The large-scale disruption to peoples’ daily lives during the COVID-19 pandemic provides a context for examining whether use of substances such as psychedelics in a naturalistic (outside of a controlled environment) setting, is associated with better mental wellbeing and resilience relative to those who use other drugs, or who do not use drugs at all. We interrogate data from the Great British Intelligence Test and identify that 7.8% out ofN= 30,598 unique respondents used recreational drugs inclusive of psychedelics, cannabis, cocaine, and MDMA during the COVID-19 pandemic. Recruitment materials did not mention drug use would be surveyed, thereby enabling us to model the relationship with mood and resilience in people who had not specifically self-selected themselves for a ‘drug’ study. We report that people form clusters, characterized by different real-world patterns of drug use, and the majority of psychedelics users also use cannabis. However, a subset of cannabis users do not use psychedelics, enabling a subtractive comparison. Those who primarily used psychedelics and cannabis during the COVID-19 pandemic had worse mood self-assessment and resilience scores compared to those who never used drugs or primarily used cannabis. This pattern was also evident for other recreational drug use clusters, except for those who primarily used MDMA and cannabis, who had better mood but were of too low incidence to have confidence in this estimate. These findings cast light on the significant differences in mental wellbeing between users of different drugs and the non-user population during a global-crisis and call for future research to explore the pharmacological, contextual and cultural variables associated with these differences, their generalisability and causal links with greater precision.