- CBD and THC are also metabolized by these same enzymes, creating bidirectional interaction potential 4, 5
- CYP2C9 polymorphisms (present in up to 35% of Caucasians) increase THC bioavailability and interaction risk 6
Drug Transporter Interactions
- Cannabis inhibits P-glycoprotein and BCRP transporters 1
- This affects medications with narrow therapeutic windows that are substrates for these transporters, including digoxin, dabigatran, ticagrelor, carvedilol, amlodipine, and diltiazem 1
Specific Drug Class Interactions
Anticonvulsants
- Valproate interactions are widely reported 2
- Altered mental status and difficulty achieving therapeutic levels are common adverse events 2
- Monitor serum levels closely when combining with cannabis 2
Anesthetic Agents
- Cannabis use is NOT a contraindication to NSAIDs, opioids, local anesthetics, ketamine, gabapentin/pregabalin, dexmedetomidine, or acetaminophen 1
- However, patients using >1.5 g/day smoked cannabis, >300 mg/day CBD oil, or >20 mg/day THC oil require special perioperative considerations 1
- Consider increased depth of anesthesia during induction and maintenance 1
- Provide additional PONV prophylaxis 1
- Anticipate increased postoperative analgesia requirements 1
Antidepressants and Psychiatric Medications
- Cannabis inhibits CYP2C19, which metabolizes escitalopram, potentially increasing serotonergic effects 7
- Monitor for serotonin syndrome signs: confusion, agitation, tremors, hyperreflexia, muscle rigidity, hypertension, tachycardia, diaphoresis 7
- With atomoxetine, additive cardiovascular effects (tachycardia, blood pressure instability) may occur 8
- With desvenlafaxine, additive CNS depression and mood alterations are concerns 9
Hepatitis C Direct-Acting Antivirals
- No clinically significant interactions are expected between cannabis and HCV DAAs (sofosbuvir, ledipasvir, velpatasvir, paritaprevir/ritonavir/ombitasvir/dasabuvir, grazoprevir/elbasvir, daclatasvir, simeprevir) 1
Clinical Management Algorithm
Step 1: Risk Stratification
- Identify if patient takes very high-risk medications (warfarin) → Strongly discourage cannabis or implement intensive monitoring 1, 3
- Identify if patient takes high-risk medications (tacrolimus, buprenorphine, immunotherapy) → Avoid cannabis or use only with close monitoring 1, 2
- Identify if patient takes narrow therapeutic index medications metabolized by CYP3A4, CYP2C9, or CYP2C19 → Anticipate dose adjustments 1, 5
Step 2: Dosing Strategy
- Start cannabis at the lowest possible dose and titrate slowly with sufficient time between doses (at least 2 hours for oral, 30 minutes for inhaled) 1
- For oral THC: start ≤2.5 mg and wait 1-2 hours for onset 1
- For CBD oil: start <300 mg/day 1
- For THC oil: start <20 mg/day 1
Step 3: Route Selection
- Prefer oral/edible formulations over smoking or vaping for patients with chronic medication use 1
- Avoid high-fat meals when taking oral cannabis, as this significantly increases cannabinoid absorption and may exacerbate interactions 1, 8, 7
- Oral onset is 30 minutes to 2 hours with duration of 5-8 hours 1
- Inhaled onset is seconds to minutes with duration of 2-3 hours 1
Step 4: Monitoring Plan
- Check serum drug levels more frequently when initiating or changing cannabis dose, particularly for medications with narrow therapeutic indices 3, 2
- In 58% of reported cases, clinicians discovered unexpected serum levels of prescribed medications 2
- Monitor for specific adverse events: bleeding (warfarin), altered mental status (valproate), GI distress (immunosuppressants), cardiovascular effects (stimulants, antidepressants) 2, 8, 7
Step 5: Patient Counseling
- Directly ask about cannabis use—patients often do not volunteer this information 1
- Warn about driving impairment: wait 5-8 hours after cannabis use, potentially longer for some individuals 1
- Cannabis users are more than twice as likely to be involved in motor vehicle crashes 8
- Advise safe storage away from children and pets 1
Special Population Considerations
Elderly Patients
- Higher risk of confusion, falls, and adverse effects due to reduced drug clearance 1, 7, 9
- Start with even lower doses than standard recommendations 1
- More intensive monitoring is warranted 1
Hepatic Impairment
- Reduced clearance of both cannabis and co-administered medications increases interaction risk 1, 7, 9
- CBD at doses >300 mg/day causes dose-related, reversible transaminase elevations 1, 8, 7
- Consider liver function monitoring with higher CBD doses 7
Cardiovascular Disease
- Cannabis causes tachycardia and orthostatic hypotension 1, 8
- Monitor more closely when combined with medications affecting heart rate or blood pressure 9
Psychiatric History
- Cannabis may exacerbate psychiatric disorders and increase risk of depressive disorders 8, 7
- Avoid in patients with history of psychosis 1
- Monitor for paranoia, severe confusion, and breaks with reality 1
Critical Pitfalls to Avoid
Product Variability
- Cannabis products have highly variable THC and CBD content, making interactions unpredictable 1, 7
- Lack of manufacturing standardization compounds this problem 3
- Adulteration with synthetic cannabinoid receptor agonists (SCRAs) can lead to unpredictable clinical outcomes and exacerbate drug interactions 1, 9
Dose Stacking
- Patients unfamiliar with oral cannabis may stack doses before the first dose takes effect (30 minutes to 2 hours), leading to excessive sedation, euphoria, hallucinations, and mood changes 1
- Emphasize waiting adequate time between doses 1
Assuming Cannabis is Benign
- Do not assume cannabis is safe simply because it may be legal in your jurisdiction 8
- Cannabis carries significant cardiovascular, psychiatric, and drug interaction risks 8, 6, 10
Failing to Document
- Failure to ask about cannabis use is a critical error 1
- Direct questioning is essential as patients rarely volunteer this information 8
- Document THC/CBD content, frequency, route, and source 1
Ignoring Perioperative Risks
- Cannabis users require specific perioperative management 1
- Heavy users (>1.5 g/day smoked, >300 mg/day CBD, >20 mg/day THC) need processed EEG monitoring, extra PONV prophylaxis, consideration for greater depth of anesthesia, and increased postoperative analgesia 1
- Cannabis withdrawal syndrome begins after 48 hours of abstinence and causes nausea and stomach pain 1
Evidence Quality Considerations
The 2024 ASCO guideline 1 represents the highest quality and most recent evidence, noting that while there is a "considerable body of preclinical work," there are "only scant clinical data" on cannabinoid-medication interactions. The 2021 British Journal of Anaesthesia perioperative consensus 1 provides the most specific dosing thresholds for clinical decision-making. The systematic review by Kocis et al. (2024) 2 identified 31 real-world reports involving 889 subjects, providing the strongest evidence for warfarin, valproate, tacrolimus, and sirolimus interactions. The FDA warfarin label 3 provides regulatory-level guidance on botanical interactions.