I play on a modified difficulty. 1.5x damage dealt, 3x damage received (For reference, Survival has 0.5x and 2x respectively), while maintaining the occurrence chances of legendaries.
Makes the combat feel more realistic on top of my other minor audio/visual mods. I can sneak attack crit everything but bosses in one shot, but if I ever get caught, everything but the lowliest of enemies will kill me in moments or very few bullets. Especially melee creeps like Mutant Hounds and the more difficult Ferals.
It forces me to make extensive use of cover, VATS, and the dog to make my way through combat without the stealth that I'm spec'ed in. On some enemies, I even need simultaneous doping from both the syringer and Psycho Jet.