What is ketamine infusion therapy?

Among the details that emerged on Thursday about the death of actor Matthew Perry was that the Friends star had been undergoing ketamine infusion therapy.

The coroner concluded that the treatment - which is offered both in the US and the UK - was not responsible for Perry's death due to ketamine, which prosecutors allege was supplied to him illicitly.

Five people including two doctors, Perry's assistant and an alleged drug dealer have been charged for providing the drug outside of his treatment regimen.

Perry, 54, had been open about his history of substance misuse, and prosecutors say the accused profited from his addictive tendencies.

Ketamine is an anaesthetic that can be used to treat depression, anxiety and pain in a medical setting.

However, it also has dissociative effects - meaning it can distort perceptions of sight, sound and time, as well as producing calming and relaxing effects. This means it is also used illicitly.

According to addiction advice service Talk to Frank, Ketamine can increase a person's heart rate and blood pressure, and can leave users confused and agitated - which may cause them to hurt themselves without realising.

Chronic ketamine use has been linked to liver damage, as well as causing bladder problems such as incontinence.

Ketamine is used to treat depression in cases where traditional anti-depressants have not been effective.

"At a biological level, it probably turns off the area of the brain that is involved in disappointment," says Prof Rupert McShane, a University of Oxford psychiatrist who runs an NHS ketamine treatment clinic. "That area is probably involved in depression."

Dr Rajalingam Yadhu, a consultant at the Royal Free Hospital in London who also runs Save Minds, a ketamine infusion therapy clinic, told the BBC that the patients he treats have long-term depression and have usually tried a minimum of seven different medications without seeing an improvement.

"These are people who have actually tried everything in life, [are] extremely suicidal - and given the chance, would kill themselves."

The treatment has also been used by high-profile individuals. As well as Perry, billionaire entrepreneur Elon Musk has said he has been given ketamine to treat depression.

In an interview with CNN in March, the X and Tesla owner said the drug was "helpful for getting one out of the negative frame of mind".

Ketamine infusion therapy works by giving the drug intravenously in smaller doses than those used for anaesthesia.

"For depression, you use a lower dose than you use for chronic pain, a really lower dose than patients receive as anaesthetics," says Dr Mario Juruena, a psychiatrist at King's College London who specialises in treatment-resistant mental disorders.

Ketamine acts faster than traditional anti-depressants - but its effects also wear off quicker.

"It has a short half-life, so the time that the patients have the effect is quite short at some points," Dr Juruena told the BBC, stressing the importance of monitoring patients' mental state for relapse back into depression.

Dr Yadhu says that, unlike other mainstream anti-depressants, ketamine has been found to affect nerves that use the chemical glutamate to interact. Glutamate is the most abundant neurotransmitter in the nervous system.

Some studies suggest ketamine may also help reverse synaptic pruning - the removal of neurons - which occurs naturally, but may also be associated with chronic stress and depression.

"When you get depressed, the connections in the brain seem to retract," Prof McShane told the BBC. "So it's almost as if in depression, some of the neurons are like a tree in winter - and then with the ketamine, it turns them more into a tree in spring."

He adds that the drug probably reduces suicidal thoughts and the "cycle of rumination" that feeds depression.

Experts are researching why it might help some patients, but not others.

Dr Juruena told the BBC that more than 60% of patients responded well to ketamine treatment - but said this was usually while taking other anti-depressants or alongside psychotherapy.

Clinicians caution that people could still experience negative side-effects from taking ketamine, even when overseen by a medical professional - though Dr Juruena says this happens less often because of the lower dosage.

Dr Yadhu says that while many of his patients' experiences were positive, some were unpleasant and could bring back bad memories.

Prof McShane notes: "Whilst ketamine can be very effective for people for whom nothing else has worked, one of the problems is you need to keep taking it - and we're simply not used to that being a good idea."

Dr Yadhu says he does not treat people showing addictive tendencies with ketamine - though some doctors are exploring it as a treatment for drug and alcohol addiction.

Receiving ketamine in an "infusion" - ie through an IV drip - is not the only way of treating people with ketamine, however.

Dr Juruena says it can also be given through an injection, a nasal spray or as a capsule.

Experts say the dosage of ketamine given in infusion treatment has to be of a precise and small amount to have anti-depressant effects.

But a post-mortem examination found Perry's blood contained a high concentration of ketamine and that he had died of the "acute effects" of the drug.

The medical examiner also found his last ketamine infusion therapy session had taken place more than a week before his death - by which time the drug would have worn off.

They said the levels of ketamine in Perry's body when he died were also of a far higher dosage.

Prosecutors alleged that Perry's assistant had given him at least 27 shots of ketamine in the four days before his death.