Matthew Perry's cause of death has been released.

The Los Angeles County Medical Examiner's office on Friday revealed that the late "Friends" actor's death in October was an accident, with the cause being "the acute effects of ketamine." Contributing factors were drowning, coronary artery disease and the effects of buprenorphine.

Buprenorphine is "an opioid-like drug used in the treatment of opioid addiction as well as acute and chronic pain," according to Perry's 29-page autopsy report obtained by USA TODAY. There were no signs of "fatal trauma and no foul play suspected," according to the report.

How did Matthew Perry die?

Perry was found unresponsive and face-down in the "heated end" of his pool on Oct. 28, according to his autopsy. The Los Angeles Fire Department confirmed to USA TODAY that firefighters responded to Perry's Pacific Palisades home at 4:07 p.m. that day and found "an adult male unconscious in a stand-alone jacuzzi."

"A bystander had brought the man's head above the water and gotten him to the edge, then firefighters removed him from the water upon their arrival. A rapid medical assessment, sadly, revealed the man was deceased prior to first responder arrival," Nicholas Prange, an LAFD spokesperson, told USA TODAY in a statement on Oct. 30.

His live-in personal assistant was the last person to see him alive that afternoon after Perry returned from playing pickleball, according to his autopsy report. The assistant had left Perry's house for several hours to run errands and discovered his body at 4 p.m. Responding officers pronounced him dead at 4:17 p.m.

According to his autopsy, there were no pills, drugs or medications found near the pool. He didn't have alcohol or drugs such as methamphetamine, cocaine, heroin and fentanyl in his system.

The role of 'high levels of ketamine' in Matthew Perry's death

The autopsy, conducted the day after his death, describes Perry as a “54-year-old male with history of chronic obstructive pulmonary disease/emphysema, diabetes; drug use in past — reportedly clean for 19 months; heavy tobacco user for many years but currently not smoking; on ketamine infusion therapy with most recent therapy reportedly one and a half weeks before death."

The medical examiner makes note that the amount of ketamine, a “dissociative anesthetic," found in his system was as high as 3,540 nanograms per milliliter; "levels for general anesthesia are typically in the 1,000-6,000 ng/ml ranges," the report notes.

Though Perry was "reported to be receiving ketamine infusion therapy for depression and anxiety," according to the report, "the ketamine in his system at death could not be from that infusion therapy, since ketamine’s half-life is 3 to 4 hours, or less." The method of intake is unclear.

"At the high levels of ketamine found in his postmortem blood specimens, the main lethal effects would be from both cardiovascular overstimulation and respiratory depression," the report reads. "Drowning contributes due to the likelihood of submersion into the pool as he lapsed into unconsciousness; coronary artery disease contributes due to exacerbation of ketamine induced myocardial effects of the heart."

Buprenorphine, which was present at "therapeutic" levels, is also listed as a contributing factor due to "additive respiratory effects when present with high levels of ketamine." There were non-toxic levels of lorazepam, too.

What are the effects of ketamine?

Ketamine hydrochloride, AKA ketamine, is a controlled substance approved by the U.S. Food and Drug Administration to induce and maintain general anesthesia via intravenous or intramuscular injection. It's not approved by the FDA for psychiatric treatment.

"FDA has not established safe or effective dosing of ketamine for any psychiatric indication because ketamine has not been approved for these uses," reads an October post on the agency's website. "These factors may place the patient at risk for serious adverse events, misuse, and abuse." 

It "distorts the perception of sight and sound and makes the user feel disconnected," which is why it's referred to as a dissociative anesthetic hallucinogen, according to the U.S. Drug Enforcement Administration. The DEA's website says that "an overdose can cause unconsciousness and dangerously slowed breathing."

Ketamine first caught interest as a counterculture drug in the 1970s and re-emerged as a club drug "Special K" in the 2000s.

Dr. Nolan Williams, an associate professor in Stanford University's Department of Psychiatry and Behavioral Sciences, previously told USA TODAY that it's unclear exactly how ketamine affects mood because "there are many mechanisms happening at once."

But rather than affecting dopamine or serotonin, neuroscience studies show that ketamine instead targets a neurotransmitter called glutamate, which promotes the brain's ability to create lasting, new lifestyle patterns.

Some experts have also speculated that the dissociative experience of a ketamine "trip" may be responsible for reducing depressive symptoms. Though there's no evidence that the trip directly affects mood, Dr. Alexander Papp, a board-certified psychiatrist and assistant clinical professor at UC San Diego, says some of his patients have credited ketamine's psychedelic properties to their improved outlook on life.

Was Matthew Perry sober?

Perry was open about his battle with alcohol and drugs, which he chronicled in his 2022 memoir "Friends, Lovers and the Big Terrible Thing." He wrote with candor and compassion and showed his dedication to continue fighting a near-fatal battle.

At the time of his death, "Alcohol, methamphetamine, cocaine, heroin, PCP, fentanyl were not detected," according to Perry's autopsy.

Jennifer Aniston said recently that Perry was doing well in his personal life before his death, she told Variety.

"He was happy. He was healthy," Aniston said. "He had quit smoking. He was getting in shape. He was happy — that's all I know. I was literally texting with him that morning, funny Matty. He was not in pain. He wasn't struggling."

Contributing: Jenna Ryu, Edward Segarra, USA TODAY