21 ms·

Ketamine no better than placebo at alleviating depression, unusual trial finds

ablyveiled 3y ago
As an ex-depressive, the best cure for depression I've found is a period of ketogenic dieting.
stbenjam 3y ago
Ketamine saved my life. It’s proven to be extremely effective against suicidal ideation. The trip is definitely part of it. I’ve switched to shrooms and one trip every 3-6 months seems to reliably keep depression and panic disorder at bay. It did require some work and I really had to process some awful memories from my childhood. But these things did more for me than years of psychiatric meds ever did - literally dozens of them. Mirtazapine made me gain weight - 60 lbs in a year. Prozac gave me bruxism and I cracked 3 dental crowns in a month. Effexor turned me into a suicidal yet somehow also emotionless zombie. I got addicted to Ativan and couldn’t sleep without it. I’m off it all, and happier than I’ve ever been.
peterlk 3y ago
> In a new study that is yet to be peer reviewed Thank you very, very much to the author for saying this
- coldtea 3y ago
  Even if it was peer reviewed, most published studies are non-replicated/bad methodology BS. So "yet to be peer reviewed" means the study paper is closer to "random generated garbage text" than to "important insight".
- passwordoops 3y ago
  For all practical purposes, peer review is mostly useless today. More often than not, it's either: -a cursory glance by someone who doesn't have time to care -a highly detailed critique from someone who will either be scooped or proven wrong, so they're looking for any reason to reject the paper, good or bad -a grad student who puts in the effort but probably still lacks the experience for a good review And if peer review actually was useful then the false cure for MS [0], arsenic-based life [1], or vaccines-cause-autism [2] would all be DOA and never been published in major journals to so much PR fanfare. Heck, most of Retraction Watch wouldn't be a thing [3]. [0] https://www.statnews.com/2017/11/28/multiple-sclerosis-paolo-zamboni/ https://www.statnews.com/2017/11/28/multiple-sclerosis-paolo... [1] https://phys.org/news/2012-07-scientists-nasa-arsenic-life-untrue.html https://phys.org/news/2012-07-scientists-nasa-arsenic-life-u... [2] https://retractionwatch.com/2011/01/06/some-quick-thoughts-and-links-on-andrew-wakefield-the-bmj-autism-vaccines-and-fraud/ https://retractionwatch.com/2011/01/06/some-quick-thoughts-a... [3] https://retractionwatch.com/ https://retractionwatch.com/
  - junon 3y ago
    Man I remember the arsenic-based lifeforms thing, always wondered what happened to that. I didn't know it was ever debunked.
  - replygirl 3y ago
    > a highly detailed critique from someone who will either be scooped or proven wrong, so they're looking for any reason to reject sounds like an ideal reviewer, tbh
    - Georgelemental 3y ago
      "Reason" might be "major flaw in your statistical analysis", but it could also be "you should have cited my paper" or "insufficient jargon."
      - replygirl 3y ago
        I'd want to hear that out and make sure I'm not mistaking "I've done some prior work that enriches yours" for "You should have cited my paper" or "You're not communicating clearly and succintly" for "insufficient jargon"
cameronh90 3y ago
> They gave volunteers ketamine while they were under general anesthesia, theoretically preventing the participants from going on a trip. Maybe it's the trip that helps.
- coldtea 3y ago
  Not to mention other possible effects of being in general anesthesia (aside from the lack of consciousness) that prevent the effectiveness.
  - cpncrunch 3y ago
    But you're neglecting the fact that this study found the same or higher effectiveness than non-blinded trials. In this trial, there was a 50% response rate and 40% remission [1], whereas in a meta-analysis of previous unblinded trials there was 40% response and 30% remission [2]. [1] https://www.medrxiv.org/content/10.1101/2023.04.28.23289210v1.full-text https://www.medrxiv.org/content/10.1101/2023.04.28.23289210v... [2] https://pubmed.ncbi.nlm.nih.gov/35688035/ https://pubmed.ncbi.nlm.nih.gov/35688035/ So it's not that this trial wasn't effective, just that the placebo effect is very effective, and it likely resulted in the improvements seen.
- reubenmorais 3y ago
  I see so many studies trying to somehow distill trippy drugs into an isolated, side-effect free, take a pill and get back to work treatment. Maybe there's something to be found there, would be huge, but my hope is that we don't waste all the will and funding down this path without more fully exploring the path where we admit that yes, the trip helps, and we'll just need to deal with the lack of blinding.
  - tokai 3y ago
    Literally the last line of the article: "Future studies of novel antidepressants with acute psychoactive effects should make stronger efforts to mask treatment assignment to minimize the effects of subject-expectancy bias." Instead of pondering if their method is at fault for their negative result, the conclusion is to double down and working even harder at masking the effects.
huuhee3 3y ago
Then it's still no worse than widely used SSRI's, which also mostly don't differ from placebo
- tokai 3y ago
  Don't post lies and FUD here please.
  - bheadmaster 3y ago
    If you're gonna accuse someone of posting lies and FUD, at least have some sort of reference [0] to point to, please. Otherwise you're just participating in a "uh-huh!", "nuh-uh!" pissing contest. [0] https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0
    - tokai 3y ago
      You know SSRIs can work while the serotonin hypothesis is wrong right? And no - I'm just going to asking people posting FUD, like SSRIs dont work, to stuff it. If huuhee had posted some of the review articles problematising the performance of SSRIs we could have exchanged different studies and had a discussion. But they didn't, as you didn't even if you think you did. And don't accuse me of having a pissing contest when you are the one hufffing and puffing.
      - pessimizer 3y ago
        Telling people to shut up needs to come with a reference. Giving your opinion doesn't. The only people who care about the fact that you disagree with them are your friends and family. Strangers only care why you disagree with them. They don't know you personally.
        bheadmaster 3y ago
        > The only people who care about the fact that you disagree with them are your friends and family. Strangers only care why you disagree with them. They don't know you personally. This is exactly my point. You've hit the nail on the head.
mtlmtlmtlmtl 3y ago
Unusual is an understatement. This just seems ill-conceived to me. You can't eliminate one effect on the brain by introducing other effects on the brain that might have their own consequences for the results. All this shows is that ketamine while under general anaesthesia is not more efficacious than placebo. Ok then. This just seems like a failed attempt to introduce better blinding to me. I'm not convinced it sheds any light on the mechanism by which ketamine is effective.
- SiempreViernes 3y ago
  Actually, what it shows is both that getting ketamine while under general anaesthesia is roughly as effective as when taken without anaesthesia (40% here vs 45% in [1]), and as effective as just taking anaesthesia (their placebo treatment). [1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992936/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992936/
  - mtlmtlmtlmtl 3y ago
    I see. But this seems to cast even more doubt onto the use of general anaesthesia as an active placebo. I mean, usually people waking from it don't feel great because they're very ill or had major surgery. Maybe in the abscence of things like that it could have some antidepressant effect. Things similar to this have been used as treatment in the distant past of psychiatry as well, when ethics was nowhere to be found. Induced comas and such.
    - SiempreViernes 3y ago
      To be precise, the anaesthesia is part of the masking procedure, the placebo is a saline injection that was administered the same way as the ketamine (in practice the ketamine was simply diluted in a saline dose that is then given to the patient). Of course, getting all those anaesthesia drugs into you could mess up the body chemistry in all sorts of ways that make the ketamine not work, but it is still very surprising that the net effect of this big cocktail of substances is that you get basically the same outcome regardless of treatment method.
rozab 3y ago
I think the criticism of this is unfair, and this result will help shed light on the mechanism. Look at the current theories for molecular mechanisms: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999402/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999402/ If these are accurate does it make sense for them to be entirely inhibited by general anesthetic?
hprotagonist 3y ago
which form of ketamine?
- cypherpunks01 3y ago
  If the term 'Ketamine' is used, that typically indicates racemic ketamine. If you mean administration route, it was IV infusion. Not too many other methods are available for a patient under anesthesia :)
zone411 3y ago
Nothing against the study, it seems interesting. But the article title is quite misleading considering that ketamine is not typically administered under general anesthesia for treating depression.
- MagicMoonlight 3y ago
  Exactly. So when they’re getting high they say it works but when you look at actual mechanisms there’s no difference. Aka the “patient wants opiates instead of physiotherapy” model of treatment
ketaminethrow 3y ago
I've been taking oral ketamine for about 2 years now. Not super frequently, probably ~6-10x/year. I feel like it's been a pretty helpful addition to my life, but it's not what I expected at all. To me, ketamine isn't really "enjoyable" or seem to modify my mood directly or anything like that. What it does do is shift my perspective for a few minutes and makes me introspective in ways I can only see as healthy. Sometimes I think about my wife, my children, my finances, my work, my parents, cleaning the bathroom, whatever life issues I might be struggling with at that moment but the perspective shift brings a clarity to the issue and the solution seems obvious. I often want to jump off the couch and feel invigorated and motivated. (Of course ketamine also makes you fatigued so it's a bit of a strange mix of feelings). I mentally want to do things but physically I am not able to—that's fine though. I'm also an experienced meditator and have done traditional psychedelics, neither of those have improved my life as much as ketamine has. Meditation is simply really hard for me despite over a decade of trying and failing to make it a daily habit. Psychedelics work very well for introspection, but they're also terrifying and in my mid-30's I am pretty sure this is something I'm content with not needing to deal with again. I once heard someone say that psychedelics are like color TV and ketamine is black-and-white. Somehow this describes the feeling exactly to me. Ketamine isn't nearly as intense as LSD/psilocybin and that's the best part IMO. My life is in relatively good shape, but a monthly-ish tune-up with ketamine seems to have really been effective.
- deleted 3y ago
  [deleted]
throwawaaarrgh 3y ago
Amazingly, talk therapy also is no better at reducing depression than placebo while under general anesthesia.
- tonyarkles 3y ago
  Thanks for that! Having a bit of a rough morning and that was a great laugh :)
  - dietnexercise 3y ago
    Could be another doctor that sells medical services and writes pharmaceutical prescriptions for free, as gifts. (Granting Equal Liberty, a non-delegable inalienable right that's not granted to Congress by the US Constitution either). /? Are diet and exercise more effective than pharmaceuticals (and talk therapy) https://www.google.com/search?q=are+diet+and+exercise+more+effective+than+pharmaceuticals https://www.google.com/search?q=are+diet+and+exercise+more+e...
    - dietnexercise 3y ago
      Protection racket: https://en.wikipedia.org/wiki/Protection_racket https://en.wikipedia.org/wiki/Protection_racket : > A protection racket is a type of racket and a scheme of organized crime perpetrated by a potentially hazardous organized crime group that generally guarantees protection outside the sanction of the law to another entity or individual from violence, robbery, ransacking, arson, vandalism, and other such threats, in exchange for payments at regular intervals. Each payment is called "protection money" or a "protection fee".
    - vasco 3y ago
      You should consider re-reading the original sentence as it appears you totally missed the joke.
- mjburgess 3y ago
  In other news, in a double-blind study, participants who were drunk during their surgery reported no development of their social lives.
arthur2e5 3y ago
This kind of headline made some round in Twitter a while ago and got justifiably ridiculed, so let me repeat those old points here. The study states "agents used for anesthetic maintenance included intravenous propofol and inhaled sevoflurane or isoflurane." All three have some known antidepressant activity: - propofol: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276046/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276046/ (This story was pretty big back then, as propofol's a common electeoconvulsion anesthetic.) - sevoflurane: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851135/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851135/ (tiny sample, but idea comes from other tiny samples where it worked) - isoflurane: https://pubmed.ncbi.nlm.nih.gov/23922809/ https://pubmed.ncbi.nlm.nih.gov/23922809/ Does it mean this study is meaningless? No, but it definitely does not prove what the abstract wants to say. What it does show is well-summarized in https://news.ycombinator.com/item?id=36030251 https://news.ycombinator.com/item?id=36030251. See replies under https://twitter.com/jonahdavids1/status/1654842991331213313 https://twitter.com/jonahdavids1/status/1654842991331213313. (And no, having general anesthesia work about as well as ketamine does not make ket useless either. Ket is less likely to stop you from breathing. And you can stay awake, even non-hallucinating [see: nasal sprays], while it works.)
- moreshadowbans 3y ago
  [flagged]
MagicMoonlight 3y ago
Hmm so people report better symptoms when they know they’re being given recreational drugs but report no change when they’re not sure what they got.
- SiempreViernes 3y ago
  No: they report milder symptoms in both cases, and the improvements are of almost the same size.
bjt2n3904 3y ago
Psychiatry, having failed to measurably solve any "mental health" problem is so desperate to find a solution that it's sampling the recreational drug cabinet. This isn't science. This isn't medicine. This is rolling back the clock to witch doctors and medicine men. Can't be depressed if your mind has been chemically lobotomized.
cypherpunks01 3y ago
This is rubbish. Ketamine is a life-saver and has been proven to relieve depression, regardless of the administration setting. It is not magic and does not work in every case, but the effects are proven across countless studies. S-ketamine has even gone fully through FDA approval. Personally I have used it at home, and at a treatment center. There is no difference in the antidepressant properties, whether someone was helping me administer it in a medical setting, or not. The antidepressant properties do not relate to the effects of simply being in a clinical trial. I strongly believe the antidepressant properties arise from the psychedelic/dissociative experience, and not directly from the physical effects. I'm not terribly surprised that ketamine may not produce strong antidepressant effects if the patient is not conscious. Anyone looking to read more about ketamine antidepressant properties should read "The Ketamine Papers: Science, Therapy, and Transformation" by Phil Wolfson, M.D., and Glenn Hartelius, Ph.D.
- arthur2e5 3y ago
  The study actually shows ketamine works as well with anesthetia (45%) as without (40%), if you read the non-anesthetia study linked in https://news.ycombinator.com/item?id=36030251 https://news.ycombinator.com/item?id=36030251. (Of course you can argue they are not using enough K at the 0.5 mg/kg mark, because disccociation starts at 1 to 3 mg/kg per StatPearls.)
  - PragmaticPulp 3y ago
    > Of course you can argue they are not using enough K at the 0.5 mg/kg mark, because disccociation starts at 1 to 3 mg/kg Dissociation isn’t necessary for the antidepressant effect, according to studies. In fact, many of the more responsible clinics target longer duration, lower peak dose infusions for this reason.
    - arthur2e5 3y ago
      Well, yeah. But the parent comment is insisting that the spiritual bits is doing something, and I was just way too lazy to look for a dose response study.
waythenewsgoes 3y ago
This study seems inherently flawed to me, how are you isolating what is happening while simultaneously administering other brain—chemistry altering drugs to the patient? These patients are all undergoing surgery, yet another variable with drastic consequences on mental health. Just taking the drug alone doesn’t even seem to accurately reflect the primary treatment path of having talk therapy while the drug is taking effect. What if the anesthesia simply inhibits the drug from working? Additionally the sample size (40 people) is extremely small to extrapolate this to the general population. I’m not sure how these flaws can be reconciled.
cubefox 3y ago
> But it’s a problem for researchers running double-blinded clinical trials, as participants can usually tell whether they have received ketamine or a placebo. [...] 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. That's a genius way to avoid unblinding. All psychoactive treatment trials have this problem: placebo controlled studies rely on patients not being able to distinguish whether they are in the test group or the control group. I hope future studies (say, for psilocybin) can also use this study design.
- BobbyJo 3y ago
  If I did drug trials for pain killers this way, would it give any useful data? Depression and pain are subjective. Personally, I think removing the subjectivity from the trial voids the trial. It is a clever design, but it really just proves the benefit is in the experience and not the physical mechanism.
  - cubefox 3y ago
    Having amnesia (forgetting whether they had a trip and whether they were in the treatment group) would probably be better than anesthesia induced unconsciousness. Though I don't know whether short term amnesia can be easily induced.
  - vorpalhex 3y ago
    Pain has subjective parts but it is not merely subjective. You can measure how much effect ibuprofen or tylenol has, even with someone knocked out. You can see pain on an mri, even with someone knocked out.
    - BobbyJo 3y ago
      Never heard that before, source? Also, anesthesia would ruin whatever you hoped to see on an MRI.
      - 3y ago
insane_dreamer 3y ago
Interesting study. However, I would argue that the study introduces an additional confound (anesthesia) rather than removing a confound (in order to isolate the effectiveness of ketamine).
- rtkwe 3y ago
  I think it's also very probable that the trip is indeed part of the therapeutic effects of ketamine therapies. On top of just the anesthesia confounding variable there's also the fact they were all getting surgery so improvements might have come from getting over the stress of whatever procedures they were having done. My main worry is this will be waved around by people as an argument against the therapy without understanding what they were actually testing which is if you need to experience the trip for ketamine to have an antidepressant effect or if the effect is more principally neurochemical. The article has hints of this and at the bottom the authors also say that's mainly what they were looking to test here.
1letterunixname 3y ago
Did they double blind all 4 combinations? K+A, K, A, and control? IIRC, K is primarily useful for TRD when nothing else works.
deleted 3y ago
[deleted]
EMM_386 3y ago
Got Ketamine in the ER to reduce my dislocated shoulder. Fell into what addicts refer to as the "k-hole". Felt I was falling into a complete void. All I can remember is yelling "no, no, NO!". Highly NOT recommended.
dimal 3y ago
Terribly misleading link-bait headline. The authors were specifically trying to determine whether the hallucinogenic effects are related to the antidepressant effects, so they blunted the hallucinogenic effects by applying ketamine while under general anesthesia. They found that in that case, there was no effect on depression. So the study showed that the hallucinations are a key part of the depression treatment, not that ketamine is no better than placebo. But now I’m sure that this will be cited by people in shitposts based on the title. Science should know better.
- ikekkdcjkfke 3y ago
  Isn't it widely known already that these drugs help resolve negative memories? The computer obviously needs to be on in order for the routine to execute..
zosima 3y ago
Some points: 1. Depression is measured by severity on the MADRS scale. But the Ketamine group seems to have started out less depressed than the Placebo group. Thus the placebo group had further to fall. Normally this will be adjusted away when calculating treatment effect, but seems not to have been done here. I think if it had been done ketamine would have had a slight (but highly nonsignificant) edge over placebo in the linear model. 2. Many of the patients are already on some kind of depression treatment, going into the study. This is kind of odd. 3. 5 of the patients in the ketamine group had experience with ketamine previously, but only 1 in the placebo group. Were those having experience with ketamine insensitive to it, as they seem to have become depressed again? Or did they believe they'd be insensitive to it? 4. Sample sizes are small, and usually larger sample sizes are needed to see efficacy in depression trials, even in highly efficacious treatments. 5. The so-called routine surgery may have been fairly anxiety-inducing for the patients and getting it done could have made them feel quite a lot better by itself. That effect may be stronger than any medication effect. 6. Yeah, of course, this doesn't tell anything on whether ketamine has efficacy against MDD or not. Just that it could look like the efficacy of ketamine +(extra) anesthesia is about the same as anesthesia by itself against MDD, upto 14 day post-treatment.
kraussvonespy 3y ago
n=1 and all but ketamine is the only med out of 30+ that I've tried for my TRD over the last 40+ years that actually helped me long term. Every other med either had side effects that were worse than being depressed or they just didn't work beyond the first few weeks which I attribute to the initial placebo effect. What I try to stress to people who ask is that ketamine is a powerful agent of neuroplasticity. So, so many people expect to take a pill and just feel better. With ketamine, you have to stay as positive as you can before, during and for days afterwards to reprogram your brain to be more positive. The people that I know that have had success with ketamine are those that either had therapists working with them during or right after the experience, or those who followed the "must work hard at being positive for 2-3 days after taking ketamine" advice. This is a med that I suspect you could actually damage yourself permanently if you just take the med and then go right back to doomscrolling social media or something similarly negative. The initial experience can make you feel better for a day or two, which is huge because no other antidepressant has that kind of quick impact. But if you work at it during that 2-3 days after, you can become a more positive person permanently. I'm hoping that it gets more accepted over time and can be prescribed by psychiatrists because compared to most other "here's some pills, hopefully you'll feel better in 6 weeks and if not, we'll give you more pills that will hopefully work in 6 weeks" depression meds, it works really fast. For someone on the verge of suicide, it can be a truly miracle med.

As an ex-depressive, the best cure for depression I've found is a period of ketogenic dieting.

Ketamine saved my life. It’s proven to be extremely effective against suicidal ideation. The trip is definitely part of it. I’ve switched to shrooms and one trip every 3-6 months seems to reliably keep depression and panic disorder at bay. It did require some work and I really had to process some awful memories from my childhood. But these things did more for me than years of psychiatric meds ever did - literally dozens of them. Mirtazapine made me gain weight - 60 lbs in a year. Prozac gave me bruxism and I cracked 3 dental crowns in a month. Effexor turned me into a suicidal yet somehow also emotionless zombie. I got addicted to Ativan and couldn’t sleep without it. I’m off it all, and happier than I’ve ever been.

peterlk 3y ago

> In a new study that is yet to be peer reviewed Thank you very, very much to the author for saying this

coldtea 3y ago
Even if it was peer reviewed, most published studies are non-replicated/bad methodology BS. So "yet to be peer reviewed" means the study paper is closer to "random generated garbage text" than to "important insight".
passwordoops 3y ago
For all practical purposes, peer review is mostly useless today. More often than not, it's either: -a cursory glance by someone who doesn't have time to care -a highly detailed critique from someone who will either be scooped or proven wrong, so they're looking for any reason to reject the paper, good or bad -a grad student who puts in the effort but probably still lacks the experience for a good review And if peer review actually was useful then the false cure for MS [0], arsenic-based life [1], or vaccines-cause-autism [2] would all be DOA and never been published in major journals to so much PR fanfare. Heck, most of Retraction Watch wouldn't be a thing [3]. [0] https://www.statnews.com/2017/11/28/multiple-sclerosis-paolo-zamboni/ https://www.statnews.com/2017/11/28/multiple-sclerosis-paolo... [1] https://phys.org/news/2012-07-scientists-nasa-arsenic-life-untrue.html https://phys.org/news/2012-07-scientists-nasa-arsenic-life-u... [2] https://retractionwatch.com/2011/01/06/some-quick-thoughts-and-links-on-andrew-wakefield-the-bmj-autism-vaccines-and-fraud/ https://retractionwatch.com/2011/01/06/some-quick-thoughts-a... [3] https://retractionwatch.com/ https://retractionwatch.com/
- junon 3y ago
  Man I remember the arsenic-based lifeforms thing, always wondered what happened to that. I didn't know it was ever debunked.
- replygirl 3y ago
  > a highly detailed critique from someone who will either be scooped or proven wrong, so they're looking for any reason to reject sounds like an ideal reviewer, tbh
  - Georgelemental 3y ago
    "Reason" might be "major flaw in your statistical analysis", but it could also be "you should have cited my paper" or "insufficient jargon."
    - replygirl 3y ago
      I'd want to hear that out and make sure I'm not mistaking "I've done some prior work that enriches yours" for "You should have cited my paper" or "You're not communicating clearly and succintly" for "insufficient jargon"

cameronh90 3y ago

> They gave volunteers ketamine while they were under general anesthesia, theoretically preventing the participants from going on a trip. Maybe it's the trip that helps.

coldtea 3y ago
Not to mention other possible effects of being in general anesthesia (aside from the lack of consciousness) that prevent the effectiveness.
- cpncrunch 3y ago
  But you're neglecting the fact that this study found the same or higher effectiveness than non-blinded trials. In this trial, there was a 50% response rate and 40% remission [1], whereas in a meta-analysis of previous unblinded trials there was 40% response and 30% remission [2]. [1] https://www.medrxiv.org/content/10.1101/2023.04.28.23289210v1.full-text https://www.medrxiv.org/content/10.1101/2023.04.28.23289210v... [2] https://pubmed.ncbi.nlm.nih.gov/35688035/ https://pubmed.ncbi.nlm.nih.gov/35688035/ So it's not that this trial wasn't effective, just that the placebo effect is very effective, and it likely resulted in the improvements seen.
reubenmorais 3y ago
I see so many studies trying to somehow distill trippy drugs into an isolated, side-effect free, take a pill and get back to work treatment. Maybe there's something to be found there, would be huge, but my hope is that we don't waste all the will and funding down this path without more fully exploring the path where we admit that yes, the trip helps, and we'll just need to deal with the lack of blinding.
- tokai 3y ago
  Literally the last line of the article: "Future studies of novel antidepressants with acute psychoactive effects should make stronger efforts to mask treatment assignment to minimize the effects of subject-expectancy bias." Instead of pondering if their method is at fault for their negative result, the conclusion is to double down and working even harder at masking the effects.

huuhee3 3y ago

Then it's still no worse than widely used SSRI's, which also mostly don't differ from placebo

tokai 3y ago
Don't post lies and FUD here please.
- bheadmaster 3y ago
  If you're gonna accuse someone of posting lies and FUD, at least have some sort of reference [0] to point to, please. Otherwise you're just participating in a "uh-huh!", "nuh-uh!" pissing contest. [0] https://www.nature.com/articles/s41380-022-01661-0 https://www.nature.com/articles/s41380-022-01661-0
  - tokai 3y ago
    You know SSRIs can work while the serotonin hypothesis is wrong right? And no - I'm just going to asking people posting FUD, like SSRIs dont work, to stuff it. If huuhee had posted some of the review articles problematising the performance of SSRIs we could have exchanged different studies and had a discussion. But they didn't, as you didn't even if you think you did. And don't accuse me of having a pissing contest when you are the one hufffing and puffing.
    - pessimizer 3y ago
      Telling people to shut up needs to come with a reference. Giving your opinion doesn't. The only people who care about the fact that you disagree with them are your friends and family. Strangers only care why you disagree with them. They don't know you personally.
      - bheadmaster 3y ago
        > The only people who care about the fact that you disagree with them are your friends and family. Strangers only care why you disagree with them. They don't know you personally. This is exactly my point. You've hit the nail on the head.

mtlmtlmtlmtl 3y ago

Unusual is an understatement. This just seems ill-conceived to me. You can't eliminate one effect on the brain by introducing other effects on the brain that might have their own consequences for the results. All this shows is that ketamine while under general anaesthesia is not more efficacious than placebo. Ok then. This just seems like a failed attempt to introduce better blinding to me. I'm not convinced it sheds any light on the mechanism by which ketamine is effective.

SiempreViernes 3y ago
Actually, what it shows is both that getting ketamine while under general anaesthesia is roughly as effective as when taken without anaesthesia (40% here vs 45% in [1]), and as effective as just taking anaesthesia (their placebo treatment). [1]: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992936/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992936/
- mtlmtlmtlmtl 3y ago
  I see. But this seems to cast even more doubt onto the use of general anaesthesia as an active placebo. I mean, usually people waking from it don't feel great because they're very ill or had major surgery. Maybe in the abscence of things like that it could have some antidepressant effect. Things similar to this have been used as treatment in the distant past of psychiatry as well, when ethics was nowhere to be found. Induced comas and such.
  - SiempreViernes 3y ago
    To be precise, the anaesthesia is part of the masking procedure, the placebo is a saline injection that was administered the same way as the ketamine (in practice the ketamine was simply diluted in a saline dose that is then given to the patient). Of course, getting all those anaesthesia drugs into you could mess up the body chemistry in all sorts of ways that make the ketamine not work, but it is still very surprising that the net effect of this big cocktail of substances is that you get basically the same outcome regardless of treatment method.

rozab 3y ago

I think the criticism of this is unfair, and this result will help shed light on the mechanism. Look at the current theories for molecular mechanisms: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999402/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5999402/ If these are accurate does it make sense for them to be entirely inhibited by general anesthetic?

hprotagonist 3y ago

which form of ketamine?

cypherpunks01 3y ago
If the term 'Ketamine' is used, that typically indicates racemic ketamine. If you mean administration route, it was IV infusion. Not too many other methods are available for a patient under anesthesia :)

zone411 3y ago

Nothing against the study, it seems interesting. But the article title is quite misleading considering that ketamine is not typically administered under general anesthesia for treating depression.

MagicMoonlight 3y ago
Exactly. So when they’re getting high they say it works but when you look at actual mechanisms there’s no difference. Aka the “patient wants opiates instead of physiotherapy” model of treatment

ketaminethrow 3y ago

I've been taking oral ketamine for about 2 years now. Not super frequently, probably ~6-10x/year. I feel like it's been a pretty helpful addition to my life, but it's not what I expected at all. To me, ketamine isn't really "enjoyable" or seem to modify my mood directly or anything like that. What it does do is shift my perspective for a few minutes and makes me introspective in ways I can only see as healthy. Sometimes I think about my wife, my children, my finances, my work, my parents, cleaning the bathroom, whatever life issues I might be struggling with at that moment but the perspective shift brings a clarity to the issue and the solution seems obvious. I often want to jump off the couch and feel invigorated and motivated. (Of course ketamine also makes you fatigued so it's a bit of a strange mix of feelings). I mentally want to do things but physically I am not able to—that's fine though. I'm also an experienced meditator and have done traditional psychedelics, neither of those have improved my life as much as ketamine has. Meditation is simply really hard for me despite over a decade of trying and failing to make it a daily habit. Psychedelics work very well for introspection, but they're also terrifying and in my mid-30's I am pretty sure this is something I'm content with not needing to deal with again. I once heard someone say that psychedelics are like color TV and ketamine is black-and-white. Somehow this describes the feeling exactly to me. Ketamine isn't nearly as intense as LSD/psilocybin and that's the best part IMO. My life is in relatively good shape, but a monthly-ish tune-up with ketamine seems to have really been effective.

deleted 3y ago
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throwawaaarrgh 3y ago

Amazingly, talk therapy also is no better at reducing depression than placebo while under general anesthesia.

tonyarkles 3y ago
Thanks for that! Having a bit of a rough morning and that was a great laugh :)
- dietnexercise 3y ago
  Could be another doctor that sells medical services and writes pharmaceutical prescriptions for free, as gifts. (Granting Equal Liberty, a non-delegable inalienable right that's not granted to Congress by the US Constitution either). /? Are diet and exercise more effective than pharmaceuticals (and talk therapy) https://www.google.com/search?q=are+diet+and+exercise+more+effective+than+pharmaceuticals https://www.google.com/search?q=are+diet+and+exercise+more+e...
  - dietnexercise 3y ago
    Protection racket: https://en.wikipedia.org/wiki/Protection_racket https://en.wikipedia.org/wiki/Protection_racket : > A protection racket is a type of racket and a scheme of organized crime perpetrated by a potentially hazardous organized crime group that generally guarantees protection outside the sanction of the law to another entity or individual from violence, robbery, ransacking, arson, vandalism, and other such threats, in exchange for payments at regular intervals. Each payment is called "protection money" or a "protection fee".
  - vasco 3y ago
    You should consider re-reading the original sentence as it appears you totally missed the joke.
mjburgess 3y ago
In other news, in a double-blind study, participants who were drunk during their surgery reported no development of their social lives.

arthur2e5 3y ago

This kind of headline made some round in Twitter a while ago and got justifiably ridiculed, so let me repeat those old points here. The study states "agents used for anesthetic maintenance included intravenous propofol and inhaled sevoflurane or isoflurane." All three have some known antidepressant activity: - propofol: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276046/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6276046/ (This story was pretty big back then, as propofol's a common electeoconvulsion anesthetic.) - sevoflurane: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851135/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8851135/ (tiny sample, but idea comes from other tiny samples where it worked) - isoflurane: https://pubmed.ncbi.nlm.nih.gov/23922809/ https://pubmed.ncbi.nlm.nih.gov/23922809/ Does it mean this study is meaningless? No, but it definitely does not prove what the abstract wants to say. What it does show is well-summarized in https://news.ycombinator.com/item?id=36030251 https://news.ycombinator.com/item?id=36030251. See replies under https://twitter.com/jonahdavids1/status/1654842991331213313 https://twitter.com/jonahdavids1/status/1654842991331213313. (And no, having general anesthesia work about as well as ketamine does not make ket useless either. Ket is less likely to stop you from breathing. And you can stay awake, even non-hallucinating [see: nasal sprays], while it works.)

moreshadowbans 3y ago
[flagged]

MagicMoonlight 3y ago

Hmm so people report better symptoms when they know they’re being given recreational drugs but report no change when they’re not sure what they got.

SiempreViernes 3y ago
No: they report milder symptoms in both cases, and the improvements are of almost the same size.

bjt2n3904 3y ago

Psychiatry, having failed to measurably solve any "mental health" problem is so desperate to find a solution that it's sampling the recreational drug cabinet. This isn't science. This isn't medicine. This is rolling back the clock to witch doctors and medicine men. Can't be depressed if your mind has been chemically lobotomized.

cypherpunks01 3y ago

This is rubbish. Ketamine is a life-saver and has been proven to relieve depression, regardless of the administration setting. It is not magic and does not work in every case, but the effects are proven across countless studies. S-ketamine has even gone fully through FDA approval. Personally I have used it at home, and at a treatment center. There is no difference in the antidepressant properties, whether someone was helping me administer it in a medical setting, or not. The antidepressant properties do not relate to the effects of simply being in a clinical trial. I strongly believe the antidepressant properties arise from the psychedelic/dissociative experience, and not directly from the physical effects. I'm not terribly surprised that ketamine may not produce strong antidepressant effects if the patient is not conscious. Anyone looking to read more about ketamine antidepressant properties should read "The Ketamine Papers: Science, Therapy, and Transformation" by Phil Wolfson, M.D., and Glenn Hartelius, Ph.D.

arthur2e5 3y ago
The study actually shows ketamine works as well with anesthetia (45%) as without (40%), if you read the non-anesthetia study linked in https://news.ycombinator.com/item?id=36030251 https://news.ycombinator.com/item?id=36030251. (Of course you can argue they are not using enough K at the 0.5 mg/kg mark, because disccociation starts at 1 to 3 mg/kg per StatPearls.)
- PragmaticPulp 3y ago
  > Of course you can argue they are not using enough K at the 0.5 mg/kg mark, because disccociation starts at 1 to 3 mg/kg Dissociation isn’t necessary for the antidepressant effect, according to studies. In fact, many of the more responsible clinics target longer duration, lower peak dose infusions for this reason.
  - arthur2e5 3y ago
    Well, yeah. But the parent comment is insisting that the spiritual bits is doing something, and I was just way too lazy to look for a dose response study.

waythenewsgoes 3y ago

This study seems inherently flawed to me, how are you isolating what is happening while simultaneously administering other brain—chemistry altering drugs to the patient? These patients are all undergoing surgery, yet another variable with drastic consequences on mental health. Just taking the drug alone doesn’t even seem to accurately reflect the primary treatment path of having talk therapy while the drug is taking effect. What if the anesthesia simply inhibits the drug from working? Additionally the sample size (40 people) is extremely small to extrapolate this to the general population. I’m not sure how these flaws can be reconciled.

cubefox 3y ago

> But it’s a problem for researchers running double-blinded clinical trials, as participants can usually tell whether they have received ketamine or a placebo. [...] 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. That's a genius way to avoid unblinding. All psychoactive treatment trials have this problem: placebo controlled studies rely on patients not being able to distinguish whether they are in the test group or the control group. I hope future studies (say, for psilocybin) can also use this study design.

BobbyJo 3y ago
If I did drug trials for pain killers this way, would it give any useful data? Depression and pain are subjective. Personally, I think removing the subjectivity from the trial voids the trial. It is a clever design, but it really just proves the benefit is in the experience and not the physical mechanism.
- cubefox 3y ago
  Having amnesia (forgetting whether they had a trip and whether they were in the treatment group) would probably be better than anesthesia induced unconsciousness. Though I don't know whether short term amnesia can be easily induced.
- vorpalhex 3y ago
  Pain has subjective parts but it is not merely subjective. You can measure how much effect ibuprofen or tylenol has, even with someone knocked out. You can see pain on an mri, even with someone knocked out.
  - BobbyJo 3y ago
    Never heard that before, source? Also, anesthesia would ruin whatever you hoped to see on an MRI.
    - 3y ago

insane_dreamer 3y ago

Interesting study. However, I would argue that the study introduces an additional confound (anesthesia) rather than removing a confound (in order to isolate the effectiveness of ketamine).

rtkwe 3y ago
I think it's also very probable that the trip is indeed part of the therapeutic effects of ketamine therapies. On top of just the anesthesia confounding variable there's also the fact they were all getting surgery so improvements might have come from getting over the stress of whatever procedures they were having done. My main worry is this will be waved around by people as an argument against the therapy without understanding what they were actually testing which is if you need to experience the trip for ketamine to have an antidepressant effect or if the effect is more principally neurochemical. The article has hints of this and at the bottom the authors also say that's mainly what they were looking to test here.

1letterunixname 3y ago

Did they double blind all 4 combinations? K+A, K, A, and control? IIRC, K is primarily useful for TRD when nothing else works.

deleted 3y ago

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EMM_386 3y ago

Got Ketamine in the ER to reduce my dislocated shoulder. Fell into what addicts refer to as the "k-hole". Felt I was falling into a complete void. All I can remember is yelling "no, no, NO!". Highly NOT recommended.

dimal 3y ago

Terribly misleading link-bait headline. The authors were specifically trying to determine whether the hallucinogenic effects are related to the antidepressant effects, so they blunted the hallucinogenic effects by applying ketamine while under general anesthesia. They found that in that case, there was no effect on depression. So the study showed that the hallucinations are a key part of the depression treatment, not that ketamine is no better than placebo. But now I’m sure that this will be cited by people in shitposts based on the title. Science should know better.

ikekkdcjkfke 3y ago
Isn't it widely known already that these drugs help resolve negative memories? The computer obviously needs to be on in order for the routine to execute..

zosima 3y ago

Some points: 1. Depression is measured by severity on the MADRS scale. But the Ketamine group seems to have started out less depressed than the Placebo group. Thus the placebo group had further to fall. Normally this will be adjusted away when calculating treatment effect, but seems not to have been done here. I think if it had been done ketamine would have had a slight (but highly nonsignificant) edge over placebo in the linear model. 2. Many of the patients are already on some kind of depression treatment, going into the study. This is kind of odd. 3. 5 of the patients in the ketamine group had experience with ketamine previously, but only 1 in the placebo group. Were those having experience with ketamine insensitive to it, as they seem to have become depressed again? Or did they believe they'd be insensitive to it? 4. Sample sizes are small, and usually larger sample sizes are needed to see efficacy in depression trials, even in highly efficacious treatments. 5. The so-called routine surgery may have been fairly anxiety-inducing for the patients and getting it done could have made them feel quite a lot better by itself. That effect may be stronger than any medication effect. 6. Yeah, of course, this doesn't tell anything on whether ketamine has efficacy against MDD or not. Just that it could look like the efficacy of ketamine +(extra) anesthesia is about the same as anesthesia by itself against MDD, upto 14 day post-treatment.

kraussvonespy 3y ago

n=1 and all but ketamine is the only med out of 30+ that I've tried for my TRD over the last 40+ years that actually helped me long term. Every other med either had side effects that were worse than being depressed or they just didn't work beyond the first few weeks which I attribute to the initial placebo effect. What I try to stress to people who ask is that ketamine is a powerful agent of neuroplasticity. So, so many people expect to take a pill and just feel better. With ketamine, you have to stay as positive as you can before, during and for days afterwards to reprogram your brain to be more positive. The people that I know that have had success with ketamine are those that either had therapists working with them during or right after the experience, or those who followed the "must work hard at being positive for 2-3 days after taking ketamine" advice. This is a med that I suspect you could actually damage yourself permanently if you just take the med and then go right back to doomscrolling social media or something similarly negative. The initial experience can make you feel better for a day or two, which is huge because no other antidepressant has that kind of quick impact. But if you work at it during that 2-3 days after, you can become a more positive person permanently. I'm hoping that it gets more accepted over time and can be prescribed by psychiatrists because compared to most other "here's some pills, hopefully you'll feel better in 6 weeks and if not, we'll give you more pills that will hopefully work in 6 weeks" depression meds, it works really fast. For someone on the verge of suicide, it can be a truly miracle med.