The Los Angeles County Department of Medical Examiner said Perry, 54, also drowned in "the heated end of his pool", but it was a secondary factor in his October 28 death, which was deemed an accident.
People close to Perry told investigators that he was undergoing ketamine infusion therapy, an experimental treatment used to treat depression and anxiety.
But the coroner said the levels of ketamine in Perry's body were in the range used for general anaesthesia during surgery, and his last treatment over a week earlier would not explain those levels.
The report says coronary artery disease and buprenorphine, which is used to treat opioid use disorder, also contributed.
Matthew Perry was open his struggles with addiction dating to his time on Friends in the 1990s. (AP PHOTO)
The amount of ketamine detected "would be enough to make him lose consciousness and lose his posture and his ability to keep himself above the water", Dr Andrew Stolbach, a medical toxicologist with Johns Hopkins Medicine said.
"Using sedative drugs in a pool or hot tub, especially when you're alone, is extremely risky and, sadly, here it's fatal."
Perry was declared dead after being found unresponsive at his home in the Pacific Palisades area of Los Angeles.
The actor, who played Chandler Bing in the hit US sitcom Friends, had taken drugs in the past but had been "reportedly clean for 19 months", said the report released on Friday.
Perry had played pickleball that day, and his assistant found him face down in the pool after returning from errands.
The assistant told investigators Perry had not been sick, had not made any health complaints, and had not shown evidence of recent alcohol or drug use.
Blood tests showed "high levels" of ketamine in his system, which could have raised his blood pressure and heart rate and dulled his impulse to breathe.
Buprenorphine, found in therapeutic levels in Perry's blood, could have contributed to the breathing problem, the autopsy said.
His heart disease would have made him more susceptible to the drugs' effects.
Perry was open about discussing his struggles with addiction dating to his time on Friends in the 1990s.
"I loved everything about the show but I was struggling with my addictions which only added to my sense of shame," he wrote in his 2022 memoir.
"I had a secret and no one could know."
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