Since the turn of the 21st century, there has been an increase in the availability and use of novel psychoactive substances (also known as "legal highs") across Europe. Currently, there is limited information available on the potential acute toxicity (harms) associated with the use of these novel psychoactive substances. There are a number of potential data sources that can provide information on the acute toxicity associated with their use: (1) user reports on Internet discussion fora; (2) subpopulation level surveys of self-reported harms/unwanted effects (3) regional or national poisons information service accesses for support on presentations to healthcare facilities relating to acute toxicity; (4) case reports/series based on self-reported use or analytically confirmed use; and (5) human volunteer studies assessing potential acute toxicological effects. Each of these data sources has its own limitations, particularly those that are based on self-reported use because there are a number of European studies that show that there is inconsistency in the substance(s) in the "drug" that an individual uses. However, by using a multilayered approach of combining different sources, it is possible to reduce the overall impact of the limitations of any one individual data source. In this review article, we will combine information from these different data sources to describe the pattern of acute toxicity associated with 4 novel psychoactive substances: 1-benzylpiperazine, mephedrone (4-methylmethcathinone), synthetic cannabinoid receptor agonists, and methoxetamine.