As Ross (Jason Schwartzman) struggles to maneuver through the chaotic landscape of addiction, his story becomes interwoven with that of the mysterious Spider Mike (John Leguizamo), a meth dealer whose tumultuous relationship with Cookie (Mena Suvari) is akin to a ticking time bomb. Amid this turmoil, Ross unexpectedly connects with Nikki (Brittany Murphy), another addict who introduces him to her troubled boyfriend, The Cook (Mickey Rourke). This dubious character operates a drug lab in a seedy motel room, and in exchange for returning Nikki home, he rewards Ross with a small supply of methamphetamine, while hinting that he may soon summon Ross for help.
Back at his own apartment, Ross is inundated with calls and messages from his caring mother and ex-girlfriend Amy, wishing him a happy birthday. Misinterpreting Amy's intentions, Ross leaves her a series of disorganized messages on her voicemail before succumbing to an intense drug-induced hallucination at a strip club. While there, he brings home April (Chloe Hunter), one of his many fleeting encounters, and indulges in a frenzied night that culminates in a desperate act of binding her with duct tape, all while he takes a crucial phone call from The Cook concerning Nikki's beloved dog, Taco, who is in dire need of veterinary assistance.
In the meantime, two bumbling police officers, accompanied by a television crew, are hot on the trail of Spider Mike's drug apparatus. Under false pretenses, they invade the residence of Frisbee (Patrick Fugit) and his overweight mother, coercing Frisbee into assisting them in an ill-fated attempt to bring down Spider Mike’s operation. As Ross’s existence spirals further into mayhem, he becomes enmeshed in a relentless cycle of addiction, violence, and desperation.
As the evening progresses, Ross, seeking to make amends, returns to his apartment with gifts for April, who is still reeling from the previous night’s chaos. Meanwhile, The Cook invites a prostitute to his motel, but his encounter with Nikki devolves into strife and separation. Desperate, Nikki reaches out to Ross, asking him to drive her back to the glittering streets of Las Vegas, leaving April still bound and helpless.
Their journey brings them back to Frisbee, who, now wired for sound, visits Spider Mike in hopes of scoring more meth to secure his own downfall. However, Cookie's attempts at vengeance take a twist when she uncovers Frisbee's wire, leading to a violent confrontation marked by chaos, culminating in the arrest of both Spider Mike and Cookie while Frisbee is taken to the hospital for his injuries.
Upon returning to his apartment, Ross discovers that April has gone missing, taken away by her neighbor, Deborah Harry. This event serves as a stark reminder that not all relationships can be salvaged. After safely dropping Nikki off at the bus station, they share a bittersweet farewell kiss, hinting at the possibility of a reunion if fate permits.
As this emotional drama unfolds, The Cook’s meth lab meets a fiery end, leaving behind destruction. He attempts to hide in an adult film store, but is soon caught by the police when the shop owner raises the alarm. Following his release on bail, The Cook reaches out to Ross, aiming for a ride back to the city to reconnect with a drug dealer and revive his old habits. Ross agrees, hoping that this will also lead him back to Amy, who lives in the same city.
The dealer proves to be generous, providing The Cook with money, meth, and new equipment to establish another lab. In exchange for this bounty, The Cook offers Ross six months' worth of meth, on the condition that Ross once again plays the role of chauffeur. Ross agrees but insists on seeing Amy first. However, her response is a heartbreaking testament to the impact of addiction: she angrily rejects him and only demands $100 from the $450 debt he owes her.
As night falls, The Cook takes a despondent Ross to an abandoned trailer on the town’s periphery, setting up a new lab. Unfortunately, these reckless pursuits lead to tragic consequences, as the trailer ultimately collapses in flames, leaving Ross to confront the horrifying reality of his and The Cook's choices.
