Tests results released by the New York medical examiner who performed the autopsy on Ledger, reveal the 28-year-old took five different prescription painkiller or anti-anxiety drugs, along with an over-the-counter antihistamine.
The six drugs detected in his blood - oxycodone, hydrocodone, diazepam, temazepam, alprazolam and doxylamine - are all designed to suppress the central nervous system and help a person sleep.
Taken together, the drugs created a potent mix with death a significant possibility, the drug experts said.
"The one dose of oxycodone or the one dose of alprazolam, fine," Professor Margaret Gnegy, director of the University of Michigan Substance Abuse Research Centre, said. "When you add them on, it's not fine."
"It's quite serious." Martin Iguchi, professor of public health at the University of California Los Angeles and an adjunct senior behavioural scientist at LA's RAND Drug Policy Research Centre, agreed.
"That kind of mixing is obviously very dangerous," Prof Iguchi said.
The New York Office of the Chief Medical Examiner, after analysing toxicology results, says Ledger died of an accidental overdose death "resulting from the abuse of prescription medications"
Ledger, the Perth-born star of Brokeback Mountain, Monster's Ball and the upcoming Batman sequel, The Dark Knight, was found dead in his Manhattan apartment on January 22.
He was naked and lying in his bed.
Some drug experts wonder how suicide could be ruled out considering the amount of drugs Ledger consumed.
"He was playing Russian roulette," said Patti Geier, a New York-based psychotherapist and licensed clinical social worker.
"I was thinking when I heard (about the findings), `How do they really know for sure it was accidental? How do they know for sure he wasn't thinking when he took them -- I've had enough'."
Prof Gnegy went one step further when told of Geier's "Russian roulette" analogy.
"I think it is more certain than Russian roulette," Prof Gnegy, who specialises in pharmacology, said. "Russian roulette you may have one bullet out of six.
"When you add all of those drugs together that deck is really stacked."
Spokeswoman for the New York medical examiner, Ellen Borakove, said suicide was ruled out because there was no evidence Ledger wanted to take his life.
Borakove refused to divulge the quantities of drugs in Ledger's blood because it was not "public information".
But a source with knowledge of the tests said suicide was ruled out because the amount of each drug in Ledger's system was low.
Borakove said there were no traces of illegal drugs, such as heroin or cocaine, found in Ledger's body.
The six drugs Ledger took, are commonly prescribed in the US and Australia.
Oxycodone is the active ingredient in the powerful painkiller OxyContin, hydrocodone is found in another popular painkiller, Vicodin, while diazepam is sold under the commercial name Valium.
Alprazolam is commonly known under the anti-anxiety drug brand name Xanax and the sleeping pill temazepam is sold as Restoril.
Doxylamine is found in common over-the-counter sleep aids or cough medicines
"That's the trouble," Prof Gnegy said.
"You take some that you think are OK, but then they all add on to each other and people don't realise that. Even antihistamines."
Ledger went public with his battle with insomnia during an interview last year, revealing he was taking the sleeping pill, Ambien.
"Last week I probably slept an average of two hours a night," Ledger told The New York Times.
"I couldn't stop thinking. My body was exhausted, and my mind was still going." Ledger said he had taken two Ambien pills, which only gave him an hour of sleep.
"For a normal person, two Ambien would knock them out for the rest of the night at least," Geier said.
Patients, however, often build a tolerance to medication, forcing them to take more than the prescribed dose.
"I knew someone who had been taking 60 Valium a day because she had built up such a tolerance," Geier explained.
"Another person was taking 30 Vicodin a day and barely even feeling it. Also, all of those drugs are depressants," she said. "When they are in your body for a while you become depressed."
Patients also took drugs in unconventional ways to give a bigger and quicker hit, including snorting crushed up drugs.
A rolled up $US20 note was found near Ledger's body, but New York police said Ledger had not used it to snort drugs
"Oxycodone can be very, very powerful if one crushes it up and snorts it," Geier said. "If you take it orally, it will take longer to work."
The mix of drugs, with most of them designed to relax the body's central nervous system, likely resulted in Ledger's body slowly shutting down, with the actor unaware he would die.
"They all work on your central nervous system," Geier explained. "Everything is slowed down and he could have just stopped breathing, or his heart could have stopped beating and he could have slipped into a coma very easily
"I'm sure he didn't know what was happening. He might have just fallen asleep." - AAP
