The title of this thread doesn't specify if a drug 'fucks you up' upon acute administration or chronic administration. I note that in the US, annually tobacco kills around 480,000, alcohol around 140,000 and ALL drugs around 106,000 people but 678,000 deaths due to 'poor diet'.
But acute toxicity per capita who use a specific drug, fentanyl is obviously the most dangerous.
As for subjectively messing a person up so they can't function, well scopolamine appears to go unmentioned, Many years ago a friend took a large dose and it took four of us to babysit them for three full days and nights. But I presume few people have experience of it's effects.
From my own experience, alcohol's legal status and social acceptability means it's responsible for messing up the user and frequently those around them. No way would I venture into town on a Friday or Saturday night. The odds of a drunk person starting a fight or just knocking me down (I use crutches) are far too high.
Maybe I'm just reading the question in a different way? I'm trying to be objective because ANY of the drugs I've seen mentioned here is capable of rendering a person irrational and/or unconscious or dead if consumed in sufficient amounts.