The film’s title is a reference to the slang term for the way users feel after going multiple days without sleep while on a methamphetamine binge. The film includes appearances from Rob Halford of Judas Priest fame, Billy Corgan, China Chow, Tony Kaye, Ron Jeremy, and Deborah Harry. The film also includes a cameo by Josh Peck, of Drake and Josh fame.
Back at Ross's apartment, he gets a message from his mother as well as his former girlfriend Amy, wishing him a happy birthday, while asking him to pay back a large debt. Ross, assuming she still loves him, calls her and leaves a message. He then goes to the local strip club while high, which results in a intense pornographic hallucination. He takes one of the dancers, April, home to have sex with while they both use meth. As they finish, the Cook calls with an emergency regarding Nikki's dog Taco. Ross, still high, leaves April handcuffed to the bed and duct tapes her eyes and mouth shut.
While Ross and Nikki are out, policemen and a TV crew raid Frisbee's trailer, falsely believing that a meth lab is located there. They take Frisbee and his overweight mother into custody, where they threaten Frisbee into cooperation in a drug bust.
The same day, Ross and the Cook stop by a local gas station to pick up a case of ephedrine and a soda, then to a liquor store to purchase a six-pack of beer (where Cook beats up another dealer after he slaps one of the cashiers for attempting to buy meth from Spider Mike), then to a adult film store, where the Cook memorably preaches about the values of pornography in America. Ross calls Amy's house again, but to no avail. He drops the Cook off at his place and rushes home to April, who is still tied to the bed. She appears to forgive him, and they proceed to have more sex.
Meanwhile at Cook's hotel room, he and Nikki have a fight after a prostitute arrives. Nikki ends their relationship, and calls Ross and asks him to take her to a bus station so she can go back to Las Vegas. Ross leaves April again, who is still tied to the bed.
While Ross and Nikki are out, Frisbee is coerced by the cops to wear a wire and make a deal with Spider Mike so they can arrest him. When he enters, Cookie attempts to make love to him in response to Spider Mike's usage of an erotic talkline. She finds the wire, and the cops rush in to make the drug bust. Spider Mike, furious at Frisbee's betrayal, shoots him in the testicles. Spider Mike and Cookie are arrested.
While this is happening, the Cook's meth lab is destroyed by a fire, and he takes off to the porn store, where he is arrested after the owner (played by metal legend Rob Halford) calls the police. He makes bail, and calls Ross asking for a ride to another dealer's house in the city after he drops Nikki off at the station. Ross learns of everyone else's arrest, and agrees to drive him there, as well as visit Amy, who also lives in the city.
At the dealer's house, the Cook receives cash, some meth, and the equipment to start a new meth lab. Ross calls Amy again, and leaves a message asking to see her and that he has her money with him. The Cook promises six month's worth of meth in exchange for being his chauffeur, which he agrees to, on the condition that he sees Amy first. Amy, who has gotten her life together, with a corporate job in the city, leaves him in the park after seeing that he's still an addict. He gives her $100 out the $450 he owed her, and leaves with the Cook.
The film closes on everyone finally sleeping after several days of nonstop drug use, except the Cook, who attempts to start up a meth lab in an abandoned trailer, but blows it up in the process.