Commonly Asked Question – What are the Drug Interactions with Cannabis?

I have been writing quite a few programs over the last few months on cannabis.  One of the most common questions that I get is on drug interactions with cannabis.

 The Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids developed by Health Canada is a great starting point if you have questions regarding pharmacology, potential indications, adverse effects, kinetics and methods of administration.  There is a large amount of great information in this publication.

What are the most concerning drug interactions with cannabis?

The drug interactions that are most concerning with cannabis are with medications that could cause sedation or cognitive impairment. These include alcohol, opioids, benzodiazepines, tricyclic antidepressants, and gabapentinoids. 

The key is when cannabis is going to be used with these medications, slow titration is recommended.  I would normally recommend starting on a lower dose of THC, and slow the titration.

What about CYP 450 enzyme interactions with cannabis? 

CYP 2C9, 2C19 & 3A4 inhibitors

Delta-9 THC is oxidized by the CYP isoenzymes 2C9, 2C19, and 3A4 into approximately 80 metabolites.  Substances that inhibit these CYP enzyme could increase the bioavailability of THC.  These include:

  • Antidepressants – fluoxetine, fluvoxamine, moclobemide
  • Proton pump inhibitors -omeprazole
  • Macrolides – azithromycin, erythromycin, clarithromycin
  • Azole antifungals – itraconazole, fluconazole, ketoconazole
  • Calcium channel blockers – diltiazem, verapamil
  • HIV protease inhibitor – ritonavir, indinavir, atazanavir, darunavir
  • Amiodarone
  • Ticlopidine
  • Grapefruit juice
  • Isoniazid

Additive tachycardia, hypertension, and drowsiness have been reported with THC and concomitant consumption of tricyclic antidepressants such as amytryptiline, and desipramine. Additive hypertension, tachycardia, and possible cardiotoxicity have been reported with THC and concomitant consumption of sympathomimetic agents such as amphetamines and cocaine. 

CBD is also metabolized by CYP 2C19 and CYP 3A4.  The bioavailability of CBD could potentially be increased by many of the same substances listed
for THC.

CYP 2C9 and 3A4 inducers

Medications that induce CYP 2C9 and 3A4 can accelerate delta9-THC and CBD metabolism.  These drugs include rifampin, carbamazepine, phenobarbital, phenytoin, primidone, and Saint John’s Wort.

Does smoking have an impact on drug interactions?

Smoking cannabis may induce CYP 1A1 and 1A2.  This could lead to a decrease in plasma levels of medications metabolized these isoenzymes (e.g. chlorpromazine, theophylline).

What about CBD and anti-convulsants?

There is also some evidence to suggest a potential interaction between CBD and phenytoin.  Patients taking CBD and anti-convulsants such as phenytoin should be monitored for increased blood levels of phenytoin, and doses of phenytoin should be adjusted accordingly to avoid the potential for excess blood levels of phenytoin and a phenytoin overdose. 

In the CBD in severe pediatric seizure (Lennox Gastaut Syndrome) trial, the clobazam levels increased significantly when CBD was used.  This is managed by a decrease in clobazam dose. 

What drug interactions are clinically significant?

The key cannabis drug interactions that are most concerning are those drugs that cause sedation (e.g. opioids, alcohol, benzodiazepines).  These drug interactions can be mitigated by starting on a low dose of cannabis and increasing slowly. 

The other drug interactions with the CYP isoenzymes are all generally mitigated by low dose and slow titration.  The key is that while the patient is on any CYP P450 metabolized drug that can interact with cannabis, he/she must be completely adherent to cannabis and the other medication otherwise the drug levels may increase or decrease significantly. 

For those patients with epilepsy, the interaction with CBD and clobazam is significant and may require dose adjustments.