10 prescription drugs that don’t mix well with marijuana

By Naveed Saleh, MD, MS
Published February 25, 2021

Key Takeaways

Marijuana contains the active cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), and interferes with drug metabolism in various ways. It can increase the levels or clearance of other drugs, as well as posing additive effects. Patients should be cautioned concerning possible cannabinoid effects. Furthermore, clinicians should try to prescribe alternative medications in the context of agents metabolized by cytochrome enzymes.

Data are limited about drug-drug interactions of cannabinoids. However, in a review published in Medicines, the authors noted, “The endocannabinoids system (ECS) has garnered considerable interest as a potential therapeutic target in various carcinomas and cancer-related conditions alongside neurodegenerative diseases. Cannabinoids are implemented in several physiological processes such as appetite stimulation, energy balance, pain modulation and the control of chemotherapy-induced nausea and vomiting (CINV). However, pharmacokinetics and pharmacodynamics interactions could be perceived in drug combinations.”

Here’s a look at potential drug interactions of cannabinoids and prescription medications.


Interaction. As a CYP3A4 substrate, CBD increases tacrolimus serum concentrations by threefold. It does not, however, affect THC levels. Physicians should monitor for negative side effects secondary to tacrolimus and prescribe alternative agents when possible. 

Taken by mouth, tacrolimus is used to prevent organ rejection following transplant. As a topical agent, it treats skin rash and atopic dermatitis.

Adverse effects. Tacrolimus administration can result in skin burning/stinging/soreness, muscle and back pain, itching, acne, headache, erythema, increased sensitivity to hot/cold, and swollen/infected hair follicles.


Interaction. This CYP3A4 inhibitor can double THC and CBD levels, thus enhancing marijuana’s effects. 

Ketoconazole belongs to the class of drugs called azole antifungals and is used to treat serious fungal infections.

Adverse effects. Enhanced CBD effects include somnolence and transaminase elevations. Enhanced THC effects can lead to increased psychoactive effects of marijuana. In other words, it increases the “high.”


Interaction. The tuberculin antibiotic rifampin acts as a CYP3A4 inducer that decreases THC concentrations by 20%. The clinical significance of this drop in THC levels remains to be elucidated. Similarly, these agents may drop CBD levels by 60%. 

Adverse effects. In those taking CBD to treat seizures, concomitant administration of rifampin may decrease efficacy of marijuana.


Interaction. Warfarin is a CYP2C9 substrate. Both THC and CBD may increase levels of these drugs, thus it’s important to monitor for adverse effects with warfarin dose reduction as necessary.

Adverse effects. Smoking marijuana can increase international normalized ratios and bleeding risk.


Interaction. This antibiotic, a CYP2C9 inhibitor, may increase THC levels, but does not affect CBD levels.

Adverse effects. Sulfamethoxazole (SMX) may boost the psychoactive effects of marijuana (ie, the “high”).


Interaction. This seizure medication acts as a CYP2C9 inducer and may decrease THC levels, although no effect is observed with regard to CBD levels.

Adverse effects. Could attenuate the psychotropic effects of marijuana.

N-desmethylclobazam (nCBZ)

Interaction. This drug acts as a CYP2C19 substrate. Although no interactions between nCBZ and THC have been observed, CBD may increase its levels by two and six times. Of note, nCBZ is the principal metabolite of clobazam, a drug used to treat seizures induced by Lennox-Gastaut syndrome.

Adverse effects. Symptoms of toxicity include lethargy, somnolence, impaired mentation, and aspiration risk—particularly in the elderly.


Interaction. This antidepressant drug acts as a CYP2C19 inhibitor. No interactions between THC and these agents have been observed. However, interactions with CBD are possible.

Adverse effects. Clinicians should monitor for CBD adverse effects including drops in blood pressure, dry mouth, lightheadedness, and drowsiness. More rarely, liver injury can result.


Interaction. As a CYP2B6 substrate, blood concentrations of selegiline may be increased by THC and CBD.

Selegiline is an antidepressant that is also used to control symptoms of Parkinson disease.

Adverse effects. Reduce selegiline dose if negative side effects observed, including lightheadedness, fainting, dry mouth, nausea, vomiting, difficulty swallowing, and stomach pain.


Interaction. This antipsychotic medication is a CYP1A2 substrate, clearance of clozapine may be increased by smoking marijuana. 

Adverse effects. In those who use marijuana habitually, antipsychotic efficacy of clozapine must be monitored. In those who quit smoking marijuana, to prevent toxicity, clozapine concentrations may need to be reduced by 50%. Symptoms of toxicity can include hyperthermia, seizures, cardiac arrhythmias, and alterations in consciousness.

Bottom line

In light of more permissive changes in the political and cultural climate surrounding marijuana use, physicians should keep an eye out for interactions between marijuana and prescription drugs—especially in the elderly and those with chronic health conditions. Furthermore, they should ask about marijuana use as part of a detailed history and physical examination. Remember to prescribe prescription drug alternatives as needed. 

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