Introduction: Over the past ten years, a large number of New Psychoactive Substances (NPS) have entered the recreational drug scenario. NPS intake has been associated with health-related risks, and especially so for vulnerable populations such as the youngsters. Currently, most knowledge on the NPS health effects is learnt from both a range of users' reports, made available through the psychonauts' web fora, and from the few published, related toxicity, clinical observations. Areas covered: This paper aims at providing an overview of NPS effects on youngsters' mental health, performing a systematic review of the current related knowledge. Expert opinion: NPS consumption poses serious health risks, due to both a range of unpredictable clinical pharmacological properties and the typical concomitant use of other psychoactive molecules, which can lead to near misses and fatalities. In comparison with adults, the central nervous system of children/adolescents may be more vulnerable to the activity of these molecules, hence raising even further the levels of health-related concerns. Further research is needed, to provide evidence of both short-and long-term effects of NPS, related health risks, and their addiction potential.