Background <p>Exposure of cannabis to heavy metals may interfere with metabolic pathways of cannabinoid biosynthesis and compromise its medical quality. Furthermore, inflorescence contamination with heavy metals presents a critical challenge for the production of safe pharmaceutical-grade cannabis, since it poses a significant health risk to consumers. The present study therefore evaluated the hypotheses that heavy-metal exposure affects cannabinoid production, leads to inflorescence-contamination, and compromises the cannabis plant function; and that the responses are genotype-dependent and heavy-metal dose-dependent.</p> Methods <p>To evaluate the hypotheses, we studied responses of four ‘drug-type’ medical cannabis cultivars to a cocktail of four heavy-metals (Cd, Pb, Ni, Co), in three concentrations each (0, 1, 5µM), and analyzed translocation and accumulation patterns of the heavy-metals in the plant organs, and the resulting impact on cannabinoid production and the plant’s physiological integrity.</p> Results <p>The results confirmed effects of the heavy metals on cannabinoid production, with a heavy-metal concentration threshold, and genotypic variability, thus confirming the hypotheses.</p> Conclusions <p>The roots accumulated the highest levels of heavy metals, demonstrating an avoidance strategy of exclusion from sensitive shoot organs; and the root-to-shoot translocation factor was Ni &gt; Cd, Co &gt; Pb demonstrating heavy-metal specificity. The accumulation patterns revealed that plant exposure to moderate-low heavy metal concentrations (5µM) poses health concerns, as the inflorescences’ Cd and Ni concentrations were above the WHO-permitted threshold for medical plant consumption.</p>