though I don't know that I'd want to spend much time conditioning myself to working the up-to-fire safety.
Obviously, each individual shooter is going to travel his own way down this path, but the up-versus-down safety discussion seems to generate a lot of passion and nearly as much loathing.
I have my own ideas & plans and I carry an ugly, striker fire pistol with no manual safety but the other 95% of what I own is all for fun, enjoyment and skill building, so I don't dwell a lot on what I could train or condition myself to do, but I do accept that this is a genuine point of interest and discussion for others.
I'll say, however, that when I wrap my hands around a Smith & Wesson 1st, 2nd or 3rd Generation pistol, my thumb over thumb firing grip puts my strong hand thumb right in the channel that the Smith & Wesson safety lever
occupies when the safety is "ON." For me, a proper & familiar grip is partially blocked by the safety when it's deployed. In this way, it seems mostly 'natural' to me to sweep that safety out of the way, which is up.
And the large lever seems to point the direction the bullets are headed which also seems natural to me when the safety is off.
The "opposite direction" safety lever on S&W pistols has long been it's most-attacked feature, it seems to me, at least in discussion. I'm not sure if it's quite as large an issue in use. But it's definitely a very personal thing and likely varies an awful lot from shooter to shooter.