Does cannabis interact with clotrimazole, terbinafine, nystatin (topical), and fluconazole?

Cannabis Interactions with Antifungal Agents

Cannabis does not have clinically significant interactions with topical clotrimazole, topical nystatin, or terbinafine, but may have theoretical interactions with fluconazole through CYP450 enzyme pathways.

Topical Antifungals (Clotrimazole and Nystatin)

Topical clotrimazole and nystatin have minimal to no interaction risk with cannabis because these agents have negligible systemic absorption when applied topically 1.

• Topical antifungals work locally at the site of application without entering systemic circulation in meaningful amounts 2, 3
• The KDIGO guidelines note that topical clotrimazole and nystatin provide "effective prophylaxis without systemic absorption and hence without concerns for side effects" 1
• Drug-drug interactions require systemic exposure to both agents, which does not occur with properly applied topical formulations 4

Important caveat: If clotrimazole is used as oral troches (lozenges) rather than topical cream, there may be minimal systemic absorption, but this remains clinically insignificant for cannabis interactions 1, 2.

Terbinafine

Terbinafine has no documented interactions with cannabis and is considered one of the safest systemic antifungals regarding drug interactions 5.

• Terbinafine is a CYP2D6 inhibitor but is not significantly metabolized by CYP enzymes that cannabis affects 6, 7
• A postmarketing surveillance study of 25,884 patients taking terbinafine with various concomitant medications revealed no new drug-drug interactions 5
• The FDA label for terbinafine lists specific drug interactions but does not include cannabis or cannabinoids 6
• Terbinafine "can generally be used without problems in older and multimorbid patients" due to its minimal interaction profile 7

Fluconazole

Fluconazole has theoretical but likely clinically insignificant interactions with cannabis through shared CYP450 metabolism pathways.

• Fluconazole is a moderate inhibitor of CYP3A4 and CYP2C9 enzymes 6, 8
• Cannabis compounds (THC and CBD) are metabolized primarily by CYP3A4 and CYP2C9 9, 8
• Co-administration could theoretically increase cannabis levels by 50-70%, similar to fluconazole's effect on terbinafine 6

Clinical significance is likely minimal because:

• The therapeutic window for cannabis is wide, and increased levels rarely cause serious adverse effects beyond increased psychoactive effects 9
• Fluconazole's interactions are most concerning with narrow therapeutic index drugs (warfarin, cyclosporine, certain antihistamines) 8, 5
• No case reports or clinical studies document adverse outcomes from fluconazole-cannabis combinations 9, 4

Practical Management Algorithm

For patients using cannabis:

1. Using topical clotrimazole or nystatin: Proceed without concern for interactions 1, 2

2. Using terbinafine: Prescribe without dose adjustments or special monitoring 5, 7

3. Using fluconazole:

   • Inform patients that cannabis effects may be slightly enhanced 6, 8
   • Advise starting with lower cannabis doses if they are new users 9
   • Monitor for increased sedation or psychoactive effects, but no laboratory monitoring is required 4
   • No contraindication exists for concurrent use 1, 8

Common Pitfalls to Avoid

• Do not confuse topical with systemic formulations: Topical clotrimazole cream has no interaction risk, while oral azoles (fluconazole) have theoretical interactions 1, 4
• Do not assume all azoles behave identically: Fluconazole has fewer interactions than itraconazole or ketoconazole 8, 5
• Do not overestimate cannabis interaction severity: Unlike drugs with narrow therapeutic indices, cannabis-related interactions rarely cause serious harm 9, 4