This study investigates predictors of substance use initiation by early adolescence, defined as trying any non-prescribed substance by age 12. Using data from the Adolescent Brain Cognitive Development Study (ABCD), researchers examined 420 variables across various domains, including demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. The primary outcome was self-reported substance use initiation, with alcohol being the most common substance initiated. The study found that sociodemographic factors were the most robust predictors of substance use initiation, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon, followed by Jewish and Black youths. Other significant predictors included race, income, prenatal exposure to substance use, history of detention or suspension, and parental conflict. Modifiable risk factors such as sensation seeking, substance use availability, peer use of alcohol and nicotine, and rule-breaking behavior also increased the likelihood of substance use initiation. The study concluded that resource-intensive methods, such as hormonal, neurocognitive, and neuroimaging data, did not improve prediction of substance use initiation over self-reported data. The findings suggest that a comprehensive assessment of sociodemographic factors and modifiable risk factors may be necessary to optimize risk prediction for substance use initiation.This study investigates predictors of substance use initiation by early adolescence, defined as trying any non-prescribed substance by age 12. Using data from the Adolescent Brain Cognitive Development Study (ABCD), researchers examined 420 variables across various domains, including demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. The primary outcome was self-reported substance use initiation, with alcohol being the most common substance initiated. The study found that sociodemographic factors were the most robust predictors of substance use initiation, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon, followed by Jewish and Black youths. Other significant predictors included race, income, prenatal exposure to substance use, history of detention or suspension, and parental conflict. Modifiable risk factors such as sensation seeking, substance use availability, peer use of alcohol and nicotine, and rule-breaking behavior also increased the likelihood of substance use initiation. The study concluded that resource-intensive methods, such as hormonal, neurocognitive, and neuroimaging data, did not improve prediction of substance use initiation over self-reported data. The findings suggest that a comprehensive assessment of sociodemographic factors and modifiable risk factors may be necessary to optimize risk prediction for substance use initiation.