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Since plant organs sense their environment locally, gradients of micro-climates in the plant shoot may induce spatial variability in the physiological state of the plant tissue and hence secondary metabolism. Therefore, plant architecture, which affects micro-climate in the shoot, may considerably affect the uniformity of cannabinoids in the Cannabis sativa plant, which has significant pharmaceutical and economic importance. Variability of micro-climates in plant shoots intensifies with the increase in plant size, largely due to an increase in inter-shoot shading. In this study, we therefore focused on the interplay between shoot architecture and the cannabinoid profile in large cannabis plants, ~2.5 m in height, with the goal to harness architecture modulation for the standardization of cannabinoid concentrations in large plants. We hypothesized that (i) a gradient of light intensity along the plants is accompanied by changes to the cannabinoid profile, and (ii) manipulations of plant architecture that increase light penetration to the plant increase cannabinoid uniformity and yield biomass. To test these hypotheses, we investigated effects of eight plant architecture manipulation treatments involving branch removals, defoliation, and pruning on plant morpho-physiology, inflorescence yield, cannabinoid profile, and uniformity. The results revealed that low cannabinoid concentrations in inflorescences at the bottom of the plants correlate with low light penetration, and that increasing light penetration by defoliation or removal of bottom branches and leaves increases cannabinoid concentrations locally and thereby through spatial uniformity, thus supporting the hypotheses. Taken together, the results reveal that shoot architectural modulation can be utilized to increase cannabinoid standardization in large cannabis plants, and that the cannabinoid profile in an inflorescence is an outcome of exogenous and endogenous factors.