<unk>  is metabolized by several liver enzymes, including CYP3A4, CYP2D6, and CYP1A2. Its active metabolite meta-chlorophenylpiperazine (mCPP) is known to be formed by CYP3A4 and metabolized by CYP2D6. Inhibition or induction of the aforementioned enzymes by various other substances may alter the metabolism of<unk>  and/or mCPP, leading to increased and/or decreased blood concentrations. The enzymes in question are known to be inhibited and induced by many medications, herbs, and foods, and as such,<unk>  may interact with these substances. Potent CYP3A4 inhibitors such as clarithromycin, erythromycin, fluvoxamine, grapefruit juice, ketoconazole, and ritonavir may lead to increased concentrations of<unk>  and decreased concentrations of mCPP, while CYP3A4 inducers like carbamazepine, enzalutamide, phenytoin, phenobarbital, and St. John's wort may result in decreased<unk>  concentrations and increased mCPP concentrations. CYP2D6 inhibitors may result in increased concentrations of both<unk>  and mCPP while CYP2D6 inducers may decrease their concentrations. Examples of potent CYP2D6 inhibitors include bupropion, cannabidiol, duloxetine, fluoxetine, paroxetine, quinidine, and ritonavir, while CYP2D6 inducers include dexamethasone, glutethimide, and haloperidol. CYP1A2 inhibitors may increase<unk>  concentrations while CYP1A2 inducers may decrease<unk>  concentrations. Examples of potent CYP1A2 inhibitors include ethinylestradiol (found in hormonal birth control), fluoroquinolones (e.g., ciprofloxacin), fluvoxamine, and St. John's wort, while potent CYP1A2 inducers include phenytoin, rifampin, ritonavir, and tobacco. A study found that ritonavir, a strong CYP3A4 and CYP2D6 inhibitor and moderate CYP1A2 inducer, increased<unk>  peak levels by 1.34-fold, increased area-under-the-curve levels by 2.4-fold, and decreased the clearance of<unk>  by 50%. This was associated with adverse effects such as nausea, hypotension, and syncope. Another study found that the strong CYP3A4 inducer carbamazepine reduced concentrations of<unk>  by 60 to 74%. The strong CYP2D6 inhibitor thioridazine has been reported to increase concentrations of<unk>  by 1.36-fold and concentrations of mCPP by 1.54-fold. On the other hand, CYP2D6 genotype has not been found to predict<unk>  or mCPP concentrations with<unk>  therapy, although it did correlate with side effects like dizziness and prolonged corrected QT interval. Combination of<unk>  with selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), or monoamine oxidase inhibitors has a theoretical risk of serotonin syndrome. However,<unk>  has been studied in combination with SSRIs and seemed to be safe in this context. On the other hand, cases of excessive sedation and serotonin syndrome have been reported with the combinations of<unk>  and fluoxetine or paroxetine. This may be due to combined potentiation of the serotonin system. However, it may also be related to the fact that fluoxetine and paroxetine are strong inhibitors of CYP2D6 and fluoxetine is additionally a weak or moderate inhibitor of CYP3A4. Accordingly, fluoxetine has been reported to result in increased levels of<unk>  and mCPP by 1.31- to 1.65-fold and by 2.97- to 3.39-fold, respectively. Smokers have lower levels of<unk>  and higher ratios of mCPP to<unk> .<unk>  levels were 30% lower in smokers and mCPP to<unk>  ratio was 1.29-fold higher in smokers, whereas mCPP concentrations were not different between smokers and non-smokers. Smoking is known to induce CYP1A2, and this may be involved in these findings.
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