I was alternating solo and coop play in the beginning of the game's existence. Gradually I began to favour 2-player games (with an occasional 3- or 4-player). However, at the time of the core set, solo seemed at least as hard as coop, often harder. Lately I have almost ceased to play solo. Yet, I still do, usually when I build a new deck and want to test it on its own. And having played some of the recent quests in the 2-player mode, I was almost shocked (though I had anticipated it) how much easier the game is solo. Of course, you cannot take any deck against any quest, but the general mechanic, and the trickery of the solo play, is just far less dangerous.
Also, not only from the difficulty and unpredictability point of view, I find the cooperative mode far more interesting. Not least because you can take unusual decks that would hardly be competitive on their own.
A question. I have not recently played much 3- and 4-player games. Are they much harder that 2-player? I know some quests, especially those with many surge cards, tend run out of the rails easily.