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
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.
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.