Esketamine Failed in Five of its Six Efficacy Trials

The remaining esketamine trial showed a statistically significant effect that did not meet clinical significance.


In a 2020 article in The British Journal of Psychiatry, researchers Joanna Moncrieff and Mark Horowitz wrote that the buzz around esketamine (Janssen’s drug for treatment-resistant depression [TRD]) was “repeating the mistakes of the past”—promoting a drug that had unclear efficacy (and clear adverse effects) as the new miracle cure for depression.

Horowitz and Moncrieff have updated that previous analysis with another paper in The British Journal of Psychiatry. They write that further investigation has only confirmed their conclusions that esketamine has, at best, uncertain efficacy—and serious harmful effects.

They write, “Esketamine has a clinically uncertain effect at four weeks, and there are no studies with longer follow-up periods more relevant for the care of people with depression.”

According to Horowitz and Moncrieff, there have been six 4-week efficacy trials of esketamine for TRD. Five of those trials showed that the drug was no better than a placebo. However, one trial did find a slight statistically significant effect in favor of esketamine (a 4-point difference on a 60-point scale)—an effect that did not meet the threshold for clinical significance. Even drug company Janssen, which conducted the study, had used a difference of 6.5 points as the reference point.

They note that there is no long-term efficacy data; these studies only lasted for a month.

So how did this drug get approved by the US FDA? After all, the UK’s NICE rejected the drug after viewing the same evidence.

The FDA worked closely with Janssen, eventually waiving the usual requirements (such as for two clinical trials showing efficacy, usually over 6-8 weeks) and allowing the drugmaker to submit only one statistically significant result from a shorter-term efficacy trial. Janssen supplemented this with a discontinuation trial (a study of what happens after people suddenly stop taking the drug), which researchers criticized for conflating withdrawal effects with relapse.

Erick Turner, who is on the FDA’s advisory committee that approved the drug, was quoted in Medscape as saying, “Accepting just one short-term trial as being enough is a historic break from precedent.” In the same Medscape article, antidepressant researcher Glen Spielmans was quoted as saying, “Based on the evidence provided in Janssen’s application, the FDA should not have approved the drug.”

What Are the Harms?

In their previous study, Horowitz and Moncrieff also assessed the adverse events due to esketamine.

For instance, there were six deaths in Janssen’s safety trial—all in the group that took esketamine. Three of them were deaths by suicide, and two of those people reported never having suicidal thoughts before.

There were also six car accidents in the esketamine group, one of which was fatal. (Ketamine use has been linked to car accidents in the past because of its dissociative effects.) But the FDA considered these accidents to be unrelated to the drug.

Ketamine is also associated with bladder damage, heart attacks, and strokes. Sure enough, of those taking esketamine, one person died of a heart attack, another died of heart and lung failure, and one person had a non-fatal cerebral hemorrhage. In addition, approximately 20% of those taking esketamine had bladder problems after taking the drug.

In the current paper, Horowitz and Moncrieff also note that the supposed “antidepressant” effects of esketamine are indistinguishable from the “high” that recreational users experience when they use ketamine.

Horowitz and Moncrieff write:

“It is not clear how drug-induced euphoria and antidepressant effects can be distinguished. Jauhar argues it is the persistence of the effect that marks it as ‘antidepressant,’ but, as described above, the esketamine trials do not confirm that a clinically relevant effect occurs.”

In conclusion, esketamine failed five of its six trials and has serious adverse effects. It causes bladder problems in at least 20% of those taking the drug. It is also linked to increased suicidality and car accidents, among other harms.



Horowitz, M. A., & Moncrieff, J. (2021). Esketamine: Uncertain safety and efficacy data in depression. The British Journal of Psychiatry, 219(5), 621-622. DOI: (Link)


  1. My schizophrenia warned me not to have anaesthesia during an operation. Embarrassed, I tried to explain to the anaethetist why without sounding odd. He got a bit shirty. He told me he would think it through. He said he might give me something less anetheticish. I was not pleased at being coerced but could see he did not want me awake.
    Long story short, after the gurney wheeled me off to theatre in a pre op pillow of intravenous vallium I came around some time later, and back on my hospital bed proper, to a continuous uncontrollable nightmare bad trip where my face was directly in front of what looked like an up close boiled egg. It was a hallucinated a bald man’s head that was dayglow luminous yellow with oggling eyes with no whites and out of his mouth came a writhing dripping dark blue tongue. Then one nonsensical landscape scene after the other after the other sped past my bedazzled brain as if I was looking out the window of a high speed train, but it was not me moving, it was the hundreds of scenes whopping into my vision unstoppably and neverendingly, and then back came the boiled egg yellow devil man head, then the hundreds of scenes, then the hideous lemon yellow head again with the mocking dark blue tongue. Exhausted, I gazed up at the hospital clock on the wall and it said 6.05 pm, realizing I was stuck paralysed in the bad trip from anaesthetic effects I tried to sleep but with my eyes closed the hallucinations got worse. I hoped to sleep off the toxic hell and eventually through force of will I drifted off asleep for hours but when I looked at the ward clock it said 6.14 pm. Only 9 minutes of sleep. So I tried again and mangaged another few hours but when I opened my lids the clock said 6.23 pm. Only another 9 minutes. And still the MacDonald’s Happy Meal lemon yellow coloured devil face was laughing into my terror. Then my consciousness cleared like a silken scarf slipping off, as shivery and fast. I gradually sat up in my hospital bed with massive wobbly relief, only to vomit up six weighty bowls of blood.

    Ketamine. That’s what the letter said in my discharge notes.

    Next op I want the whiskey bottle and a torn strip of the anaesthetist’s shirt as a rag to gnaw. Nothin else.

    Was my schizophrenia right to warn me to refuse anaesthetic?

    And was that warning from my schizophrenia….

    or my ability at prophecy?

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  2. Yes, your schizophrenia was indeed right when it told you esketamine was bad for you. Unfortunately, your schizophrenia couldn’t tell you about ketamine antagonists and the anesthesiologist didn’t know anything about the subject, which I can’t reveal if I want a comment to actually get printed.

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  3. I’ve known for a long time about the corruption of the FDA, but for some reason approval of this drug was especially, dare I say it, depressing. Maybe it’s because of the blatant disregard for good science and patient welfare without even an attempt to justify a bad decision.

    What can we trust the FDA to do right? Can we even believe its endorsement of the Covid vaccines? Some drugs have helped people, but are these a minority of all those approved?

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  4. It seems what is crucially missing from the conversation here are the psycholytic effects of ketamine. It tends to bring out a lot from the unconscious and often makes it easier to approach it then it would be sober. I am not surprised that when not addressing this aspect at all the results are mixed at best.

    Merely numbing and dissociating while increasing neurological fluidity will not cure depression and can backfire. This should not be surprising.

    That being said, while I did receive benefits from ketamine when combined with mindful introspection, I can also not confirm that it has profound long-lasting effect against depression, but clearly for some people it can have that. But there is no doubt in my mind it can be very helpful for accessing a new perspective and as such has a role to play in the treatment of depression.

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  5. One of the problems I have with commenting is a result of having familiarity with orthomolecular medicine for 45+ years. Something that is old hat for me, such as nutrient therapy for schizophrenia syndromes, is bizarre and strange for readers who have psychosocial beliefs about the syndromes’ origins, so I’ll inadvertently write things that get my correspondence sent to the electronic wasteland instead of getting posted on the site.

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  6. It was or should have been the deaths associated with this drug that would render un-useable or ineffective. This drug may not have had the backing of big names, though, like other drugs, etc. that do and “pass” despite deaths and other awful side effects. If it weren’t for the deaths it would have been smooth sailing for this drug whether it allegedly worked or not. But, we need to be honest, there are no drugs that can cure or alleviate depression. The only way the drugs that are on the market do is basically by numbing the person into a zombie so they don’t feel anymore—which is a “relief” from the depressive symptoms. However, making people into zombies also produces brain damage. The most important issue is this: if you take any drug and think it’s making you less depressed, anxious or whatever you have either been brainwashed or you’re lying to yourself or probably both. Drugs are not put on Earth to make us feel better. There are a million ways to feel better and only you can decide what works for you—but drugs, as in psych drugs (both psychiatric and psychadelic) do not work and are not meant to work. But then this article is not meant to point that out. It’s just meant to point out another data failure in using humans as “guinea pigs” in another dangerous drug experiment. Thank you.

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  7. We need to eliminate the P Value in statistical/clinical research. Thats the only way to debunk all of these worthless psycho babel bullsh*t a*s fu*king pseudo “illnesses.” And the drug companies who profit off of making drugs that seemingly claim to work but never actually do. And only end up causing more harm than good. And not to mention would be one step closer to thoroughly debunking, retiring and burying all of the moral/social deviancy labels only meant to enslave, corral and otherwise control people. Most especially given the fact that these “illnesses,” have never even measured up let alone even been able to achieve even statistical significance. Atop the fact that they literally went off and made their own criteria as to what they think is “clinically significant.” Dear Jesus, Lord Help Us All.

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