Eddie Morra (Bradley Cooper), an author suffering from writer's block, living in New York, is stressed by an approaching deadline. His girlfriend Lindy (Abbie Cornish), frustrated with his lack of progress and financial dependence, breaks up with him. Later, Eddie meets Vernon Gant (Johnny Whitworth), the estranged brother of Eddie's ex-wife, Melissa. Vernon, involved with a pharmaceutical company, gives Eddie a nootropic drug, NZT-48. After taking the pill, Eddie finds himself able to learn faster and recall memories from his distant past, with the only apparent side effect being a change in the colour of Eddie's irises while on the drug - his eyes becoming an intense shade of electric blue. He uses this ability to finish ninety pages of his book. The next day, the effects having worn off, he seeks out Vernon in an attempt to get more. While Eddie is running an errand, Vernon is killed. Eddie returns, steals Vernon's NZT supply and calls the police. Using NZT, Eddie completes his book.
Testing his new ability on the stock market, Eddie makes large returns on small investments. Realizing he requires more capital, he borrows one hundred thousand dollars from a Russian loan shark, Gennady (Andrew Howard), and successfully makes a return of two million dollars. He increases his NZT dosage, and rekindles his relationship with Lindy.
Eddie's success leads to a meeting with a business tycoon, Carl Van Loon (Robert De Niro), who wants Eddie to advise him on a merger with Hank Atwood (Richard Bekins). After work, Eddie starts experiencing blackouts, apparently having moved great distances in between periods of lucidity. He finds himself at a nightclub, a hotel party, in a hotel room with a blonde woman (Caroline Winberg), and in a subway station where he easily subdues several men using techniques seen in old kung fu movies, boxing matches, and documentaries. When the blackouts stop, he finds himself on the Brooklyn Bridge, when he finally limps home. Later, Eddie sees a news report detailing the murder of the woman he had slept with, and is unable to remember if he was the killer.
Eddie meets with Melissa, and discovers that she too had been on NZT. When she attempted to stop taking it, she had experienced a severe mental rebound effect, as well as a limp like Eddie, while others had died after stopping. On his way home, Eddie is attacked by Gennady, who takes Eddie's last NZT pill. Eddie visits Lindy and asks her to retrieve his backup stash, which he had hidden in her apartment. On her way back, she is followed by a man (Tomas Arana) who'd been stalking Eddie. He corners Lindy in a park, and Eddie tells her to take an NZT pill. The pill enables her to escape and she returns the stash to Eddie.
Eddie experiments with the drug, and learns to control his dosage and food intake to prevent side effects. He continues to earn money on the stock exchange, and hires bodyguards to protect him from Gennady, who threatens him in an attempt to obtain more NZT. He buys an armored penthouse, and hires a laboratory to reverse engineer NZT. For his part in the merger, Eddie is promised forty million dollars, and he hires an attorney (Ned Eisenberg) to help keep the police from investigating both Vernon's and the woman's deaths.
On the day of the merger, Atwood's wife informs Van Loon that he has fallen into a coma. Eddie recognizes Atwood's driver as his stalker. While Eddie participates in a lineup, his attorney steals Eddie's whole supply of NZT from his jacket. Soon afterwards, Eddie discovers that his pills are gone and begins to enter withdrawal, as well as finds that his bodyguards have been killed; the former causing him to hurry home when Van Loon questions Eddie about his knowledge relating to Atwood's coma. Gennady breaks into his apartment, demanding more NZT. He reveals that, to increase its potency, he has been injecting it. Eddie stabs Gennady, and drinks his blood for the NZT in it. His increased mental acuity restored, Eddie kills Gennady's henchmen and escapes. He meets with his stalker, surmising that Atwood employed the man to locate more NZT. The two join forces and recover Eddie's stash from his attorney (who did not pass the NZT to his client).
A year later, Eddie has retained his wealth, his book has been released, and he is running for the United States Senate. Van Loon visits him and reveals that he has absorbed the company that produced NZT and shut down Eddie's laboratory. He offers a steady supply of the drug in return for power when Eddie inevitably becomes president. Eddie reveals that he has multiple laboratories working on NZT, and that they had eventually developed a way to get the bugs out of the drug and to reverse engineer it, for the purpose of ceasing to take the drug and retain the enhanced mental faculties facilitated by NZT. He dismisses Van Loon, and meets Lindy at a Chinese restaurant for lunch, where his perfect Chinese language skills with the waiter and his electric blue eyes prompt cynicism from Lindy (and the audience) as to whether or not he is actually off NZT.
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