Take a drink whenever they loudly announce their plans.
Take another drink if their plan goes horribly wrong.
Take a drink whenever they excitedly check their flanks, expecting their cutie marks.
When they say something to the effect of "CUTIE MARK CRUSADER <INSERT OCCUPATION HERE>!" you must repeat what they said and take a drink. If you mess up your repetition, you must repeat the process—including the drink—until you get it right.
Take a drink when Sweetie Belle's voice cracks.
Take a drink whenever Sweetie Belle interacts with Rarity.
Take a drink whenever Scootaloo talks about or interacts with Rainbow Dash. (Be very careful with the episodes Cutie Mark Chronicles and Sleepless In Ponyville.)
Take a drink whenever Babs Seed blows her mane out of her eyes.
Take a drink whenever Babs covers her flank with her tail.
Take a drink every time he says "Eyup" or "Nope".
Now take a drink for every word he says that isn't one of those two words. (Watch out for the opening of Applebuck Season if you know what's good for you.)
Take a drink every time you see him working on the farm.
Take a drink every time you see him with his relatives.
Take a drink every time he says "Twily!"
Take a drink every time he's in the same shot as Princess Cadence.
Take a drink whenever he blatantly defies the laws of reality.note What is "blatant" depends on how smashed you want to get. For instance, you could say teleportation is not blatant (Twilight Sparkle does it regularly), but drinking a chocolate milk of glass and making the chocolate milk explode definitely is.
Whenever there's a Foe Yay moment between him and one of the Mane Six ponies, have a drink. Have an ambulance on standby.
His interactions with Twilight alone will pretty much render anyone but the strongest drinkers unconscious.
Take a drink whenever he touches the ponies period, both before and after his Heel-Face Turn.
Take a drink whenever she (or another pony) expresses the words "love, love, love."
Take a drink whenever she invades Shining Armor's personal space.
Take a drink whenever she uses magic.
Take a drink whenever she (as Cadence) acts blatantly out of character.
Take a drink whenever everyone else completely dismisses Chrysalis acting out of character as perfectly normal.
Take a drink whenever he... whenever he makes an appearance, really. Might as well make it a strong one, because that's not very often.
Take a drink whenever he speaks. Again, make it a strong one, since it's a rather rare occurrence.
Take two if he mentions crystals.
Take a drink whenever dark magic is used.
Take two when it's used by the protagonists.
Take a drink if somepony interacts with him.
Take a drink whenever Derpy makes an appearance.
In The Last Roundup, take a drink for every line of dialogue that Derpy says.