Polycyclic aromatic hydrocarbons (PAH) are products of incomplete combustion of organic matter through tobacco smoking and are well-known inducers of drug-metabolizing enzymes. Exposure to PAHs in humans results in marked induction of cytochrome CYP1A2. For instance, the average clearance rates of caffeine, chlorpromazine, clozapine, haloperidol, olanzapine, and theophylline increase by 30–100% in smokers compared with nonsmokers. Switching to novel tobacco products that reduce the exposure to harmful and potentially harmful constituents, including PAHs, could reduce CYP1A2 activity compared with that of continuing smoking. This would mean that, smokers taking medications that are primarily metabolized by this enzyme will have higher systemic clearance due to increased enzyme induction. The aim of this review is to summarize the evidence from clinical studies on the effects of switching to a heat-not-burn tobacco product (IQOS® with HEETS®) on CYP1A2 activity and to review the corresponding potential effects on drugs primarily metabolized by CYP1A2. Four clinical studies that are part of the clinical assessment of IQOS with HEETS looked at CYP1A2 activity by measuring the caffeine metabolic ratio (CMR) in plasma in switchers to IQOS with HEETS and those who continued smoking or abstained from smoking. Results showed that after five days of exclusive IQOS with HEETS use, CMR levels were significantly decreased to an extent similar to that of smoking abstinence in all clinical studies, with a difference of IQOS with HEETS vs. cigarette smoking between 21.7% and 37%. The CMR levels remained decreased in IQOS with HEETS users in one study (ratio of 72.1% at Day 5 and 70.4% at Day 90) while the effect was partially diluted in the other one (ratio of 63.0% at Day 5 and 77.1% at Day 90) which may be explained by the concomitant cigarette smoking during the ambulatory period. The observed reduction in CYP1A2 activity when using IQOS with HEETS, comparable to that seen in smoking abstinence, suggests that monitoring smokers using medications primarily metabolized by CYP1A2 with a narrow therapeutic margin may be recommended upon switching to IQOS with HEETS.