I've been using the 22/250 (as well the AI) and the Swift since 1978 that's when I met the boys at the Powder Horn (Bill, George JR and Sr, as well as Scenar). They introduced me to the wonderful world of the big 22's. At first I was like many on this thread, a sceptic with no experience. But, these fellas were great hunters and new their guns and so I trusted them.
After using them for 46 years, I've more than a bit experience in seeing small big game like deer, lopes and black bears as well large game like elk taken with them. I realize that rounds like this are not for all, nor do they need to be. Those that are "twitchy" (and a lot of hunters are...) and those that just have to shoot no matter what need not apply. By this I mean one has to be a bit patient, cool and calm in the presence of game and have the patience to wait for the right shot angle (those that are like this will be so irregardless of cartridge size).
IMO we all have our limitations, we have times when we should and should not be shooting. Range, wind, angles of the shot, our ability to be calm, and our choice of weapon be it a bow, pistol or rifle. The key is to have the discipline to know when you should or shouldn't take the shot. For me, I want to be 110% sure that it's going to be a one round knock out!
Regarding mono's vs standard cup n cores, I've used them both A Lot! I've found the 55's-63' standard cup n cores to be much quicker killers than the Mono's. Note I didn't say they'd kill them any deader, it's just that the time that elapses between the shot and the time the critter is on the turf is quite a bit quicker with the standard cup n core bullets. Probably a matter of seconds but it's real.
The farthest we've shot game is 505 on a lope we just couldn't close the gap on, It took one 55 NSB and a step and pitched over...ready for the grill, well almost ready for the grill
Another thing I read is how one needs to take head, neck shots etc. This is horse hockey and to me shows a lack of experience. My preferred shot it tight behind the front on a broadside or a slight quarter away shot. If one uses this shot selection with the 55's-63's the critter will hit the turf 93% of the time at the shot. And be down and out, where as a high shoulder shot often times the critter needs another one (with the 22's or with bigger guns).
The V-Max will work on good broadside shots but is a bit in the gray area for me and being as elk are generally on the menu as well I prefer a bit stouter bullet. I've used a hand full of different one's over the years but the following are far and away my rock stars.
*55 Horn w/c
*60 Horn HP ( as well the SP)
*63 Sierra (my fav)
*52/55/60 Nosler Solid Base
Any of these will do one proud on any of the game I hunt here on a yearly basis in Montana. Including on shoulder blade shots on elk, the bullet will punch thru and tear up the lungs and then it's game over!
I won't go into the number of critters I've take with the Big 22's and or have seen taken but suffice to say it's well into the triple digits. In the last several years alone we had49 one shot kills on 49 head of game (the 50th took two as the first shot hit a bit far back) between 35 and 410 yds with the 60 Horn HP (mainly) and a few with the 63 Sierra. Of those 93% of them went right down, I mean straight freaking down! There was only a couple of them that ran, the longest being a 110 pound doe that I shot at 120 yds, she went about 35 yards which really shocked me....Generally though the game has went straight down.
Rarely will a bullet stay inside, the pretty much always exit. Even on a big cow I shot a couple years ago. A bit over 300 yds, the 63 went in behind the left front and exited low on the right shoulder. She went 15 yds or so and went to Croak City Wyoming.....
Over the last 46 years I recall very few that needed a second shot, and recall very few that ran if at all.
A couple years back I built a 6.5 pound "all up" (scope, sling rounds) 22/250 AI with a 8 twist. it shoots the heavies extremely well. I'll be interested to get serious with it see how it perks on game. As effective as the 55's-63's have been and with the speed of how quickly they kill I'll be shocked and amazed if the heavies can do it any quicker. If anything I expect it to be a bit slower of kills. But the heavies will play nicer in the wind that's for sure (once one gets out there a ways).
Bottom line with all of this we need to find what we're comfy with and go with it. For me and my family I'm very comfy with using the Big 22's and could use them and them only for the rest of my days no problem (I'm 65 so I've seen some killing).