i realize how demented this sounds but hear me out okay.
when sam first sees the "angel" in houses of the holy, dean offers him a drink from his flask—sam refuses. at the end of the episode when sam's faith has been crushed by the disappointing reality, dean offers his flask again, and sam accepts it this time.
the difference between these two scenes lies in sam's faith: in the first sequence, sam is filled with a religious fervor and a hope for his own redemption. in the second, he's crippled and lost and hopeless. there's a few interpretations of this which i think all kind of overlap and influence each other.
first and foremost, the most literal, baseline interpretation of this is probably that sam is interpreting dean's gesture (somewhat accurately) as being dismissive of his experience in the first sequence, but as compassionate in the second. there is a marked difference in how dean offers the flask to sam each time, and dean too has undergone a change throughout the episode to influence his understanding of god and faith.
but these scenes can also have interesting symbolic meaning, too. this is alcohol that dean is offering. it's a substance from which abstinence is associated with moral purity—the prohibition movement was led by protestants seeking to eliminate corruption and violence from the world, and it was framed as a battle for morality. therefore, temperance is seen as good, pure, and righteous. when sam is consumed by his faith, he abstains. when he loses his faith, he imbibes.
and through that moral lens, there's another interesting interpretation that can be found. the flask belongs to dean, and he is seen drinking from it. when sam drinks from it, too, they're literally swapping spit. metaphorically, drinking from the same flask can be seen as a kiss, and this isn't the only time this metaphor is used, either. in sex and violence, nick drinks from dean's flask, then lets dean drink from it again—and this sharing of saliva is what puts dean under his siren's spell.
in sex and violence, sharing a flask is depicted as an explicitly sexual act, a stand-in for a kiss. nick is dean's sexual fantasy, the ideal little brother, and he snags dean through an indirect kiss.
so if sharing a flask is a sexual act, then it can apply here: abstaining from alcohol is morally righteous and good, and imbibing is morally tarnished. sam, in his ecstasy, wants to be good—he thinks he's been chosen for redemption, after all. he wants to live up to the potential that the "angel" sees in him. he refuses the drink, and only when he's lost his faith does he accept it.
but it's dean's flask. accepting the drink would also be a sexual thing—he would be kissing his brother. it would be an act of incest, something impure and unholy and sinful. he wants to be good, so he rejects not just the drink but dean himself, because to engage with him would be a sin. this rejection is embedded within a plot which drives sam and dean apart, their religious philosophies at war. they drift further apart with each clash of theologies, and they both reject each other's perspectives in their loyalty to their own.
it's only after he loses his faith that he stops trying to be good, that he accepts the drink, that he takes dean back into himself. he kisses his brother when he returns to him, and it's after this reuniting kiss that they're able to come together again and find compromise and concession, their respective ideologies shifting toward each other's until they've found equilibrium again. through the flask, they literally kiss and make up, and their codependency is secured through that kiss.