The aim of the current study is to assess if the patterns of use, socio-demographic characteristics, and use of other drugs differ among people who only use cannabis and those that use synthetic cannabinoids. Data from the second wave of the European Web Survey on Drugs, a web-based cross-sectional survey from 10 different European countries including individuals aged 18 and over (n = 37,109). Participation was anonymous, self-selecting, and voluntary. Cannabinoid exposure was taken as the dependent variable and categorized into the four following variables: (1) neither last year use of cannabis nor of synthetic cannabinoids (SC) independently of lifetime use, (2) cannabis use, (3) synthetic cannabinoids use, and (4) use of both, in the last 12 months. Independent variables included socio-demographic data, other drug use in the last month, and patterns of cannabis use. The use of SC was associated with higher odd of polysubstance use in the last year (OR 2.17; 95%CI 1.27–3.72) and use of other drugs during the last month. Low income (OR 2.34; 95%CI 1.20–4.58) and unemployment (OR 3.02; 95%CI 1.34–6.83) were related to SC use alone and cannabis plus SC use (OR 1.53; 95%CI 1.13–2.05) (OR 4.12; 95%CI 3.45–4.91). Social vulnerabilities were associated with the use of cannabis in the last year, but more markedly with synthetic cannabinoids use. Those who used synthetic cannabinoids reported using other drugs more often than those who used or did not use cannabis. The findings highlight the importance of social vulnerabilities and poly-drug use when assessing the use of new psychoactive substances such as SC and how these differ when compared to cannabis.