Introduction: research into the psychoactive substances use is very broad and diverse; however, in Mexico there is still a lack of specific information that highlights the possible differences in the use of these substances considering a gender perspective beyond the male/female dichotomy. Objective: explore the psychoactive substances use in high school degree students according to their gender and compare possible differences. Method: a non-experimental, cross-sectional, ex post facto study was designed with three comparison groups: cisgender-women, cisgender-men and other gender identity (non-binary, fluid, transgender-man, transgender-woman, among others). 4,136 students in the Gulf of Mexico area participated in a non-probabilistic sampling (2,120 cisgender-women, 1,964 cisgender-men, and 52 to be other gender identity). Results: the alcohol use was substantially higher in cisgender-women, while the tobacco use in cisgender-men. Illegal drug use was significantly higher in people to be other gender, especially the use of inhalants, methamphetamines, ecstasy, and hallucinogens. The marijuana, cocaine, amphetamines and heroin use was greater in cisgender-men, while that of tranquilizers was greater in cisgender-women. Discussion and conclusions: the results allowed an approach to a population group little addressed in studies of drug consumption, that of people who assume a gender different from the dichotomy (man/woman), making visible that they are a group with high consumption that it can place them in certain conditions of vulnerability.