It always works at the right dose. It was completely side effect free for me though nearly every time I used it, I was coming up on a psychedelic. A few times I used it when sick and didn't notice any. From what I remember there's only a short list anyway.
Have you ever tried rectal administration? I find it to massively reduce the bodyload of 2C-E, and psychedelics in general. The dosage is approximately halved also.
I've never used ondansentron with psychedelics (don't really get nausea from any of 'em), but for DXM it works wonders, so it would probably work with psychs for you.