Previous data suggest that regular tobacco smoking may lead to nonspecific airway hyperresponsiveness (AHR) independent of airway obstruction, possibly because of effects on bronchial inflammation or mucosal permeability. Little is known concerning the effects on AHR of other widely smoked substances besides tobacco such as marijuana or cocaine. The smoke of both marijuana and cocaine contains respiratory irritants that elicit cough and produce abnormalities in airway dynamics and bronchial mucosal histopathology in habitual smokers. Therefore, regular smoking of one or both of these illicit substances could cause AHR or augment the AHR associated with tobacco smoking. The present study examined the influence of habitual smoking of marijuana, cocaine, and/or tobacco on nonspecific AHR in 542 (456 male) healthy participants (mean age, 34.8 +/- 6.8 SD yr) in an ongoing cohort study of the pulmonary effects of habitual smoking of illicit substances. Subjects with a history of intravenous drug abuse, significant occupational exposures, asthma, or recent upper respiratory tract infection were excluded. Inhalation challenge studies were performed using solutions of diluent and methacholine chloride (1.25 to 25 mg/ml) aerosolized by a DeVilbiss no. 646 nebulizer attached to a breath-activated dosimeter inhaled by three to five inspiratory capacity breaths. Positive responses to methacholine were defined by > or = 20% or > or = 10% declines in FEV1 from the postdiluent control value after inhalation of each concentration of methacholine. Participants were categorized by smoking status (nonsmoking and smoking of marijuana, cocaine, and/or tobacco alone and in combination); most analyses were performed in men and women separately.(ABSTRACT TRUNCATED AT 250 WORDS)