Pills are pickups that can provide useful or inhibiting effects. They take up the same slot as cards and runes.
At the start of each run, an effect is randomly assigned to each color of pill. The pill effect for that color will remain constant throughout the run. (However, it is possible for PHD or Virgo to reassign some of the effects.) The set of pill effects for any given run is usually known as the pill pool.
The pill pool for each run has increased from 9 to 13.
Replaces the floor map with a ? for the rest of the floor. If no other curses are active for the floor, the Curse of the Lost will appear under the level name when TAB is held. This effect cannot be negated by Black Candle. Also the only pill to have its flavour text appear on a piece of paper, like curses do.
Injures Isaac by a full heart. If a Bad Trip pill is used while Isaac only has a single heart left or less, the pill will turn into a Full Health pill instead. (This damage counts as red heart damage for the purposes of getting a Devil Deal.)
Balls of Steel
Grants Isaac two soul hearts.
Bombs Are Key
Switches number of bombs and keys.
Spawns five active bombs behind Isaac over a period of five seconds, at one a second.
Removes one red heart container upon use. While Isaac has one or fewer red heart containers, it will act as a Health Up pill instead.
Adds one empty red heart container upon use.
Empties all but one red heart container and spawns 1-4 full red heart pickups. If Isaac only has half of a heart left, it will heal him to one heart. If used without any red heart containers, no health will be deducted, but red hearts will still spawn. If used in a Black Heart or Eternal Heart-containing Super Secret Room, it will spawn those types of hearts instead.
For a short time, poop spawns wherever Isaac moves, like Explosive Diarrhea but with poop. A higher move speed means you can touch more tiles in the same time. A pun on laxatives. Unlocked by completing Challenge #25: Have A Heart.
Briefly pixelates the screen 3 times over 30 seconds.
Gives the Curse of the Maze effect for the remainder of the floor. The effect can stack with other curses. If no other curses are active for the floor, Curse of the Maze will appear under the level name when TAB is held. This effect cannot be negated by Black Candle. Unlocked by completing Challenge #25: Have A Heart.
Among the attribute modifying pill effects, only five of the seven visible attributes are covered: health, range, tears, speed, and luck. Both shot speed and damage can't be altered by pills.
Pill effects are narrated upon use, as are cards and runes.
Currently, the "Retro Vision" pill effect can crash the game on some machines, resulting in restarting the current floor when the game is continued.
Use of unidentified pills is recommended for outside of combat as Hematemesis, R U a Wizard, Paralysis, and Addicted! can be detrimental mid-fight. However, Percs, Power Pill, Lemon Party, Bad Gas, and Pheromones are nearly useless outside of combat. The shield effects like from Power Pill can be utilized for Curse Rooms.
Lemon Party is an internet shock site featuring a group of elderly men performing oral sex.
I Found Pills (and Ate Them), R U a Wizard? and I can see Forever are all image macro memes.
Balls of Steel is a reference to Duke Nukem; it is one of Duke's more famous quotes.
In the original game, Wrath of the Lamb, there was another positive pill effect called "Friends Til The End", which summoned 3 blue attack flies. This effect was improved and given to the Rune Berkano in Rebirth. Note that the "Infested?" and "Infested!" pill effects in Afterbirth are similar to the original "Friends Til The End" effect, only with spiders instead of flies.
The pill effect was re-added.
48 Hour Energy is a reference to the drink 5 Hour Energy.
"One makes you larger" and "One makes you small" reference the song "White Rabbit" by Jefferson Airplane, which in turn references Alice in Wonderland.
"Percs" is a reference to a street name for the prescription drug Percocet, which is more generically known as Oxycodone. This drug is meant to be used to treat pain, but often abused for recreational purposes.
"Pretty Fly" is a reference to The Offspring's song, "Pretty Fly (For a White Guy)".