Scientists are reformulating the party drug Ketamine to remove its terrible side effects

Having begun life as an anesthetic in 1962, then quickly co-opted as a party drug, ketamine is now the source of much excitement among psychiatrists for its potential to treat depression. There is one major challenge, though, as anyone who’s ever seen someone out of their mind on “Special K” can well imagine: the negative and potentially dangerous side effects of the drug mean it’s rarely used in clinical research. And so, to advance the field, neuroscientists are trying to figure out just what makes Special K so special. Their hope is to create a treatment with all the positive effects of the original drug, and none of its downsides.

The latest step towards this goal, from a team of researchers led by neuroscientist Lisa Monteggia at the Peter O’Donnell Jr. Brain Institute at the University of Texas-Southwestern, was published this week in Nature and highlights the importance of one particular receptor in the brain. It follows on from research last year where scientists showed that hydroxynorketamine, a chemical byproduct of ketamine created as the body breaks the drug down (a “metabolite”), effectively reversed depressive-like symptoms in mice without the negative side effects.

Monteggia’s study shows that this particular metabolite blocks the NMDA receptor in the brain. Earlier work shows that ketamine also blocks this receptor and so, in finding that the metabolite has the same effect, Monteggia believes she’s discovered the key to creating a ketamine-like antidepressant. “It pinpoints the fact that it is this receptor we need to engage or block to trigger a rapid antidepressant effect,” she says. “This is the target; this is the pathway.”

The research was conducted on mice, so further work in humans is necessary before any discovery can be put into practice. But the results allow researchers to narrow their focus in trying to recreate the positive effects of ketamine.

“We’re trying to screen current drugs out there to see if they could have the same sort of effects molecularly,” says Monteggia. “Others are trying to go about it in terms of creating novel drugs.”

A Ketamine-like drug without the side effects could prove to be a powerful step forward in the treatment of depression, as studies show that it reduces symptoms in a matter of hours, including for the one-third of patients who are resistant to existing forms of antidepressants. The drug triggers entirely different mechanisms from the current US Food and Drug Administration-approved classes of antidepressant (such as SSRIs, like Prozac, and NRIs, like Wellbutrin) and so seems to be effective—and fast—at treating those who don’t respond to existing drugs.

“Those [who don’t respond to existing antidepressants] are the ones who become most at risk of suicide,” says Monteggia. “If you could identify more rapid antidepressants, it could have very real implications for people not only with depression, but who are potentially suicidal.”

Though trials are promising, neuroscientists are still uncertain about the long-term effects of repeatedly taking ketamine. Taking the drug can cause hallucinations and severe nausea in the short-term, while repeated doses can lead to impaired memory, panic attacks, and bladder problems.

These side effects of ketamine, along with a political aversion that developed from its use as a party drug, mean its use is tightly controlled and not currently approved by the FDA for treatment of depression (though it is approved as an anesthetic). As a result, patients can only access it at in-patient psychiatric units or expensive “ketamine clinics” that offer IV ketamine infusions under clinical supervision. (This is known as “off label” use, where a drug approved by FDA for one specific use is used for a different condition; this practice is carefully regulated, but not illegal.)

Monteggia hopes that a ketamine-like drug with fewer side effects will not only be be far more widely used, but will advance understanding of depression overall, and the various ways of treating it. In understanding exactly how ketamine works, she hopes to uncover details about the mechanisms that can alleviate depression. The precise workings of existing drugs are not well known but, by identifying the processes activated by ketamine, Monteggia hopes to understand depression itself more fully.

“Can we use this ketamine finding to understand how widely prescribed antidepressants work? Is there a point where they [the effects of Prozac and Ketamine] intercept?” she asks. In the long term, she hopes neuroscientists will build on this research to figure out how to prescribe different antidepressants based on individual differences in depression. “This has been one of the most exciting developments in the field of psychiatry in a long time,” she adds.

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