I'm running two high level campaigns at the moment, and for me, it's genuinely because it's just less fun.
Prep is a weird thing where it takes less time, and yet more time (depending on the session/encounters). Sometimes it is genuinely better to prep next to nothing, because you almost have little-to-no control over what your party can do (other than managing their threats). Sometimes, you're spending a ton of prep-time just on managing statblocks and numbers.
Spellcasters become "mini-DMs", where they can tell you, "hey, 50 sessions ago I picked up a demon's dagger. I'm going to use it to go to hell real quick" and then yeah - better be quick on your feet to improv that out-of-nowhere decision.
Plot/narrative wise, I lose interest hard. You've gotta up the stakes - world threats, plane threats, multiverse threats. You can work hard to tie character plot and motivations to it, but it isn't easy. It's really easy to care about that village you've been staying at for the past few weeks. It's much harder to care about the death of a multiverse (it's too big; less personal).
Fights take so long. And even worse - you're either looking at super-dangerous rocket tag fights, or you're using multiple encounters (which, combined with longer fights, means you're spending more time in initiative then outside of it).