Ketamine was first synthesized in the 1960s as an anesthetic, a sedative. It was useful in the rescue mission. Then in the 1980s, it became a popular club drug. It had nicknames like Special K and Cat Valium. Now, a form of ketamine, esketamine was approved by the FDA for antidepressant augmentation. So how does a drug that is so multipurpose actually work? Ketamine is what scientists call a dirty drug. It doesn’t just target one system in the brain, but dozens. It has a weak effect on opiate receptors and one study actually showed that when patients took naltrexone (which blocks opioid receptors), they did not experience the anti-depressive effects of ketamine. These same receptors are targeted also by drugs like heroine and cocaine. Most importantly, ketamine affects the glutamate system. Glutamate is used in the brain for neurons to communicate. At high doses, ketamine seems to block glutamate, making it an effective anesthetic. But at low doses, glutamate production is enhanced. This can have a variety of effects, some individuals hallucinate or feel they are losing touch with reality. It may also help build new connections or synapses between neurons. Now, when people are under stress for a long time or depressed for a long time, they can start to lose the connections. When ketamine is administered, some of those effects seem to start to reverse. It is believed that ketamine may help regenerate neuronal connections. One of the appeals of ketamine is the rapid onset of action and unique mechanism of action versus other antidepressants or even augmenting agents. Another aspect is that as many as 4 million adults in the US have treatment resistant depression, making another option appealing.

Per Dr. Andre Atoian: “Ketamine is the agent that works when most others have failed. It is something that really allows us to give patients a new hope. They’re in this situation where nothing’s really working and they’re suffering, they’re miserable.”

It’s hard to deny that ketamine’s potential effects on depression sound promising. However, Dr. Nolan Williams of Stanford University weighs in some more: “There’s still a lot we don’t know.”

He says that because ketamine manipulates so many different receptors in the brain, it’s been hard to nail down all of them. It is still unclear how it might affect different patients both short- and long-term. Researchers still have not figured out how to preserve its benefits as an antidepressant.

The challenge is how to maintain these new connections. Is it to give ketamine repeatedly? We know we can’t give it every day. It is a potential substance of abuse and it will harm the brain in that degree. Doctors still caution that ketamine should be used after many other levels of care have been exhausted.

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