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A guide to ketamine and how it can be used to treat depression

Ketamine is in the news following the death of Matthew Perry, but for many depression sufferers around the world, it remains a vital therapy

We think of ketamine as a street drug, which can result in some horrific side-effects, from hallucinations to bladder issues. But it is increasingly used as cutting-edge therapy to treat depression, anxiety and PTSD.  
In the mid-2000s, researchers at the US National Institute of Mental Health conducted the world’s first clinical trial of ketamine for patients with severe, treatment-resistant depression.
It proved successful, initiating a renewed surge of interest in the drug, which had previously been best known as an anaesthetic, and a substance abused by partygoers seeking out-of-body experiences. 
Around 15 years later, Matthew Perry would come to experience ketamine at a rehab clinic in Switzerland during the pandemic. In his typical self-deprecating style, Perry wrote in his autobiography Friends, Lovers and the Big Terrible Thing, “It’s used for two reasons: to ease pain and help with depression. Has my name written all over it – they might as well have called it ‘Matty’.” 
In his book, Perry described ketamine therapy as like ‘being hit in the head with a giant happy shovel,’ and ‘not for me,’ but it appears he continued receiving the drug at specialist clinics in California, as well as potentially self-medicating. It is suspected that the latter could have contributed to his accidental death in October at the age of 54. 
A coroner’s report released last week revealed traces of ketamine in his system when he was found dead in a hot tub at his Los Angeles home. Because ketamine is metabolised by the body within a matter of hours, this could not have been linked to his last medical infusion with the drug, a week and a half before his death. 
But for many depression sufferers around the world, ketamine remains a vital therapy. Seventy-seven-year-old Gene Stull from Mendham, New Jersey says he experienced his first bouts of depression in his 30s and struggled with the disease for 40 years before starting ketamine therapy in 2016.
“I’ve got children and six grandchildren but I was suicidal and I literally just couldn’t see myself being alive any more,” he says. “I’d tried various medications and sometimes they’d work for a year before abruptly stopping or they wouldn’t work at all. But with ketamine, those thoughts all went away within a few days. Initially, I was having infusions once or twice a week but I now haven’t needed one for three-and-a-half years and I haven’t slid backwards.” 
The potential therapeutic benefits of ketamine were first uncovered by researchers in the 1980s and 1990s who were using the drug to try to understand schizophrenia. By administering it to healthy volunteers, they hoped to provoke psychosis-like symptoms, but instead they noticed that the participants’ mood improved. 
Fast-forward three decades, and ketamine injections are now used in multiple specialist centres around the UK for treating patients with recurrent episodes of depression, for whom conventional antidepressants have proven ineffective. Studies have shown that in some patients, ketamine can diminish suicidal ideations within a matter of hours, while it also appears to offer benefits across the varied spectrum of depression symptoms, enabling patients to process past traumas, relieving the anhedonia, or loss of pleasure, which many experience. 
In May 2023, the most recent clinical trial of ketamine for depression at Massachusetts General Brigham showed that 55 per cent of patients experienced sustained improvement after six months without serious side effects. 
“I think the consensus is that about 50 per cent of people with treatment-resistant depression respond to ketamine infusions,” says Professor Allan Young, director of the Centre for Affective Disorders at King’s College London. “I think it’s fairly clear that it is an effective treatment.” 
Professor David Nutt, head of the Centre for Neuropsychopharmacology at Imperial College London, has long been one of the biggest advocates in the UK for ketamine as a medical treatment. 
He says that the inherent benefits of the drug are disrupting the damaging patterns of thought which many people with mental illnesses find themselves trapped within. “People get locked into thought loops they can’t escape from,” says Prof Nutt. “The reason depression’s such an evil illness is because when you start off thinking you’re such a worthless person, you kind of know it’s not true. But eventually depression commandeers your mind, so you believe the lies your brain is telling you about yourself. Ketamine disrupts that, so the brain doesn’t go back to where it was; it stays more flexible.” 
Prof Young says it appears that ketamine may have an impact on the underlying biology of depression (which actually causes the brain to lose volume and complexity) and can aid recovery back to a healthy state. 
But because ketamine helps depressive patients to alter their perspective on themselves and their life, Prof Nutt says that the benefits of the drug are most profound when applied alongside psychotherapy. “People with ketamine often say, ‘For the first time, I can step outside of my disorder’,” he says. “You basically take the guilt, and the self-centredness out, see where the problem really was, and then use therapy to deal with it.” 
While the coroner’s report found that Perry had evidence of coronary artery disease, it is not known whether that directly contributed to his death. Instead, Prof Nutt says it likely illustrates the known dangers of using ketamine alone, and particularly near water, due to its sedative qualities.
“If you use a dose by yourself while you’re sitting in a bath or a hot tub, there’s a chance that you will fall asleep and drown in the same way as people do when they take a lot of alcohol,” he says. “Recreational ketamine is quite often associated with drowning because people often become insensitive to changes in temperature. You also get examples of people going out and looking at the stars in the night sky and lying on the ground, but they freeze to death because it’s -10C.” 
While Prof Nutt argues that ketamine remains largely a very safe medicine when administered under the guidance of trained medical professionals, Prof Young feels that there is a need for more research into potential bladder toxicity, particularly for patients who require repeated doses over long periods of time. 
“We know that ketamine abusers get something called ketamine-induced urinary tract toxicity, and that can be quite bad news, as the bladder can shrink,” says Young. “We haven’t had much of a signal of that with therapeutic studies. But nevertheless, it needs to be kept an eye on, especially when people are getting long term ketamine.”
Most research studies have not examined the safety of ketamine therapy beyond one year. There are some concerns, particularly in the US where there is an abundance of unregulated private clinics, that higher doses of the drug may also tap into brain pathways that are susceptible to addiction. 
No one knows if this is what happened to Perry, but on X (formerly Twitter) Jules Evans, who runs the Challenging Psychedelic Experiences Project studying psychedelic-induced adverse events, noted that there were at least 20 private ketamine clinics in the vicinity of his home. “The question is, how often do people who receive ketamine treatment – or other psychedelic treatments – then seek out the drugs outside of clinical settings?” he posted. 
However, Prof Nutt is convinced that when administered appropriately, ketamine treatment does not fuel addiction. Instead, he describes cases where the drug has actually been used medically in conjunction with psychotherapy to treat a recreational ketamine addiction.
“While previously the person was using ketamine just to get high and basically to obliterate, we were using it to get them to a state where they can actually engage in different kinds of thinking,” he says.
As with all street drugs it can be ‘cut’ with other white powdered substances, which may or may not be harmful. In a therapeutic setting ketamine is administered via an injection or through an intravenous infusion.
According to Prof Nutt, the therapeutic dose is typically higher than that used by many people experimenting with ketamine for recreational purposes. On the street ketamine is sold as a white powder and normally snorted.  
“Recreational doses usually start off low, and then because of tolerance, they get higher and higher and higher,” he says. “The dose used medically is more than the beginner’s recreational dose, but it’s less than an addict’s recreational trips.” 
He believes that the key difference relates to the mindset and intentions of an individual receiving ketamine therapeutically. 
“In both cases it disrupts brain processes but if you use ketamine just to blunt things or to come down from a night on MDMA, then you’re not going to get a therapeutic response because it’s doing a different job,” he says. “If you use it to break down your resistance to facing your problems or relive your traumas with a therapist, that can push you in a completely different direction.” 
The acute effects are very rapid, with some people noticing a difference within a couple of hours. One study found that 71 per cent of depressed patients respond in some way to a ketamine dose within 24 hours. 
But while Stull and other patients began to experience a major shift in their symptoms within a matter of days, there are still around 50 per cent of treatment-resistant depression sufferers who do not respond at all. 
Prof Young says we still need to understand more about why ketamine appears to work in some patients but not others, as well as the reasons behind the significant variability from one patient to another.
“Some patients may respond very quickly; others, it takes a few weeks to build up,” he says. “There’s a big question about how long you continue before deciding it doesn’t work. There’s no definitive answer to this, but you probably would want to have it twice a week for four weeks before we say it’s not working.” 
At the moment, receiving ketamine injections on the NHS requires depression patients to be referred to one of a small handful of specialist centres around the UK. 
At the moment, many patients seeking ketamine therapy in the UK are forced to go privately. Prof Nutt works with a clinic called Awakn Life Sciences, which operates a centre in London where a complete course of ketamine therapy costs more than £7,000, making it inaccessible for many patients. 
In 2019, the US Food and Drug Administration regulator made headlines by licensing a new ketamine-related drug called Spravato as a medication for depression. However, while this is available on the NHS in Scotland, the National Institute for Health and Care Excellence (NICE) watchdog, which decides which drugs are approved for NHS use in England, has yet to greenlight it.
Prof Nutt is frustrated that ketamine is not available more widely as a treatment for depression in the UK, despite the evidence for its efficacy; decisions he feels are related to mistaken perceptions of the cost of the drug.
Though ketamine therapy is admittedly much more expensive than Prozac, it will likely only be used as a last resort and is far more cost-effective than admitting someone to a psychiatric ward.

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