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Ketamine has long been considered a safe anesthetic, one perceived as carrying little harm and having the potential to help treat some of the most refractory mental health conditions.

So when the Los Angeles county medical examiner that actor Matthew Perry's death was chiefly due to the "acute effects of ketamine," many were surprised -- but not psychiatrists familiar with the drug, and with substance use disorders (SUDs).

"In clinical settings, ketamine is known for its safety profile. That doesn't mean it is safe," psychiatrist Drew Ramsey, MD, of Spruce Mental Health in Jackson, Wyoming, . Ramsey noted a mixture of "celebrity, substance use disorders, character pathology, psychedelic medicine, and concierge medicine" may have contributed to Perry's death.

Perry has made no secret of his SUD, acknowledging his nearly with alcohol and opioid addiction in his recent memoir. In addition to high levels of ketamine, the autopsy also showed that Perry had therapeutic levels of buprenorphine on board, which is used as both maintenance therapy for opioid addiction and as a pain medication.

Perry also had coronary artery disease, the autopsy showed.

While he drowned in the "heated end of his pool," according to a from the Los Angeles medical examiner, that was a secondary factor in his October 28 death, which was deemed accidental.

"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 autopsy report stated, .

Andrew Stolbach, MD, MPH, a medical toxicologist with Johns Hopkins Medicine in Baltimore, who reviewed the autopsy report at the , said the amount of ketamine found in Perry's blood "would be enough to make him lose consciousness and lose his posture and his ability to keep himself above the water."

"Using sedative drugs in a pool or hot tub, especially when you're alone, is extremely risky and, sadly, here it's fatal," Stolbach told the AP.

Smita Das, MD, PhD, MPH, of Stanford University in California and chair of the Council on Addiction Psychiatry at the American Psychiatric Association, noted that clinicians would closely monitor many parameters, such as heart rate and simultaneous medications, when giving ketamine.

"When that sort of monitoring or supervision isn't in place, then there are a multitude of different things that can happen with external factors -- if there are other medical conditions that aren't accounted for that might put somebody at risk, or there are other substances involved," Das told MedPage Today. "All these things can contribute to a poor outcome."

The autopsy report stated that Perry was being treated with ketamine infusion therapy, but the medical examiner said levels in his body were in the range used for general anesthesia during surgery, and could not have been from his last therapy session, which had been a week and a half earlier.

"It's possible he was getting IV ketamine treatments and also illicitly abusing ketamine," Ramsey told MedPage Today. "Illicit ketamine is fairly easy to get these days. There's been an underground market for illicit ketamine for years."

There's also been a "proliferation of ketamine clinics and at-home ketamine delivery," Ramsey said. "You can get screened and be treated by mail-order ketamine now."

Das noted that this is occurring "without a clear set of guidelines or protocols" on how to use these potential treatments appropriately.

This likely spelled disaster for Perry, said Ramsey: "We have a polysubstance situation where there are a lot of meds on board, [and] this is someone who is already medically compromised, with coronary artery disease and a long-term history of substance use."

"I'm sending very caring, healing vibes to the sober companions and clinicians involved and Matthew's family and community," Ramsey added .

Ketamine is not FDA-approved for treating any psychiatric disorder, but a derivative called esketamine (Spravato) is approved in nasal spray form for treatment-resistant depression. That product carries a boxed warning on sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts and behaviors.

Nonetheless, ketamine is being investigated for and has shown some promise in numerous mental health conditions, including depression, anxiety, and post-traumatic stress disorder (PTSD).

Some providers are getting ahead of the game, opening ketamine infusion clinics that have been rising in popularity over the last several years -- even if they don't necessarily have scientific evidence behind them.

Das says that's cause for concern, especially if patients aren't being closely monitored while they use ketamine, which isn't free of side effects. These include nausea, drowsiness, dissociation, hallucinations, headache, and increased blood pressure and heart rate. Ketamine also "rarely can cause very extreme paranoia and even suicidal ideation," Das said.

"If someone is using a ketamine product, especially in an unstructured way, it can lead them to having a bad trip or a really uncomfortable experience," she said. "It can also lead to reckless behavior or worsening of psychiatric symptoms, panic, confusion, and it can interact with other medications."

Still, Das said she's "hopeful" because strong research is ongoing "around novel treatments for treatment-resistant depression, anxiety, and PTSD, [and] some of this does include ketamine. Hopefully, once that research is completed, there will be an addition of these protocols to standard practice guidelines."

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