Non-psychedelic ketamine could be the next best way to treat depression

In 2019, the FDA made the groundbreaking decision to approve a form of ketamine as a clinical treatment for patients with treatment-resistant depression, a condition estimated to affect up to three million American. The drug, called Spravato, was the first hallucinogen approved to treat mental illness. This approval, along with large-scale clinical trials of LSD, MDMA, and psilocybin (the active ingredient of magic mushrooms), marks a major shift in the medical community’s perception of psychedelics. : Instead of treating them as purely drugs of abuse, many clinicians are now looking to repurpose them as a therapy.

So far, Spravato has been revolutionary to the field of psychiatry in general, in part because it appears to work so differently than other existing antidepressants. The drug, John Krystal, Chief of Psychiatry at Yale-New Haven Hospital told The Daily Beast, “made us question most of our common assumptions about treating depression. ”

“All previous antidepressants required weeks to months for meaningful clinical improvement, while ketamine resulted in rapid clinical improvement, sometimes within hours of dose,” says Krystal. Firstly.

That’s great news for those looking for relief. But there’s a confusing wrinkle to this early success: We don’t even really know how ketamine works to treat depression.

Mystery isn’t necessarily a deal-breaker for mental health drugs. Lithium is one of the oldest medications used to treat bipolar disorder, and we still don’t fully understand what it does in the brain. But it To be a problem if we wanted to create a better version of ketamine — one that could treat mental disorders without sending users into the K-hole or experiencing other unwanted side effects.

Although ketamine is impressively effective in reducing symptoms of depression, it is not a perfect drug. Some users experience vivid hallucinations or become completely detached from reality. They may think they are dead, or that one of their limbs is missing. They may feel as if they are falling into another dimension, or melting into the floor, or that their body is not their own. One participant in 2015 research of ketamine reports that the world has become “like spaghetti” and thinks he’s being brainwashed, a la A Clockwork Orange.

There may be unpleasant physical side effects, such as dizziness or vomiting. Many doctors have also expressed concern about the potential for abuse and possible withdrawal effects when patients stop taking the drug.

Figuring out exactly how ketamine works could allow scientists to find or create a drug that mimics the benefits of antidepressants without the nasty side effects.

So what do we know so far? Ketamine was originally used in much higher doses as a anesthetic—It was approved by the FDA for this use in 1970. Todd Gould, a neuroscientist at the University of Maryland, told The Daily Beast that the prevailing theory is that ketamine relieves depression through a similar mechanism. similar to that of an anesthetic: by inhibiting a type of receptor in the brain called the NMDA receptor. It is thought that by stop these receptors on neurons produce the inhibitory neurotransmitter GABA, which actually removes inhibition in certain parts of the brain. Through a series of processes, this leads to nerve cells forming new connections with each other, alleviating symptoms of depression.

While there’s no doubt that ketamine sticks to the NMDA receptor, some scientists, including Gould, suggest there’s more to the story. Other drugs Also inhibiting this receptor does not have the same potent and consistent antidepressant effects as ketamine.

Some scientists are still trying to figure out why ketamine and other NMDA receptor blockers have such different effects, but other researchers pursuing the depression-ketamine link have turn their attention elsewhere.

“[Spravato] led us to question most of our common assumptions about the treatment of depression.”

– John Krystal

Gould, for example, thinks it might not be the ketamine that treats depression, but one of its metabolites. These metabolites are modified versions of ketamine, which are produced when the drug is processed by the liver to make it easier to remove ketamine from the body.

In 2016, a research team led by Gould and Carlos Zarate Jr., a neurobiologist at the National Institutes of Mental Health, found that one of these metabolites reduced depressive-like behaviors in mouse. The metabolite – called (2R, 6R) -HNK – also appears to have fewer negative side effects than ketamine. Although it is difficult to tell if a rat is climaxing or experiencing hallucinogens, the researchers found that while ketamine causes loss of coordination and abnormal responses to sensory stimuli in rats, the metabolite does not.

But whether these results translate to humans remains to be seen, as human experiments are just beginning. The National Institute of Mental Health is currently working on Clinical stage 1 trial, to evaluate the safety of this metabolite in 48 healthy volunteers.

Krystal said the metabolite hypothesis was an interesting one, but he pointed to a research in humans measured concentrations (2R, 6R)-HNK in the blood of patients after they received a ketamine infusion. This study shows that higher levels of (2R, 6R)-HNK are indeed associated with decreased response to antidepressants.

This is the exact opposite of what scientists expected to see. One possible explanation is that the researchers measured metabolite levels in the blood, which is much easier and safer than trying to get measurements from central nervous system bathing fluids. However, it remains unclear how levels of this metabolite in the blood reflect levels in the brain, where mental health effects can actually be felt. However, Gould, one of the researchers involved in the study, admits that the findings are confusing. Further research in humans is needed to find out what is going on.

While the original mechanism of action remains controversial, Gould says there is more agreement on the drug’s side effects. In general, scientists agree that, one way or another, ketamine activates a brain pathway known as mTOR pathways that help nerve cells make and fortify new connections with each other. Increased neuronal connectivity may be the real cause of antidepressant responses. Scientists at Yale University found some support for this when they blocking the mTOR . pathway in animals and found that exposure to ketamine no longer resulted in new neuronal connections or antidepressant effects.

Some scientists suggest that the mTOR pathway could be a good shortcut to improving mental health, potentially allowing us to start forming new connections and alleviating depression without having to worry about it. unpleasant side effects of ketamine.



Michael Verbora, Field Trip’s medical director, holds a pack of Ketamine lozenges at a psychedelic therapy clinic in Toronto, Ontario, Canada, on August 28, 2020.


With this in mind, scientists at Yale and Navitor Pharmaceuticals recently developed a drug that activates the mTOR pathway. In mice at least, this drug seems to mimic the effects of ketamine by increasing neuronal connections and producing even more promising antidepressant effects, school entrance exam results from small Phase 1 studies in humans seem to indicate that this drug is relatively safe and effective at reducing depressive symptoms. ONE Phase 2 clinical trial of this mTOR activator, involving 400 people with treatment-resistant depression, will begin this month.

This could be the start of a really effective solution to treatment-resistant depression – a solution to avoid cumbersome surgery and implants, and also avoid taking the patient on a hallucinogenic ride for hours on end. For Gould, accelerating human clinical trials of these new drugs is of paramount importance. “I can study this in mice until they come home,” he said. “But we’re not trying to cure depression in mice.” Non-psychedelic ketamine could be the next best way to treat depression


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