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Ketamine placebo effects


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Randomized trial of ketamine masked by surgical anesthesia in patients with depression​

In conclusion, a single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder.

The evidence strongly suggests that Ketamine does not actually have any anti-depressant effects aside from placebo.
More research is needed.

Paper attached.


  • s44220-023-00140-x.pdf
    3.7 MB · Views: 4
Interesting. I have no personal experience with Ketamine's anti-depressant effects because I've never ingested it in a state of mind that would benefit from such effects, but there are more than a few studies that have concluded a statistically significant anti-depressant effect of ketamine compared to the control sample. Here are two:
Antidepressant effects of ketamine in depressed patients
Ketamine as an antidepressant: overview of its mechanisms of action and potential predictive biomarkers

I've also seen anecdotal evidence by a few people with severe treatment-resistant depression (one of whom lost both of his sons to suicide), which swore by ketamine and said it literally saved their lives.

I suppose more research is needed indeed. If Ketamine turns out to have no significant anti-depressant properties for the majority of people, then you can always opt in for MDMA treatment, as it definitely has proven anti-depressant effects.

Thanks for sharing!
I can't say I place any faith in testimonials when it comes to this type of thing.

Ketamine does affect glutamate, that is how it potentiates psychedelics.

In the first paper you link to they used saline solution as the control, this is the problem, the people knew they didn't get ketamine, which is considerably more psychoactive than saline is. That's why the later paper is so relevant, because people who thought they had been given ketamine reported mental health benefits regardless of if they had been given ketamine.

If Ketamine turns out to have no significant anti-depressant properties for the majority of people, then you can always opt in for MDMA treatment, as it definitely has proven anti-depressant effects.
MDMA is essentially Meth with a methylenedioxy group attached to it. It has incredibly similar pharmacology to meth and though users do report mood elevation the idea that MDMA or meth are viable antidepressants strikes me as absurd. MDMA, like meth, often leaves users feeling drained and unwell after use, despite feeling wonderful when a user is high.

There are viable and valuable antidepressant drugs out there in the world. Harmala alkaloids show considerable promise.
I cannot recommend that people take meth or MDMA as a solution to their mental health problems.

As for Ketamine, evidently just thinking you have taken it provides as much benefit as taking it.
I think that much of the antidepressant effects from ketamine are probably a result of the subjective experience it can elicit, as opposed to more concrete antidepressant mechanisms of the compound.

Remove the experiential aspect of psychedelics and I doubt that they’ll be anywhere near as effective at treating depression. The subjective experience is difficult to separate from the pharmacology here..

I don’t think that the antidepressant effects are placebo.. I just don’t think they can be reduced to purely chemical processes. But probably a bit of both going on. The tryptamine psychedelics do seem to have some interesting stuff going on pharmacologically too.

I agree about MDMA.. it does seem to make a lot of people feel depressed/drained in the days/weeks following. I couldn’t think of a worse compound to use as an antidepressant personally. But each to their own. Once in a while that experience of openness/empathy can be powerful enough that it overshadows the feeling of depletion that ensues.

The bottom line to me with a lot of these substances is that its largely the content of the experience that is behind much of the antidepressant effects.
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Remove the experiential aspect of psychedelics and I doubt that they’ll be anywhere near as effective at treating depression. The subjective experience is difficult to separate from the pharmacology here..
I have to agree here. Looking at the pharmacology is a good starting point to understanding how a substance affects you, but it will never be able to provide the full picture. That can be obtained only via personal experience and interpretational mechanisms.

Also, it seems to me that the way I've expressed my sentiment regarding MDMA has been interpreted as in recreational use of MDMA, which is not what I was referring to. There's a growing body of evidence that professional MDMA therapy carried out in certified clinics working with war veterans has tremendous long-lasting anti-depressant effects, much like psilocybin therapy has.

How or why MDMA works in this way, I won't pretend I understand. I'm just looking at the data and at those veterans' personal experience reports.

I'm not saying MDMA is the only way, or THE way to deal with mental health issues. I'm just pointing to it, as well as ketamine, as being yet another tool in the healthy individual's toolbox.
@Nydex Hey sorry I didn’t mean to discount people’s experiences with MDMA and agree it absolutely is an incredible therapeutic tool. More just meant in the chemical sense I find the lingering effects can be quite draining and depressing in and of themselves.

But it’s ability to help people to express themselves openly sure makes it a special compound and it’s no wonder so many people find it tremendously helpful.. I wouldn’t say it’s ‘basically meth’ either.. it may be structurally close but it clearly is a very different experience. But IMO it does present some of the potential pitfalls that other amphetamines can have like the feeling of being drained/depleted in the days/weeks to follow. Just speaking personally though. It is a wonderful compound :)
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Did the study account for the possibility that anaesthesia itself may have blocked any antidepressant effect from ketamine? Please could you quote from the research study to show how this was controlled for as it would help support your assertion if you can. Also, by the sounds of it all these patients had comorbidities (presumably, hence the need for surgery…) and if they were in the USA this could prove to be expensive.

[Sorry, had trouble accessing the pdf but I'll be taking a look in due course to see if any of my questions are answered there.]

From the lay article about the study:
To disentangle the subjective experience of ketamine from the biochemical effects of the drug, researchers at Stanford University recruited 40 participants who were preparing to undergo general surgery and who also had mild to moderate depression. The scientists gave the volunteers ketamine or saline as placebo right after they were put under anesthesia, but before their surgery, essentially blinding them to any psychedelic or dissociative effects. Then, for the next 3 days, the researchers surveyed the participants on their depression symptoms, scoring them on such factors as sadness, loss of appetite, and lack of sleep.

After the procedures, about 40% of the participants guessed correctly whether they had received a placebo or ketamine—no better than chance, that is—indicating that the anesthesia had done its job in masking the drug’s dissociative effects. Both groups experienced a 15-point drop in their depression scores, and about 40% of patients in both groups still had more than a 12-point decrease 3 days after infusion, meaning they were in remission for their depression.

That improvement is similar to the antidepressant effects reported when participants take ketamine and have a dissociative experience, says Eduardo Schenberg, a neuroscientist at the Phaneros Institute who was not involved with the study.

One possible interpretation is that the anesthesia itself alleviated depression. Anesthesia has been shown to help depression in other studies. However, the doses of anesthesia used in this study were much lower than those that have been used in other antidepression studies, the authors note.

It might be the case that anasthesia helps ease depression.
It also might be the case that depression is more of a problem of the mind than an issue with the brain.
The paper the other year showing that depression is unrelated to serotonin levels may relate to the topic.

At this point it appears that our species lacks a working model for explaining depression as a function of neurobiology.
At this point it appears that our species lacks a working model for explaining depression as a function of neurobiology
That is something I'm very much inclined to agree with. It appears the study maybe was compromised by the antidepressant effects of the anaesthetic itself, and the effects are not additive. Taking more ketamine might not make anyone any happier in the long run ( 😉 - speaking from experience) and it can be somewhat difficult to quantify the level of depression, or a lack thereof.

Must dash, thanks for quoting the article.
So much research has been done into the antidepressant effects of NMDA antagonists over the past few years. Even the pharmacological mechanisms are pretty well known by now. And that ketamine increases neuroplasticity in mice and human neurons is definately not due to placebo effect, or at least, i don't see how it could be.
However, i can imagine that other anesthetics and depressants can interfere with the mechanisms triggered by ketamine, as others have also suggested here.
especially when people are usually given a benzodiazepine before receiving the prime anesthetic.
Skimming through the text i didn't find any mentioning of benzodiazepines, but it is such a routine practice, that it is imaginable they just didn't even bother mentioning it.
In the discussion the authors nuance the outcome and put it in perspective:

“We review the available evidence for several potential interpretations of this result, while noting that the relatively small sample size, the unusual background of surgical anesthesia on which treatments were delivered and our two-arm study design limit broadly generalizable conclusions about ketamine’s efficacy or mechanism. To the extent that the treatment effect in the ketamine group is similar to that of other studies, our data raise the possibility that antidepressant effects of ketamine may be achieved in the absence of a typical ketamine-induced conscious dissociative experience. However, a conscious dissociative experience may yield an even more robust response, significantly greater than that seen with placebo, in a situation in which treatment-arm masking is maintained without the use of anesthesia.”

It’s difficult to make claims or conclusions on one study especially when the data is so limited.
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