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Gerard Sanacora, a professor of psychiatry at Yale University, has treated hundreds of severely depressed patients with low doses of ketamine, an anesthetic and popular club drug that isn’t approved for depression.

This sort of “off-label” prescribing is legal. But Sanacora says other doctors sometimes ask him, “How can you be offering this to patients based on the limited amount of information that’s out there and not knowing the potential long-term risk?”

Sanacora has a simple answer.

“If you have patients that are likely to seriously injure themselves or kill themselves within a short period of time, and they’ve tried the standard treatments, how do you not offer this treatment?” he says.

More and more doctors seem to agree with Sanacora.

Dozens of clinics now offer ketamine to patients with depression. And a survey of providers in the U.S. and Canada showed that “well over 3,000” patients have been treated so far, Sanacora says.

A number of small studies have found that ketamine can do something no other drug can: it often relieves even suicidal depression in a matter of hours in patients who have not responded to other treatments.

Ketamine’s potential as an antidepressant was recognized more than a decade ago. And studies done since then provide “compelling evidence that the antidepressant effects of ketamine infusion are both rapid and robust, albeit transient,” according to a consensus statement from a task force of the American Psychiatric Association. Sanacora is one of the task force members.

But there are still a lot of unanswered questions about ketamine, says James Murrough, an assistant professor of psychiatry and neuroscience at the Icahn School of Medicine at Mt. Sinai in New York.

“We haven’t had large-scale trials. We don’t know how much or how often it should be given for it to be effective or safe,” says Murrough, who is an author of a review of ketamine published in the journal Nature Reviews Drug Discovery.

Doctors know a lot about the short-term effects of ketamine because it has been used as an anesthetic in emergency rooms for decades. But there’s still not much information about the effects of using ketamine for years.

That’s worrisome because ketamine’s antidepressant effect tends to wear off after a few days or weeks, meaning patients need repeated infusions to keep depression at bay, Murrough says.

Still, Murrough thinks the case for using ketamine is much stronger than it was just a few years ago.

“There’s warranted caution that’s balanced with an optimism that says we’ve never had a new medication for depression since the era of Prozac,” Murrough says.

Prozac arrived in the 1980s, and became the first of a new class of depression drugs that target the neurotransmitter serotonin.

Ketamine acts on a different neurotransmitter called glutamate. The drug’s success has pharmaceutical companies excited about the possibility of creating a whole new class of drugs for depression, Murrough says.

“Companies are reopening programs,” he says. “They are pulling [old] drugs off the shelf that they know act on the glutamate system.”

One promising candidate is a chemical sibling of ketamine called esketamine. It’s now in the final phase of testing before consideration by the Food and Drug Administration, which designated esketamine as a breakthrough therapy.

And esketamine is just one of several ketamine-like drugs in development, says Sanacora, who consults for companies developing these drugs.

“This is probably the most interesting and exciting new development that I’ve seen in my career, and probably going back over the past 50 to 60 years,” he says.

The benefits of illegal drugs such as ketamine are widely known, yet the focus is still on antidepressants of doubtful value

Ketamine’s potential for fighting depression has been studied for years. Current reviews conclude that it is highly effective against depression – a promising new medicine, but potentially dangerous, both physically (you can lose your balance) and psychologically (it can produce psychotic-like states). But how does it work?

First-line antidepressants are almost exclusively what are called selective serotonin reuptake inhibitors (SSRIs), with the emphasis on “selective”. That means they keep serotonin in the connections between neurons (the synapses, where all the action is) far longer than it would normally remain. Serotonin is a neurochemical that appears to moderate the information travelling between neurons. The theory is that depression grows from too much information, consisting mainly of self-criticism, negative memories and negative expectations, cycling in an endless loop. More serotonin should diminish this unhelpful deluge.

But do SSRIs actually work? Despite great promise, the big picture reveals a mixed bag of results – and opinions. Many studies have revealed extremely limited effectiveness for SSRIs when compared with placebos. These disappointing results drew attention to studies conducted by the pharmaceutical companies, in which poor results were systematically buried. (Did we really trust the drug makers to present an unbiased picture?) Yet other well-controlled studies suggest that SSRIs do help depressed people at least some of the time. The final verdict? SSRIs help some people on a good day, according to some studies and not others. Most experts agree that it would be a very good thing to find other drugs that work more reliably.

Along comes ketamine. Ketamine has been around since the early 1960s, when it became available as an anaesthetic for use with humans and animals. Its psychotropic (mind-altering) effects were soon discovered. Ketamine changed people’s perception of themselves and the world around them to a degree comparable to LSD and other psychedelics. Thus began its career as a street drug and its designation as a controlled substance. You know how the reasoning goes: we can’t let people go around changing their reality. Nevertheless, it has been used as a party drug for decades, often under the nickname “K”.

The main neurotransmitter for communicating between brain cells is glutamate. Little bundles of glutamate molecules, sent from one neuron to the next, tell each neuron how rapidly to fire – a very important message. But glutamate molecules have to enter the receiving cell through a doorway designed to welcome them. And one of the main doorways is called the NMDA receptor.

Thanks to swarms of glutamate molecules shooting into NMDA receptors all over the brain, an incredibly complex, incredibly subtle network of firing neurons creates our sense of reality. When the brain is functioning normally, the pattern of firing neurons matches what is going on in the world outside your brain. If you happen to be schizophrenic, then not so much.

What ketamine does is block many of those NMDA receptors, so the glutamate molecules have nowhere to land. Consequently, the network that fashions reality starts to fall apart. The harmony of synchronised neurons breaks down, and your perception of the world starts to drift. That’s why ketamine is called a “dissociative”. Ketamine has been used on the battlefield where wounded soldiers can dissociate from their pain. So ketamine’s main contribution is to free you from what’s in front of your face.

Nobody knows exactly how ketamine nails depression. Yet I don’t think it’s so mysterious. When people are depressed, they undergo the same cycling thought patterns over and over again: I’m no good. Nobody really likes me. I don’t deserve to be happy. I’m too selfish, too greedy, too unpleasant. It’s called rumination. What’s more, the negative self-thoughts reinforced through rumination promote feelings of sadness, shame and hopelessness, while those feelings reinforce the spiralling negative thoughts. A vicious circle indeed.

What ketamine might do is break the cycle, perturb the relentless repetition of depressive self-appraisals. The “reality” that you are a bad, worthless person gets fragmented, because ketamine fragments everything you think you know. Ketamine permits you to sojourn into different psychological realities. That is one of the risks associated with clinically dispensed ketamine, but for depressives, a little holiday from the daily grind of pessimism might be a welcome relief.

It would be great if ketamine-based treatment moves beyond its interminable research phase: is it really safe? Can we be absolutely sure? Let’s not forget that booze can also make you lose your balance, and it’s quite legal. And depression itself can generate psychosis, often for lengthy periods. Ketamine doesn’t look so bad on balance.

I would like to see ketamine become available, at least through the safeguards of the doctor-patient relationship, to the millions who suffer depression. But there is a lesson to be learned from ketamine’s protracted debut. We are so afraid of the drugs people take for fun, to feel good, or at least to feel different for a few hours, that we ban them almost reflexively and punish those who use them. Why? What’s so bad about adults taking a vacation from the imperious reality we call “normal” – a reality that, sorry to say, isn’t decreed by God or nature but by culture, by a semi-arbitrary history of conventions? We should divert some of our hyped-up fear of abuse potential into a societal experiment, a sandbox, so to speak, for exploring the benefits of various popular drugs – drugs (such as ketamine, marijuana, ecstasy and psilocybin) that are illegal because people sometimes want to take them. Surprise, surprise: these drugs might just help people feel better.

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Party drug’s power to fight depression puzzles scientists.

The anaesthetic ketamine — a hallucinogenic club drug also known as Special K — has tantalized researchers who are seeking new ways to treat depression. The drug can lift a person’s mood in hours, even when depression is severe. But several ‘ketamine-like’ medications have failed to alleviate depression in clinical trials over the past decade.

Now, some researchers think they know why. Emerging evidence suggests that scientists have misunderstood how ketamine fights depression. So they might have attempted to mimic the wrong biological mechanism when designing drugs to improve mood while avoiding the disorienting ketamine high.

On 20 May, researchers at a meeting of the Society of Biological Psychiatry in San Diego, California, will present results suggesting that some of ketamine’s power comes from its ability to affect brain cells called glia, which support neurons. Their finding adds to recent studies contradicting a long-held idea that the drug works mainly by blocking proteins called NMDA receptors, on the surface of brain cells, which transmit signals between those cells.

At the upcoming meeting, a team led by neuroscientist Mark Rasenick of the University of Illinois at Chicago will report on tests of antidepressant drugs in cultured rat glial cells. All of the drugs that the researchers studied caused a cluster of proteins to shift position in the glial cells’ membranes, signalling to the cells to form new connections with their neighbours. But ketamine produced this effect in 15 minutes, as compared to 3 days for conventional antidepressants.

Moreover, drugs that block NMDA receptors but are not antidepressants did not show the effect at all. This suggests that ketamine’s ability to bind to NMDA receptors might not be its primary weapon against depression.

Rasenick’s team is not the first to suggest a different target for ketamine. A paper published in Nature in May 2016 concluded that one of ketamine’s breakdown products — not the drug itself — probably lifted depression in mice¹. And this compound affected cell proteins called AMPA receptors, instead of NMDA receptors.

The team behind the study plans to test the breakdown product in clinical trials later this year. But study co-author Carlos Zarate, a psychiatrist at the US National Institute of Mental Health in Bethesda, Maryland, says that it is too early to abandon the NMDA-receptor hypothesis, and more data are needed.

Others agree. “We have to be careful not to interpret [the latest] clinical findings as definitively negative,” says Gerard Sanacora, a psychiatrist at Yale University in New Haven, Connecticut. Rodent studies have shown, for example, that blocking NMDA receptors can have an antidepressant effect².

And there could be more-prosaic explanations for why so many ketamine-like drugs that target NMDA receptors — including candidates from the drug giants Roche, Pfizer and AstraZeneca — have failed in clinical trials. Participants might have received doses that were too small or infrequent to buoy their moods. And in trials with control groups, the placebo effect can make it difficult to determine whether a psychiatric drug is working.

Ketamine copycats

Creating an effective substitute for ketamine remains the goal for many researchers. Although a growing number of physicians prescribe ketamine for their patients, the drug must be administered intravenously. It can also produce disorienting ‘out of body’ feelings, and it has the potential for abuse.

The companies that are still testing drugs to inhibit NMDA receptors are trying to make sense of the latest findings on ketamine and its would-be imitators. “We do need to tease all this apart,” says David Nicholson, chief research-and-development officer at Allergan in Parsippany, New Jersey. In February, Allergan began treating around 500 people with a molecule called rapastinel, which binds to NMDA receptors and showed promising results in earlier trials.

Yet, the most enduring mystery involves ketamine itself, as researchers try to untangle what makes the drug so potent. Alan Schatzberg, a psychiatrist at Stanford University in California suspects that ketamine could act against depression in many ways: jump-starting the process by some as-yet-unknown mechanism, perhaps, and then blocking NMDA receptors to permanently rewire the brain.

Schatzberg also points out that ketamine can act similarly to morphine and rapidly bind to opioid receptors in the brain, which could explain why its effects are apparent within hours. And some studies have found that people with depression are more likely to benefit from ketamine if they do experience that out-of-body feeling, suggesting that it might be related to the drug’s main mechanism³.

In the meantime, the hunt continues for drugs that can replicate ketamine’s mood-boosting power. That could be difficult, says Steven Levine, a psychiatrist and president of Ketamine Treatment Centers in New York City. “Ketamine is a dirty, dirty drug,” he says. “It goes a lot of places, it does a lot of things.”