Edward "Eddie" Morra (Bradley Cooper) is a writer who lives in New York City and has recently been dumped by his girlfriend Lindy (Abbie Cornish) in addition to failing to meet the deadline to turn in his new book, which he hasn't started yet. One day, Eddie comes across Vernon Gant (Johnny Whitworth), the brother of his ex-wife, Melissa Gant (Anna Friel). Vernon is a drug dealer, and he offers Eddie a sample of a new nootropic drug, NZT-48, claiming it has the ability for humans to access 100% of the brain's power, as opposed to the normal 20%. Eddie accepts, and, much to his surprise, the drug does indeed work, allowing him to finish his book.
Eddie asks Vernon for more of the drug, and Vernon agrees, after Eddie runs a few errands for him. When Eddie returns to Vernon's apartment, he finds Vernon murdered and promptly calls the police. He quickly deduces that Vernon was probably killed by someone who wanted his stash of NZT, and he searches Vernon's apartment for it. He finds the stash of NZT and a wad of cash and uses it to turn his life around. He abandons his writing career and starts tradingstocks, borrowing capital from a Russian thug, Gennady (Andrew Howard). Eddie becomes rich at an incredibly fast pace and is soon employed by the powerful businessman Carl Van Loon (Robert DeNiro). Eddie also gets back together with Lindy. Meanwhile, he feels that he is being followed by a man in a tan coat (Tomas Arana). He also starts using more and more NZT, causing side effects to occur: lost time, frenetic activity, and heart palpitations.
Eddie fails to accomplish a task assigned to him by Van Loon because of an NZT hangover, and fears he might even have killed a woman during some lost time. He is contacted by his ex-wife Melissa (Anna Friel) and learns that she had been an NZT addict. Worse, he learns that withdrawal from the drug causes major health and mental problems, possibly resulting in death. She warns Eddie to taper off the NZT before it's too late. When Gennady comes calling, he tries one of Eddie's pills. Gennady quickly realizes the drug's effects and threatens Eddie until he agrees to give him more NZT, which Eddie supplies.
Despite Melissa's warnings, Eddie manages his consumption of the drug down to an acceptable level, and uses his fortune to hire a scientist to work on reverse engineering NZT, a process that could take years. He assists Carl again, this time on a big company merger deal with rival businessman Hank Atwood (Richard Bekins). Before the deal can take place, Atwood falls ill. Noticing the man in the tan coat working with Atwood, Eddie realizes the man's true mission—to steal Eddie's stash of NZT for his boss, whose illness is really NZT withdrawal. Before the deal can take place the stash is successfully stolen, not by the man but by Eddie's lawyer, Brandt, who is revealed to also be working for Atwood. Seeing no way out and desperate for more NZT, Eddie returns home to find he has been followed by Gennady, but manages to kill him and his two thugs with intelligence gained from what he believes to be the last of the NZT — drank directly from the deceased Gennady's bloodstream. Later that night Atwood dies, Brandt having kept the NZT for himself. Eddie agrees to work with the man in the tan coat to retrieve his stolen NZT stashed away at Brandt's mansion.
One year later, Eddie's book has been published (titled Illuminating the Dark Fields — a reference to the novel on which the film is based), and Eddie is running for the United States Senate. In the midst of his campaign, Carl approaches Eddie with the revelation that he bought the company that secretly makes NZT and the back room NZT lab Eddie was financing has been shut down. Carl offers him an unlimited supply of NZT (admitting that they both know he is headed for Presidency); however, Eddie must use his political position to push Carl's agenda in return. Eddie refuses the offer, informing Carl that he no longer needs the drug: his prolonged use, combined with a modified version of the drug, has allowed him to come off of the drug and has permanently enhanced his brain. However, in the film's last scene Eddie eats lunch with Lindy, conversing with the waiter in Mandarin Chinese, leaving it ambiguous as to whether or not he is actually off of NZT-48.
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