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.
The problem is real, though. Drugs with overt recreational effects very frequently distract the patient from the therapeutic effect in unproductive ways. The recreational effects generally disappear quickly as tolerance develops, which can give patients the false impression that the medication “stopped working”.
A common example would be ADHD stimulants, where the early stimulating and mood-boosting effects disappear over time while the concentration-enhancing effects mostly remain. This leads a lot of patients to assume the medication isn’t working because it doesn’t feel like those first few doses, which can lead to discontinuation or abuse.
Ketamine has a similar story arc. The antidepressant effect doesn’t require full blown dissociation, but so many headlines and fame-seeking authors have hyped it as “psychedelic medicine” that some patients assume it isn’t working until they disassociate/hallucinate. This can create a sort of nocebo effect where patients may actually be improving but they think they’re not because they didn’t have the wild hallucinations they read about in some exaggerated internet article.
I took LSD twice in my life only and it changed my outlook ever since. It's been almost 10 years. I wasn't depressed and had other benefits from it, but I can see how that experience could've fixed depression, and know of people who say it did for them even though I'm not in any hippy-like community or whatever.
I think a possible reason why medical research prefers a pill that works forever for continued use is that if you buy something cheap twice in your life and it fixes whatever needs fixing the pharma industry can't make money off of you the same way they can put you on antidepressants for life. I'm not in the medical field so I'm just speaking out of my ass based on personal anecdotes though.
Or because it's not really medicine and person specific? I've taken LSD several times in varying doses and it's never been anything more than "a really really fun time". Nothing profound, but damn fun times, the same effect as any fun memorable party
Perhaps if you are looking for something profound or want a change of mindset, psychedelics might be able to help you reach it - similar to how shamans used psychedelics to talk to their gods or whatever - but if you're just looking to have fun that's what you'll get
Last time I remember taking LSD I was on a bus going from NYC to Boston and I guess I was either bored or knew we were going to have a longer than usual trip home because of traffic. I wind up talking with the guy behind me for hours who describes something to me he was working on that sounds like modern day Spotify (this was circa 2005ish?). We get into spirituality at some point. We have a 7 hour trip and get home early morning before the subway is running. We walk around the Commons a bit. He had a cane but didn't need it… just used it as a fun prop in life. He had me believing his name Joshua or in Hebrew Yeshua aka Jesus. (edit: copy pasta)
Anyway if you take drugs to party and then go to a party, you'll party. If you take drugs and do therapy you'll do therapy. If you take drugs just to see what happens and you're open to whatever happens, things will happen. Maybe you'll just have an oddly memorable time and you ponder what it means, slowly altering how you think about other things for the rest of your life.
The anecdotes you give don't necessarily suggest this is person-specific. They don't refute that, in the general case, there might a good chance for a person who is depressed to have their symptoms alleviated by an LSD trip. Were you depressed (in the DSM-5 sense) any of the times you took LSD and had "a really really fun time"? A person who is not depressed obviously won't notice the mindset shift which alleviates their depression.
I've been "depressed" if you want to call it that based on the DSM-5 definition both before and after the LSD trips. And no not during - that's one of the benefits of fun events - you forget about depression because you're too busy with other things, at least I do anyway
My brain "hooks" on the depression - if I consciously notice the darkness, which I do most of the time unless 100% fully mentally engaged in something (usually only happens during social gatherings I want to be at), then the darkness is pertinent and consuming. If somehow I forget about it, it clears up temporarily until I get tired or stop being engaged
LSD had no effect in this case - drinking or smoking pot would've had the same effect in the circumstances i've taken it, or even just being sober - would just be less trippy
I did LSD once in the depth of grief where I was having trouble processing the loss of multiple family members. I went in with a "roll up your sleeves and clear out the garbage" mindset and it had an incredibly profound effect. Other times it was just fun, though I've also found elusive solutions to problems I've been working on, similar to dreaming.
> I think a possible reason why medical research prefers a pill that works forever for continued use is that if you buy something cheap twice in your life and it fixes whatever needs fixing the pharma industry can't make money off of you the same way they can put you on antidepressants for life.
Drug discovery is difficult enough that the pharma companies don't have the ability to make a meaningful choice between fix-once-and-you're-set-for-life versus manage-symptoms-forever.
How do you test a medication that only needs to be taken once or twice? This is very challenging to study scientifically.
Psychedelics bridge the gap between medication and therapy. A trip is not guaranteed to be therapeutic, but a trip with proper guidance it's more likely to be.
How can we know which aspects of that guidance are useful, and which are superfluous?
It's going to take a lot of work to get to the level of certainty that our medical system expects for medication.
> How do you test a medication that only needs to be taken once or twice? This is very challenging to study scientifically.
Most vaccines you only take once, you can still test if they work or not. Same with poison antidotes and things like that. Like I said, I'm not a doctor, but the fact that it's only once doesn't seem like the problem.
Yes, because you can measure the amount of antibodies as many times as you want; and you can be pretty certain they are the direct result of the vaccine.
How do you measure depression? How do you know what changed it, or how much?
That seems to be their objection to mushrooms, can't charge a lot for something that grows in your lawn. Turn it into a pill with some chemical tweak and you get a patent.
Continuing your ADHD example, the mood-boosting effects may very well be secondary, not directly caused by the drug itself. It feels great to finally have the balance of stimulation you always needed, but never had. The experience also has novelty, which is known to be very important to ADHD brains; because novelty is stimulating.
After some time, the novelty of the experience wears off, and you start to get more familiar with the limitations of medication. That's disappointing. Disappointment feels bad. Again, this is not caused by the drug itself, but by the surrounding experience.
ADHD itself is riddled with secondary experiences: they make up the name itself! People with ADHD do not struggle to pay attention, we struggle to direct it. Hypoactivity is a reaction to living without enough simulation. Neither is a direct symptom of the disorder, but they are ubiquitous enough to
People who live with undiagnosed/untreated ADHD are likely to end up with a lot of trauma. That trauma is unaffected by medication.
So if you start taking ADHD medication, you need to know what it does and doesn't help with. Medication can't make up the entirety of treatment, just like cognitive behavioral therapy can't replace medication.
> The antidepressant effect doesn’t require full blown dissociation
I'm not sure, isn't that kind of what's being shown by this study? Or like, is there levels of disassociation that you're distinguishing between? Are you able to enumerate those levels for those of us who are unfamiliar with disassociation?
"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.
Well, what they're trying to do is provide better blinding. Doing proper blind studies of ketamine is quite hard because its subjective effects are far too noticable.
That line just says people should do better at this in future to get more accurate results. It's not a statement about the ultimate form the treatment should take.
yes ofc, but if the treatment is the trip it will never work blinding it like this. If anything they should be looking for drugs that give comparable trips, with no potential for depression treatment.
I agree in principle, though having tried most of the various types of trippy substances, I've yet to encounter one that hasn't showed potential for a short term antidepressant effect. I guess I haven't tried those weird delta opioid ligands(salvia divonorum). I guess deliriants(like diphenhydramine) would have about zero antidepressant effect too, but that would have possible negative effects, even being liable to cause trauma.
I believe benzodiazepines have also been tried as an active placebo but I don't remember what the results were.
Diphenhydramine as a first generation antihistamine acts on a large number of receptors and can even be used as a mild anxiolytic, so I'd guess it could very well have antidepressant effect.
No idea about deliriants like atropine/scopolamine, but in low doses, they were traditionally used to spice up beer (hence Pilsen named for Bilsenkraut, black henbane), so I could imagine short antidepressant effect there too.
> Diphenhydramine as a first generation antihistamine acts on a large number of receptors and can even be used as a mild anxiolytic, so I'd guess it could very well have antidepressant effect.
It does, and this observation led to the development of dedicated antidepressant drugs. There are several such cases where interesting side effects turned out to open a world of possibilities, including an anti-TB drug that also led to antidepressants, and of course Viagra.
You basically can't do science like this and prove anything useful outside of group A is the more effective than group B. And that's assuming your test subjects can't tell the difference. That would tell you that at minimum either A or B has a non-zero effect because they both can't do nothing and be different. But proving that A is an improvement over not A is the important bit. A and B could both be worse than nothing but A is just less bad.
"find something that has a similar trip but does nothing" is actually equivalent to the original problem.
One of the objections against the improvement observed that is mentioned in tfa is precisely that you can get "trips" from general anaesthesia:
'Schenberg points out that people often report dreamlike and visual, auditory, and affective experiences under anesthesia. “Maybe people who had dreamlike experiences during the anesthesia had more improvement than the people who didn’t,” he says.'
So maybe the trip does indeed help, but evidently it is not necessary to be able to remember if you had one to get the reported benefits.
As a relatively seasoned meditator, I am absolutely sure that this is the trip that helps, not the chemistry. One way to look at meditation (and, I hear, psychedelics) that fits my experience is that it has the potential effect of opening the range of "ways of looking", to change the way one builds the perceived world. What propulsed my meditation to a totally different level was to see it as a practice of actively engaging with other ways to perceive the world, and let those act on the psyche, rather than as some form of "mental gym". As I understand, what makes a psychedelic a psychedelic is that it propulses the user into a state where the workings of the mind is apparent (Psyche-delic, this which reveals (delic) the mind (psyche)), and new ways of perceiving are opened. If one considers depression as primarily a form of "negative filter" that turns all external objects as dull and uninteresting, it makes sense that psychedelics can help get out of it, and that a necessary condition for that is to actually consciously experience those transformations of perception.
Unfortunately, this means that the standard way of doing medicine research, with control group and placebo, is unlikely to ever be applicable to this area of research, and that a new epistemiology of medical research has to be developped for it. I find it super interesting.
(side note: if the idea of meditation as active engagement with "ways of looking" is intriguing you, I highly recommend looking up the teachings of Rob Burbea)
On one side it showed me (after a long time) how you can be very empathic for all people around you and also reminded me or showed me how really good happiness feels.
And while the effects lasted a little bit for 1-2 weeks, it also is something I know I could do again if I like to.
This definitely gave me an additional/new viewpoint.
Indeed, I remember a while back there was a TikTok filter going around where it made old people look younger.
One of the people using it said it basically had cured her self-perception issues; she had been bullied for her looks as a child and internalized that she was ugly. But as an adult when she saw her younger face in the app, she realized immediately how the characterization of that face as ugly was just the perception of child bullies.
And it wasn't something that photographs could do for her -- it was the fact that it was her younger face superimposed on her current body, and that it was moving as she moved which gave her a new "way of looking" as you put it. In a sense, AI gave her a chemical-free trip.
There is a similar thing going on with one type of treatment for amputees that suffer from phantom pain in the missing limb. It uses a box and a mirror positioned such that the subject can see a reflection of their existing arm/hand but the mirror spatially locates it to where their missing arm/hand would be.
It isn't a sure-fire cure, but apparently it offers enough relief to enough sufferers.
Yes, I've recently come to realise that ketamine allows me to slip into a meditative state as a result of its consciousness-suppressing anaesthesia. For someone such as myself with ADHD and aphantasia this is a revelation as normally I find myself unable to quiet my restless mind enough to get there. And explains why both my most profound epiphanies and my greatest changes of mindset have all involved ketamine in one way or another.
I look at it as shutting your computer off and plugging in a USB drive with repair software and wondering why nothing got fixed after you turned it back on. Aren't we just meat computers?
Thank you! Yes, the trip is caused by activation of the HTR2A receptor. It is not magic. everything you experience is both affected by and affects the biology of the body.
You know, I have a fried, diagnosed with depression 15 years ago, tried everything, nothing worked. Know what they finally found her problem was? Familial (genetically caused) hypoglycemia.
We cannot even diagnose depression, it is still too subjective nad personalized. Stop looking for these one size fits all miracle cures and look at your own body.
I think I see what you mean, in the sense that without the substance the trip does not exist. The distinction I was trying to make was between the subjective experience compared to potential brain changes induced by chemical reactions.
The "chemistry" side of the debate would be that the trip is a side effect of the substance modifying neurological pathways (or similar), but what is actually important are those physical modifications to the brain, not the experience.
The "trip" side of the debate would be that the only important thing is the experience, and that whether it is induced by drugs, fasting, meditation, prayer, video games, etc. does not matter that much.
Obviously, there is also the possibility that both sides are valid: the fact that the experience can be transformative in itself does not prevent the physical effect of the molecule on the brain to be beneficial as well. There is even the possibility that one of the two has a positive effect, while the other is rather negative.
They are not looking at creating a "trippy" experience per se, but rather to generate an experience that produces a potential shift in the way to relate with the world
This might be true if what you want is to emulate the experience under actual psychedelic drugs; I do not think that this is necessary if your only aim is to create _transformative_ or _healing_ experiences.
One of the core concepts of Rob Burbea I mentionned above is the idea of "imaginal middle way", which, in short, consists in seeing mental images as "neither real nor not real", "simultanously discovered and created". Going deeper into that topic would require way too much text and time for a simple comment here, but I can tell from experience that this way to engage with imaginative faculties can have deep and long lasting effects. And the important aspect here is that, while engaging with the image, one is constantly balancing between reification (considereing the image, for instance of a divinity, as having independent reality) and disdain (considering the image as "just made up").
I've always been very interested in taoism, but never took it much further than reading the Tao Te Ching and a few other related things like The Tao of Pooh and The Te of Piglet. This form of meditation seems exactly right for me. Do you have any recommendations for how to pursue it? Thanks.
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].
Exactly. This is like testing to see whether scaring someone with a spider cures hiccups but in order to keep it blind only showing them the spider when their back is turned.
In which case, the headline would be correct. If ketamine can only treat depression by inducing a trip, then it's the trip that treats the depression, not the ketamine, which suggests future avenues of research into trips themselves, possibly excluding ketamine altogether.
Not really. If it is the _experience_ that is the main cause for reduction of depressive symptoms, it means that other ways to generate similar experiences (such as meditation, talk therapy, prayer, sensory deprivation...) could have a similar effect. If it is the physical effect of the medicine on the brain which is responsible for the effect, it would mean that it might be possible to design drugs that have the same effectiveness without being psychoactive.
> Apart from potential side effects of anesthesia,
Bingo. If they were going to study the effects of some drug on amputees, it would be better if they didn't amputate limbs to test it. People don't have a good understanding of the damage from general anesthesia, so it's probably easier to get them to agree to do this study (and therefore perhaps easier/cheaper than selecting people already undergoing general anesthesia, and coordinating with the anesthesiologist and controlling for confounding factors like why they're being anesthetised in the first place)
But ethically, it would be much better if they didn't put people under to perform a stupid study on them, since it is damaging to the people getting anesthetized.
Is it still a widespread theory that depression is a purely physical condition that can be treated with just a chemical intervention? I thought the medical community moved past this notion.
Ketamine depression treatment doesn’t have to induce a “trip” to elicit the effect, according to studies and the protocol.
It can produce some sensory distortions, but anyone who is going into a full “k hole” is almost certainly taking too much. It’s not a case of more is better.
Is there a clear definition of a trip that these studies subscribe to? I would guess they attribute any change in perception to "tripping". K-hole is not the expected experience in most Ketamine-based treatments afaik.
yes, but the phase 3 (efficacy) trial just barely crossed the threshold (if I remember correctly), mostly because the company wanted to use one stereoisomer because the other was not patentable (and this is the one that is less trippy)
The problem is that their conclusion is not going to be read as “wow, it’s the trip that helps more than just the chemical.” Instead it’ll be read as “well I guess this chemical doesn’t work at all.”
The notion that the trip is the therapeutic element seems oddly frightening or threatening to a lot of people.
… Or at least it’s not what they’re looking for. The quest is for a pill that works deterministically without any need to involve consciousness.
>The notion that the trip is the therapeutic element seems oddly frightening or threatening to a lot of people.
The result of years of "altered state of mind" anti-drug propaganda. There is a significant perception that "altering your state of mind" is immoral (even though we do that every day, all day, and in fact even some foods can "alter your state of mind"). If cannabis could actually cure cancer just by smoking it, there are some people who would respond "well now we need to take the 'high' out of it, because getting 'high' is wrong". These type of people would never accept that the "high" might be the actual mechanism of psychological action, especially with psychedelics and dissociatives, where the user probably won't be able to interact with what passes for objective reality.
For example, DMT is very useful for, among other things, learning more about life and death. If the beliefs are correct, and DMT is released in the brain at the point of death, then DMT itself could be good preparation for the weirdness that happens at and before death (like Alzheimer's or dementia). Taking the "trip" out of DMT would make it completely useless.
'There is a significant perception that "altering your state of mind" is immoral '
This is probably a straw man. The immoral part comes from some percentage of the trippers ending up doing things like climbing naked up power lines to steal the copper for future trips.
It's a question of whether society should tolerate the % damage that occurs versus the % high it gives those not participating in the damage.
That's an issue of set and setting, and of proper education. Also, what in the world scenario have you put forth? Who is "climbing naked up power lines to steal the copper for future trips"? I've never heard that one in all the years of propaganda I've heard (like the old canard about someone taking LSD and believing after the trip that they're an orange).
> How is people misinterpreting the result that way a fair criticism of their work?
Part of it comes down to overall scientific responsibility and being careful about defining the scope of the claims and conclusions. I haven't seen the final paper here, but if the Conclusions section says "This research indicates that ketamine given while patients are already sedated with general anesthesia doesn't not appear to provide a benefit for patients suffering from depression." then that's great.
If their Conclusions section says "By isolating ketamine-the-substance from the ketamine trip by administering the substance while the patient is under general anesthesia, this work demonstrates that there is nothing inherently anti-depressant about ketamine and that ketamine treatment for anti-depression is no better than placebo.", that's going to potentially have a huge ripple effect.
Throughout this thread there's a fair bit of discussion about "the trip is the treatment". The first conclusion leaves a number of other lines of inquiry open for exploration. The second conclusion opens the door for funding agencies and physicians to put an end to additional research and terminating treatments that are potentially effective.
Scientific communication absolutely must be very careful with the breadth of the claims and state them loudly and explicitly. While journal and conference proceedings have historically been generally only consumed by other practitioners of a field, now that everything is online and accessible to the general public there is definitely an increased burden for clear communication with explicit, conservative, narrow unless otherwise warranted conclusions.
> 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".
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.
> Ketamine is a life-saver and has been proven to relieve depression, regardless of the administration setting.
It’s really not uncommon for some trials to fail to differentiate from placebo when it comes to depression studies. That doesn’t make this study “rubbish”, it just shows that you need to examine the body of evidence rather than cherry-picking studies that appear to match the outcome you want while dismissing those that say the opposite.
Ketamine is a temporary boost for some people, but it has also been overhyped in recent years. The single biggest downside is that it’s not a long-term solution. The duration of the antidepressant effect is relatively short (days to weeks) and the antidepressant effect appears to diminish with repeated dosing.
It can be a great help for suicidal patients or for getting traditional treatment started, but it’s not a singular solution to depression for most people.
Ketamine prescribing also got out of control fast. I traveled to a city where Ketamine clinics were advertising on the radio and billboards and competing with coupons and discounts and exaggerated promises of efficacy. Reddit and other forums are also filling up with stories of people who think their ketamine “stopped working” because they weren’t properly informed that it was a temporary effect for most people that needed to be combined with traditional therapy. Way too many clinics and influencers looking to ride the hype train without honestly assessing the situation.
> It’s really not uncommon for some trials to fail to differentiate from placebo when it comes to depression studies. That doesn’t make this study “rubbish”, it just shows that you need to examine the body of evidence rather than cherry-picking studies that appear to match the outcome you want while dismissing those that say the opposite.
But this study doesn't say the opposite. It fails to show an effect. That's different from proving the absence of an effect. Every Ph.D. student in an empirical field learns this in their first year. I'm surprised this study gets so much attention.
You can make a study verifying that a pound gold and a pound feathers accelerate downwards at the same speed in a vacuum, and perhaps you messed up the vacuum, so they actually fall with different speeds in your study. Doesn't prove gravity is messed up. You just failed to prove that it's not. Can have many reasons. Same with this study.
But this study doesn't say the opposite. It fails to show an effect. That's different from proving the absence of an effect.
This was my first thought, jaded as I am from bad scientific reporting (such as the linked article) which doesn’t distinguish between these two cases, so I had a look at the actual study.
In this case, it looks like the 95% confidence interval just barely overlaps the null hypothesis, however the mean effect favors placebo:
The mixed-effects model showed no evidence of effect of group assignment on post-infusion MADRS scores at 1 to 3 days post-infusion (-5.82, 95% CI -13.3 to 1.64, p=0.13).
(See also figure 2, which clarifies the direction of effect.)
So, potential methodological issues aside, I’d actually consider this evidence against a strong benefit relative to placebo, and possibly very weak evidence of harm.
I couldnt disagree more with your second paragraph.
I have a partner who has been prescribed Ketamine for the last 3 years. I firmly believe that the drugs ability to rebuild neural pathways and thus work around / resolve damage to be the only reason why partner is still alive today, and is now ready to return to work after so many years and such a brutal road.
In Australia, being prescribed Ketamine is very difficult, and thus very uncommon. While I do not believe it should be opened up to everyone, my experience over the last few years makes me a massive fan of the drug for specific situations.
Doing studies isn't bad in itself, of course they will produce conflicting outcomes and need to be studied as a large body of evidence.
Yes, it cannot be used as a long-term solution. It's more of a fast-acting effect and has been over-hyped beyond its capabilities.
My immediate reaction was just that their conclusion ("has no short-term effect on the severity of depression symptoms" and what the co-author said in the linked article) is not reasonable to draw based on the study they designed, because they failed to consider whether the therapy needed a conscious patient or not.
> It can be a great help for suicidal patients or for getting traditional treatment started, but it’s not a singular solution to depression for most people.
Is there any singular solution to depression for most people?
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.
(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.)
> 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.
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.
>I'm not terribly surprised that ketamine may not produce strong antidepressant effects if the patient is not conscious.
That's incorrect, it actually produced larger antidepressant effects (50% response rate and 40% remission [1]) than when the patient is conscious (40% response rate and 30% remission according to a large meta-analysis [2]).
They only measured response for the next three days. Is it possible k has an effect for longer than three days while placebo only lasts three days or so?
Unlikely. I see another comment says "The duration of the antidepressant effect is relatively short (days to weeks) and the antidepressant effect appears to diminish with repeated dosing."
> It is not magic and does not work in every case,
That is exactly what they are saying in the study. No better than placebo means Ketamine does not cure depression. If ketamine cured depression it would work in every case.
Increasing serotonin receptor density trough Ketamine use may relieve depression, but so can being cared for.
Your beliefs do not matter, biology matters. And it may in fact be that your "strong beliefs" in ketamine are why it helps you.
Something can be effective, especially more effective than a placebo, without being a cure. We have many "treatments" for all sorts of illnesses where the treatment isn't a cure. SSRIs for depression are a treatment, not a cure, just as one example. Hell, even Nyquil is a treatment for symptoms without being a cure.
When it comes to mental health we also have these big umbrella categories (depression, schizophrenia) that are made up of groups of illnesses. Schizophrenia has so many different causes, and thus different treatments, that viewing it as a single illness can actually be problematic.
Anyways, my point is that what you're saying makes no sense at all.
I don't have a position on the paper (I haven't even read it), but this statement you just made seems unjustified:
> If ketamine cured depression it would work in every case.
Depression can have many different causes, and people have many different biological variables, so it should not be surprising that a given treatment isn't 100% effective.
There are many example of this in the real world. With your logic, one might say: the sars covid-19 virus doesn't cause illness because some exposed people showed no symptoms. The families of the dead people would disagree.
Then why this singular focus on ketamine and psychedelics all the sudden? If it has many different causes why focus on activating a single serotonin receptor?
> and people have many different biological variables, so it should not be surprising that a given treatment isn't 100% effective.
Yes, and that is why we need to stop recommending mediation to people without knowing/researching the cause of each individuals depression. Why is there such limited nutritional and genetic testing on people with severe depression?
> With your logic, one might say: the sars covid-19 virus doesn't cause illness because some exposed people showed no symptoms. The families of the dead people would disagree.
If SARS2 does not cause illness in me that is all I care about. And if it does not cause illness in me you should all be interested in me.
> Then why this singular focus on ketamine and psychedelics all the sudden? If it has many different causes why focus on activating a single serotonin receptor?
Because it does work really well for a lot of people for whom other things don't work really well. Why would that be controversial?
No, in fact it does not "work well for a lot of people" as the study found. I am not making it controversial, you are, by denying what they found in the paper.
What you are really hearing is the massive marketing that is flooding the airwaves so some corporations can make a profit off of sick people and when it does not work they can say "Oh well" and walk away with the money and all you get is rebound depression.
Erm... you realize this isn't the first study on ketamine, right?
This is one study, that has not yet been peer-reviewed, that explicitly acknowledged the study design could be subject to significant subject-expectancy bias, using one particular treatment regimen, with a treatment group of ~20 people. At most, this study tells us that we have more to learn about what's going on and why we see significant effects. Both groups did see significant effects relative to base rates that are unlikely to be random even at that small sample size! Funny how you've come to radically different conclusions on the findings than the scientists themselves.
I am actually only vaguely aware of the marketing around this -- I've been following this space for about a decade and have read quite a few studies around it. Even if this study is generalizable and ketamine is no more effective at treating depression than the idea that ketamine will have an effect in treating the depression (placebo), we know from the evidence that it's having a significant effect relative to simple regression to the mean (depressed people simply getting less depressed without treatment). If it's a placebo, it's a powerful placebo, and placebo effects that are effective aren't a bad thing.
The FDA does not approve medicine based on beliefs.
I am sharing my personal perspective, alongside the fact that controlled studies have proven it is one of the most effective treatments known to exist.
Nobody thinks ketamine cures depression, it is one treatment.
Anyone who talks in such terms shouldn't have their opinions on medicine listened to. There's a reason that medicine typically sticks to such terms as QALY (quality adjusted life year) and other such terms to produce the best outcomes in a resource constrained environment.
By your reasoning, many things are "life savers", but not every intervention is equal, is it?
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.
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).
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.
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.
Anything that puts you under and also inhibits REM sleep, can have effects against depression. REM sleep is important for memory consolidation, and consolidation of memory is linked to depression in that the reliving and reconsolidation of painful memories is thought to be involved in at least some types of depression.
This is why sleep deprivation can have an acute antidepressive effect, and also why cannabis can have a similar shorter effect in some cases. Usually when there's no tolerance.
I think it's quite possible indeed that something similar happened during this study.
I've never personally done ketamine, but what these studies fail to take into account is the simple fact that for most of these classes of compounds, the subjective psychological experience is the entire mechanism of useful action, and looking purely at the physiological side is missing the forest for the trees. Unfortunately, delving into the subjective with double blinding is damn near impossible, since the whole point of blinding is to remove the subjective aspects of the study.
I know my DMT trips have been so potent of an experience, that if you took that out of the picture and just left the physical aspects, it would be little more than vasoconstriction and elevated heart rate, and I fail to see how that would do anyone any therapeutic good.
I think this was the entire point of this study. The interesting and positive experience is what knocks people out of their depression. It’s not that drug experiences are particularly magical in and of themselves, apparently getting anaesthetised is about as effective. Taking hallucinogens or disassociatives just happens to be a low effort way of having an interesting experience. It helps that it also feels a little transgressive and edgy.
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.
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..
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].
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"
> 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.
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.
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.
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.
Maybe I'm misunderstanding context, but my cat may need an MRI and I've learned it's standard in all veterinary medicine to use anesthesia for scans in order to keep the patients immobile.
Yeah, but they aren't trying to watch the effect of a drug happening. Anesthesia is accomplished with drugs. You can't give a person 3 different drugs, then expect a brain scan to tell you how one works in isolation.
Am I missing something blindingly obvious here? I would have assumed that the therapeutic effects of a strong mind-altering substance relies on being conscious to, you know, experience the effects.
Saying "It didn't work while the subject was asleep so therefore must be placebo" is just a bizarre position to take.
Imagine if a study stated "Cognitive Behavioural Therapy found to be ineffective on unconscious patients".
The trip is very short, but the effect as a useful antidepressant has to last a lot longer. It's not clear why the trip itself would have anything but short term effects on depression.
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:
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.
(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.)
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.
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.
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.
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.
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
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).
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.
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.
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.
I don't think SSRIs "mostly don't differ from placebo".
SSRIs only seem to work while you take them.
Some report side-effects that make them not worth it.
Others report that they're life-changing.
The case for Ketamine is that some periodic (but not permanent) use would bring you out of depression, rather than put it in check by indefinite drug use. As far as I understand, this is what's being challenged.
I suspect the response varies greatly by individuals: some respond a lot and some don't respond at all.
My experience with SSRIs was very positive. I took a low dose for depression for a few years and it helped significantly. I went off it a few years ago and my depression hasn't returned.
That study found a small effect size compared to placebo, and a large placebo response.
That seems consistent with OP's comment of "SSRIs...mostly don't differ from placebo" (emph added).
Also not addressed in the paper is the fact that SSRIs and SNRIs have well-known and pronounced side effects, with make it questionable whether double-blind studies are really fully blinded.
I’ve used both, ketamine and SSRI (fluoxetine to be exact). Ketamine didn’t do anything for me, other than being a funny experience, but it certainly did nothing for my depression.
Fluoxetine also didn’t magically cure my depression, but it made me more risk taking. And I certainly got the anti-depressant effect from the rewards of taking such risks (asking someone out, applying for a new job, asking for extra ketchup on your fries).
It’s still the patients job to fight the disorder, and SSRI can certainly help.
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.
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.
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.
> 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.
There's a simple reference that doesn't even need to be quoted: SSRIs are approved for treating depression in all major countries on Earth. And this approval required they pass phase 3 clinical trials, demonstrating effectiveness over placebo.
Also, given that they are typically preferred over other classes of anti-depressants (try-cyclics etc), we also know they have demonstrated better effectiveness than other drugs.
Given all this, it is obviously up to the person flippantly contradicting well-established medical practice to provide citations, or rightfully be accused of spreading FUD.
Do you disagree that SSRIs are an FDA-approved treatment for depression, should I find references for that? Or do you not know what is the standard for FDA approval?
Does drug being approved by FDA prove its effectiveness? If you can demonstrate without reasonable doubt that it does, i.e. that it's virtually impossible for a drug to be both approved by the FDA and as effective as placebo, then that would make a good argument.
In any case, any argument is better than just a "Stop spreading FUD and misinformation, you antivaxxer"-style comment.
The standard for drug approval by the FDA is that the drug has proven to be more efficient than the controls in a phase 3 clinical trial, to the satisfaction of the FDA's experts. The ESA has similar requirements, as do the NHS and other national bodies.
Given this, I consider that the right prior is to believe that a drug that has been FDA, ESA, NHS and many other national bodies is actually more effective than placebo. Which means, the onus is on you to bring evidence if you want to claim they are not - otherwise, "Stop spreading FUD and misinformation" is the exact right response.
> "Stop spreading FUD and misinformation" is the exact right response.
I strongly disagree. Everyone should have the right to "spread FUD and misinformation" as much as they like, and those who care should learn how to argue for the truth. Otherwise our society is pretty much guaranteed to devolve into a bunch of gullible morons.
The fact that nobody is willing to dig up any proof of effectiveness of SSRIs beyond "well, they're in use, so they must be good", but are perfectly okay with silencing people who disagree with them is both funny and scary to me. And annoying. Who the fuck are they to silence others?
It's exhausting to argue every obvious point over and over. If you want to claim that well established practices are wrong, it's up to you to bring the evidence. I'm not going to cite studies to prove the earth is round either.
If I say there's no teacup flying in orbit of Saturn, is the burden of proof on me? Or on the person telling me to stop spreading FUD and misinformation, because everyone knows there's a teacup orbiting Saturn?
Yes the burden of proof is on you. And in this analogy, the tea cups of saturn have been regularly observed for decades, so you have your work cut out for you.
Yes the burden is still on you. You're not just claiming you have not yet seen sufficient evidence of something existing, you are claiming it explicitly doesn't exist, ie that there has been some search conducted that should have found it if it had been there, but got a null result.
Of course in this case, not only can the tea cup be seen by Earth's telescopes, pictures of it are widely published in every book on saturn.
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.
Maybe it's the trip that helps.