^ Oh yeah, high melle or unarmed + 10 endurance + doctor = teh brokenzz. The ratio of resurces invested to resources gained per fight is silly. It's quite boring, though, since you never realy need anything you can find (no ammo to deal damage, you heal a lot of what you recieve, etc).
Well, my most enjoyable playthrough yet involved party control enabled, one perk per level (self imposed no sniper/slayer/extra criticals/cheeze, only "power" perk was bonus rate of fire), a mod which balances down the tons of loot everywhere, 25% of the vanilla drop rate from monsters (so practically no loot from random encounters), 25% value for items you sell, 4X price on anything you buy (that one I didn't work very well in practice), almost no stealing, no rushing to caches of strong loot ahead of time and... only 7 AP
Bruiser + Gifted. Tagged speech, lockpick and traps (mod adds traps, they're not too strong but are fun and tackticky). Oh, and hardest difficulty and hardest combat. And stimpaks which irradiate you on use.
Also, semi-self imposed - always try to clean up every quest in an are before returning if possible, so as to enjoy local fights without skipping ahead for equipment. And ofc, no grinding levels (loot I couldn't grind as nothing dropped stuff).
My advice? Do everything you can in an area before moving on to the next area (it's a bit tricky with places where that's impossible, so you need to judge it). Play smart, don't waste resources and skill points, loot all the containers you can. Run away from fights before you know you can take them. It's pretty doable with insane limitations, so as long as you play it anywhere close to the default settings you shouldn't really have problems.
Also, try this in the early game - don't sell meat, but drop it on the ground to bait gecko's while you run through toxic caves and then back out. If you can get gecko skinning and then kill all the gecko's in the klamath-arroyo arrea you should have a nice time.