The exception is probably hallucinogens, which offer some interesting experiences that are probably hard to get elsewhere, and there's some that are largely harmless. I'd advise anyone to be really, really careful about the drugs that are both chemically addictive and tolerance building. Chemically addictive means withdrawal symptoms if you're not using, tolerance building means you need progressively more not to get to the same point. Nicotine, actually, probably gives you the least bang for your buck with a pretty brutal chem addictive/tolerance building mix. Anything that does similar you need to be wary about.
As for the most commonly used things - alcohol and THC (marijuana, hash) - you really, really can get the lower inhibitions, relaxation, creativity, etc. with some mental training. Quitting alcohol was surprisingly easy for me because eventually, I was doing much worse socially on it than without it. When you're comfortable saying and doing what you think sober, alcohol just messes up your reaction times and coordination and makes you fat and sick. The hardest part about quitting was the social aspect, but after about six months when people got the message that I was really done, that fell off too. I always tell everyone drink around me, use, whatever you please, but it's surprising how many of my friends who go out with me eventually quit. It's like a hell of a lot people drink because they're expected to more than because they actually like the effects.