1. When we find Sam again, he's been awake for four days straight and he's resorting to desperate measures. The kind of desperate measures you buy from a tweaker in an alley. Needless to say, the pills don't work -- as Lucifer says, all Sam's doing is "bringing free drugs to the party."
2. Crowley's "hands off the Winchesters" memo seems to have expired. Yes, the demons that have mostly stayed out of the boys' way this season are back, and they're pissed. It's been a while since the boys have been forced to whip out Ruby's knife, but Dean uses it a whole lot in this episode. By the time Meg (Rachel Miner) shows up, Dean needs a friend so badly he's... well, willing to call Meg a friend.
3. Sam makes a friend in the psych ward. His organs are beginning to fail from lack of sleep, but leave it to Sam Winchester to find himself a hunt anyway. Sam bonds with Meredith, another patient, over shared candy bars (at least, until he's no longer physically strong enough to open the wrappers) and he tries to cure her depression the Winchester way.
4. Castiel is married! He's going by the name Emanuel (he chose it from BouncingBabyNames.com, naturally -- it means "God is with us") and is hitched to a sweet lady named Daphne.
5. That helpful ghostly presence is still around. You know the random gust of wind that seems awfully familiar with Bobby's notes and books.