Dr. Terrence Early, a psychiatrist in Santa Barbara, CA, is convinced he's found the holy grail of care for severely depressed patients — those who've tried a litany of antidepressants, and even electroconvulsive therapy, to no avail. "These are the very sickest patients," Early, who estimates that he's treated 80 people over 500 sessions with the method, says. "And the results have been dumbfounding."

The surprising source of these stunning outcomes? Ketamine — used among medical practitioners as an anesthetic, but perhaps best known as "Special K" and popularized as a recreational drug because of its powerful hallucinogenic properties. But in lower doses, Early is convinced that ketamine can also make a meaningful difference for those suffering from severe depression: in his own practice, he's seen "the vast majority of patients" improve after a single treatment.

It's unclear how many US psychiatrists are currently treating patients with ketamine, though Early — who runs an informal online network for practitioners using the drug — estimates that the figure runs in the low dozens. And according to a growing body of research, Early and that cohort might be onto something. This week, investigators behind the largest clinical trial on ketamine yet — an evaluation of 72 patients out of Baylor College of Medicine and the Mount Sinai School of Medicine — announced the impressive results of their new study at the annual meeting of the American Psychiatric Association.

All of the patients in the trial had been diagnosed with treatment-resistant depression — a description that characterizes around one-third of those suffering from depression — meaning they'd tried at least two conventional antidepressants without experiencing relief. Investigators randomly divided those patients into two groups: half received a dose of ketamine intravenously over a span of 40 minutes, while the other half received an IV drip of midazolam — an anesthetic that doesn't seem to have antidepressant properties.

Within a period of 24 hours, 63.8 percent of patients who'd received ketamine experienced marked improvements in depressive symptoms, versus 28 percent of those in the placebo group. And after a week, nearly half of the ketamine patients were still benefiting from that single dose.

The findings build on several earlier studies comparing ketamine to a placebo, most of which have reached similar conclusions: in doses with around 25 percent the potency as those used in anesthesia, ketamine often improves symptoms of depression quickly, and those benefits linger for anywhere from three to 14 days. This latest research, however, is particularly compelling because it compared ketamine to another anesthetic, rather than an inert placebo. "We wanted to pit ketamine, head-to-head, with something that patients would notice [and] that would affect their central nervous system," says study co-author James Murrough, MD, an assistant professor of psychiatry at Mount Sinai. "It's a higher bar to test the hypothesis that this antidepressant effect of ketamine isn't a side effect of being anesthetized."

Already, experts have devised a theory to explain how ketamine treats depression: It acts on the neurotransmitter glutamate — in contrast to conventional antidepressants, which instead target serotonin, dopamine, and norepinephrine. The mechanism, researchers suspect, elicits a surge of glutamate, which in turn stimulates new neural connections, essentially repairing circuitry damaged by depression. In fact, ketamine works so quickly that some patients experience noticeable mood changes within four hours — a stark contrast to the six-week period required for traditional antidepressants to either take hold or prove ineffective.

"You can tell within hours if a patient is going to respond or not," says John Mann, MD, a professor of translational neuroscience at Columbia University who has done extensive research on ketamine. "Compared to a waiting game of more than a month, that's a very big thing."

But despite ketamine's promise — and the handful of psychiatrists and patients who already swear by it — those investigating the drug warn that it's too soon to be hooking patients up to IV drips. Research thus far has only studied ketamine on small patient pools, and investigators have yet to determine optimal ketamine doses or methods of delivery. "Anyone using ketamine clinically right now ... is doing so on the basis of relatively limited experience and highly limited trial data," Mann says. "There are still important clinical questions that need to be addressed."

A comprehensive understanding of ketamine's short and long-term side effects also remains to be established — although side effects detected thus far appear relatively mild, and tend to ebb off within a few hours. Some patients suffer from slight elevations in blood pressure. Others experience what one psychiatrist using ketamine, Dr. William Goldman, describes as "similar to using nitrous oxide at the dentist ... or a short-acting high from marijuana" — essentially milder versions of the hallucinogenic effects that ketamine yields when ingested in higher quantities. And compared to the potential side effects of conventional antidepressants, which can include appetite changes, sexual dysfunction, and insomnia, ketamine's downsides appear downright benign. "That's an important bottom line here," Murrough says. "None of the side effects we've seen have persisted beyond the treatment session."

It may take years, researchers say, before ketamine is FDA-approved to treat depression: that process will require significantly larger clinical trials that also evaluate long-term outcomes. And because ketamine is already off patent — meaning not particularly profitable — pharmaceutical companies aren't interested in funding those studies, Murrough notes, though several are currently devising drugs that act similarly to ketamine. "What we need are the tens of millions of dollars to move this research along," he says. "Someone is going to have to invest, but the question is who's interested."

Because the drug is already approved as an anesthetic, doctors like Feary and Goldman can continue to prescribe ketamine, in what's known as "off-label" use. At least, for now. "Those of us that do ketamine therapy will run into resistance," Feary anticipates. "I have no doubt that some overzealous regulator will come shut us down eventually."

But even Murrough, who cautions against the practice and doesn't use ketamine on his own patients, has a tough time criticizing those choosing to do so. "That clinicians are doing this speaks to the desperation of these patients," he says. "Who am I to tell them, ‘sorry, but you need to wait five years for more research before you can feel better'?"