The movie starts with Edward "Eddie" Morra (Bradley Cooper), standing on the rooftop of his luxury penthouse. Someone is trying to break into his apartment, as he prepares himself in tears to jump off the roof.
3 months earlier, Eddie is a New York City author struggling with writer's block with a deadline looming, and struggling after being dumped by his girlfriend Lindy (Abbie Cornish). One day, Eddie comes across Vernon Gant (Johnny Whitworth), the brother of his ex-wife, Melissa Gant (Anna Friel). Vernon, a drug dealer, offers Eddie a nootropic drug, NZT-48, claiming it allows the user to access 100% of their brain's capacity instead of the "usual" 20%. After some convincing, Eddie accepts the pill and arrives home.
Eddie takes one dose in front of his apartment and finds the claim is true; with his heightened brain activity, he realizes that his landlord's young wife studies law from a book that he remembered from college that he saw in her hand, and helps her write 50 pages of her report assignment. He arrives in his apartment and completes 90 pages of the book for his delighted publisher, but is concerned that he has little recollection of the time he was under the influence of the drug. Vernon makes Eddie complete mundane tasks in exchange for more of the drug; when Eddie returns to Vernon's apartment after one errand, he finds Vernon shot dead and the apartment ransacked. He quickly finds Vernon's stash of NZT-48, a small amount of cash, and a book of addresses, which he takes before the police arrive.
Eddie, using NZT-48, quickly finishes the book but believes he is capable of much more with the drug. He finds the ability to identify trends in the stock market, and is able to quadruple investments on a daily basis. Seeking to grow a fortune quickly, he obtains a short term loan of $100,000 from Russian mafia thug, Gennady (Andrew Howard), which he is able to turn into $2 million in a few days at a "trading arcade"; though he knows he has drawn media attention, he is troubled by a man in a tan coat (Tomas Arana) that appears to be following him. Eddie is able to rekindle his relation with Lindy during this time.
Eddie's success leads to a meeting with the powerful businessman, Carl Van Loon (Robert De Niro), who wants Eddie's advice the next day on a proposed merger with a competitor, Hank Atwood (Richard Bekins). Eddie spends the day influenced by NZT, drinking and partying heavily, and eventually coming to his senses in a hotel room with a blonde woman (Caroline Winberg). Worried about having no memories of the past day, he quickly leaves, followed by the man in the tan coat. Eddie meets with Van Loon the next day, having not yet taken a look at the assignment nor a dose of NZT, but as they discuss it, Eddie realizes that Atwood may also be a NZT user based on his sudden rise in wealth. Just then, a news reports breaks that the woman Eddie was with the night before was found murdered.
Worried about his sudden sicknesses, Eddie talks to Melissa, who was a former user of the drug, explains that quitting NZT cold turkey has extreme side effects, with nausea, vomiting, headaches, which is only the beginning, and instead that Eddie should reduce his dosage slowly; even still, two years since quitting the drug has left Melissa sluggish and lazy. Eddie returns home but is accosted by Gennady, who takes his last NZT pill giving time for Eddie to get the funds to repay Gennady. Eddie tells Lindy that he had stored a stash of the drug at her apartment and asks her to bring it over; as she does, she is followed by the man in the tan coat. Eddie convinces her to take one pill, giving her heightened awareness to injure the man and escape; though she returns the stash to Eddie, she fears what he's become with the drug and leaves him again.
Eddie works on reducing his dosage to manageable levels to avoid complete memory blackouts. He continues to build his wealth, hires bodyguards to protect him, and pays a laboratory to try to reverse engineer NZT. Also, the Russian mobster found out about the drug and now he is blackmailing Eddie to get the drug. Eddie aids Van Loon in the merger deal, who promises Eddie $40 million if the deal goes through. Meanwhile, Eddie is marked as a suspect in the murder case; he hires a top attorney Morris Brandt (Ned Eisenberg) to help defend him. Worried for his safety, Eddie buys a highly secured penthouse safehouse.
On the day of signing the merger, Atwood's wife shows up instead and announces that Atwood had fallen into a coma, though confides that Atwood still wants the deal to go through. As Eddie and Van Loon escort her back to her car, Eddie recognizes the driver as the man in the tan coat, and realizes that Atwood was trying to get his stash of NZT from Eddie. Later, Eddie is required to participate in a line-up for the murder, while Brandt holds his custom-made jacket. Eddie is not recognized by the witness and is let off as a suspect, but later he discovers that the stash of his NZT in his jacket has gone missing. He realizes that Brandt took the stash from his coat when he sees him on television as Atwood's attorney.
As Eddie starts withdrawals in his safehouse, Gennady and his henchmen try to break in looking for more NZT. Eddie contemplates jumping to end it all (the scene from the beginning of the movie), but remembers he may have one more pill. He finds it just as the Russians break in, causing him to drop the pill into a grate. Gennady demonstrates that he has found a way to take NZT directly by injecting a solution of it into his blood by a syringe, and he started an import-export business. Eddie uses the moment and attacks Gennady, killing him with a kitchen knife. Desperately needing NZT, but with no pills to hand, Eddie resorts to drinking Gennady's blood to successfully regain his enhanced faculties. One of the henchman returns to find him and the corpse, but Eddie blinds the Russians' eyes by using a syringe needle as a blowdart. He then tricks the blinded goon into killing his sidekick by impersonating the second henchman (using his acquired Russian language skills), before eventually killing the blinded Russian. Later, learning that Atwood died, Eddie convinces the man in the tan coat of Brandt's deception, and the two recover Eddie's stash of NZT from Brandt's residence.
A year later, Eddie has remained wealthy, his book has hit the market, and he is running for the United States Senate. Van Loon visits him, initially as a friend, but soon reveals he has bought the company that made NZT and closed down the laboratory Eddie had hired to make it, seeking to provide Eddie with an unlimited supply in exchange for political favors to escape from the law. Eddie surprises Van Loon by revealing that he has been several steps ahead; not only had he hired multiple laboratories to work on NZT, but he himself has been able to wean himself off the drug while retaining his acute mental abilities. He recognizes that Van Loon has a terminal heart condition and will die soon, and he escorts him back in his car. Later on, Eddie meets with Lindy in a Chinese restaurant. He orders his meal speaking Mandarin with the waiter. Eddie realizes that Lindy is staring at him. "What?" he asks. Then the credits roll.
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