NEFADOZONE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution
• Rationale: Nefazodone has been shown in vitro to be an inhibitor of CYP3A4. In vitro studies have shown that cannabis undergoes major metabolism by CYP3A4 and CYP2C19 and minor metabolism by CYP2D6. Additionally studies have found that CBD is a potent inhibitor of CYP3A4.  Furthermore study with synthetic cannabis showed that it had inhibitory action on CYP1A2. Consequently, caution is indicated in the combined use of nefazodone with any drugs known to be metabolized by CYP3A4.
  

TRAZODONE

• Cytochrome P450 enzyme substrate: CYP3A4
• Action to be taken: Caution, possible dose reduction
• Rationale: Trazodone has been shown in vitro to be an inhibitor of CYP3A4. In vitro studies have shown that cannabis undergoes major metabolism by CYP3A4 and CYP2C19 and minor metabolism by CYP2D6. Additionally studies have found that CBD is a potent inhibitor of CYP3A4.  Furthermore study with synthetic cannabis showed that it had inhibitory action on CYP1A2. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. It is likely that ketoconazole, indinavir, and other CYP3A4 inhibitors such as itraconazole may lead to substantial increases in trazodone plasma concentrations with the potential for adverse effects. If trazodone is used with a potent CYP3A4 inhibitor, the risk of cardiac arrhythmia may be increased and a lower dose of trazodone should be considered. Consequently, caution is indicated in the combined use of trazodone with any drugs known to be metabolized by CYP3A4.

References

1. Serzone (nefadozone) package insert.Bristol-Myers Squibb Company Princeton, NJ 2003
   
2. Oleptro (trazodone) package insert. Labopharm Europe Limited, Dublin, IRELAND 2010
3. Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
4. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.​​
   
5. Yamaori S, Ebisawa J, Okushima Y, Yamamoto I, Watanabe K. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: Role of phenolic hydroxyl groups in the resorcinol moiety. Life Sciences. 2011;88:730-736.