<p>Psychedelic-assisted therapies are widely described as context-dependent, shaped by “set and setting” and by patients’ broader “matrix” of living conditions. Yet, the field has rarely grappled with the potential ramifications of this context-dependency, including whether an individual’s adverse social circumstances might not only blunt benefits but also amplify harms. This article develops a context-dependent harm hypothesis by analogy to conventional serotonergic antidepressants, for which pre-clinical and clinical evidence supports potential amplification of the harms of detrimental environmental and social contexts. A similar risk is plausible for psychedelics, given that both conventional antidepressants and psychedelic drugs may boost neuroplasticity and environmental sensitivity. This article reviews the limitations of the current psychedelic evidence base that precludes the evaluation of this hypothesis, including the frequent enrollment of socioeconomically advantaged participants and inadequate reporting of social circumstances. It concludes that environment-drug interactions require further attention for scientific, ethical, and clinical purposes. If context-dependent harm exists, adverse living conditions may constitute temporary contraindications until social conditions support positive therapeutic outcomes.</p>