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Many of these substances are plant-derived with deep-rooted histories of use in non-medical contexts, where they have been viewed as either tools for social cohesion or sources of discord, depending on cultural and societal contexts. This review explores psychoactive substances; psychedelics, cannabis, and stimulants, in a legitimized medical context, focusing on the ethical considerations shaping research and the regulatory and prescribing challenges involved in translating these compounds into viable clinical treatments. It highlights the diverse voices; Indigenous, philosophical, psychiatric, and using communities advocating for careful consideration of their broader implications. Key issues include navigating the blurred boundaries between therapeutic benefit and potential misuse, ensuring rigorous scientific methodologies, and addressing the sociopolitical factors shaping public perception and policy. 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