I turned hardcoe mode on at the start of my very first character and it's never been off since unless I was doing a fresh start for whatever reason.
I didn't find that it added any difficulty in
Dead Money, although the constant health erosion had me eating a fair amount of snack foods to cover it. If anything, though, the SLP meter was a bit annoying in my initial run, because the Clinic's auto-docs originally did not remove fatigue as they claimed to and I was taking things quite slowly to make sure I discovered everything. The slow accumulation of radiation wasn't really a problem either, since you can get plenty of Rad-Away.
I will say this, though: doing a run where you only heal with food is a good way to eat through your supply of chips, even if you have the Old World Gourmet perk, since none of them heal for all that much. Getting Dean to teach you how to make Sierra Madre Martinis helps, assuming you can make them (oddly, you can learn how without enough Survival skill to craft them), although their amount of healing is fixed at +75.