It has been estimated that three-quarters of patients who take clozapine are cigarette smokers. The polycyclic aromatic hydrocarbons in cigarette smoke (not the nicotine) induce the CYP1A2 enzyme and hence the metabolism of clozapine, since CYP1A2 is responsible for about 70% of clozapine’s metabolism. For a cigarette smoker of at least 5 cigarettes per day, their clozapine level could be reduced by up to 50%. This can require a much higher dose to produce the same effect, given concurrent cigarette smoking. A meta-analysis (https://bmjopen.bmj.com/content/4/3/e004216) suggests that smokers can require twice the dosage of non-smokers to achieve the same effect. Note that clozapine dosage changes should be made slowly, to avoid rapid changes in clozapine levels. If a patient’s smoking status changes, one should consider checking a clozapine blood level. If a patient suddenly stops smoking, their clozapine serum could elevate to a toxic level, leading to serious side effects. This can occur if a patient chooses to quit smoking suddenly or enters a hospital where smoking is not allowed (even if nicotine replacement options are offered). If a patient on clozapine stops smoking, the dose of clozapine should be lowered by 10%, with further reductions as indicated. A stepwise reduction should be planned of 10% of dose for about 3-5 days. Dosage can continue to be tapered down, with a goal of as low as 50% of original dose, depending on the patient’s clinical status. This interacting effect might be similar for smoked marijuana, yet the quantitative impact is not clear as products and strengths vary substantially and research is limited. Also, cannabinoids (other than cannabidiol) have been shown to make psychotic symptoms worse in people with schizophrenia.