24 comments

  • ipnon 59 days ago
    This is the million dollar question in psychedelic research today: Are the serotonergic effects of the psychedelic tryptamines primarily responsible for the therapeutic effects, or is the profound religious-mystical component indistinguishable from the positive changes observed? It is a profoundly expensive question. If pharmaceutical companies can deliver a pill that cures depression and gives life meaning without forcing users to face their angels and demons, then the FDA would give approval before the ink on the submission form had dried. As it stands, it would seem the predominant opinion in the community of psychedelic researchers is that the religious-mystical effects are the primary therapeutic vector. It is very difficult to meet God and walk away cynical and melancholy.
    • avidiax 58 days ago
      I have not heard the claim that it's the mystical experience doing the work. I have heard some theories about the glutamate system in the brain, which is strongly affected by e.g. ketamine, psilocybin.

      My experience with ketamine treatment for TRD is that it was lots of awesome shapes and colors and sense of melting into the floor, but definitely no communion with "god" or "mystics", no special reexamination of the self or amazing new perspective. Despite that, I still experienced some improvement in symptoms.

      I would hope that pharmaceutical research can reduce the time and expense related to this treatment and the side effects like nausea, and less on the moral panic that some people use these drugs for fun somehow.

      • s0berpotato 58 days ago
        I was introduced to the idea through a podcast of Lex Fridman hosting John Vervaeke. The idea is that being trained in some methods enables you to better re-frame ideas, reality etc. when under the effect of these substances and then to be able to integrate them to your life once you are sober. Basically to identify when something you identified and felt while under the effect is more "real" since your brain makes connections which don't usually happen. The training allows you to see these connections as something more than noise.
        • orange_fritter 58 days ago
          "Integration" is a buzzword but probably for good reason. It's not healthy to compartmentalize your own mind, because those compartments eventually express themselves in often dysfunctional ways if you're not fully tapped in to them. Meditation can help with "integration" as well although I'm sure every drug and method has different efficacy. I see this as a stepping stone to better mental health, because sometimes crazy stuff gets churned up and your next step is to process it in a healthy way, hopefully working with a decent CBT professional.
      • Stevvo 58 days ago
        "I have not heard the claim that it's the mystical experience doing the work."

        This claim has been the prevailing view of almost every psychedelic researcher from the 60s until ~10 years ago. It was also a big contributor to there being almost zero human research into psychedelics over that time period.

        It's still the prevailing view today, but not talked about because researchers can actually get funding if they lie about it.

      • hallway_monitor 58 days ago
        The trip you had was different than what people experience on LSD or psilocybin. You still had a trip. You broke out of your normal frame of mind and were able to comprehend things from a perspective that you couldn't previously conceive of. It seems to me like this is the important component and not whether you think you met God or your creator. It seems to make sense that the changes in yourself afterwards are due to the experience and not to the chemistry, and I wonder if the people focusing purely on the chemistry have never had a trip.
        • galangalalgol 58 days ago
          It also lines up with people getting similar benefits from serious meditation practice or dramatic life experiences.

          The common theme is that all these things change perspective, and none of them are entirely safe.

        • ohbleek 58 days ago
          My experience is that the majority of the people focusing on the chemistry have ever oriented a trip and it was the impetus for going into research that focuses on the chemistry.
      • dylan604 58 days ago
        >My experience with ketamine treatment for TRD is that it was lots of awesome shapes and colors and sense of melting into the floor, but definitely no communion with "god" or "mystics", no special reexamination of the self or amazing new perspective

        I've heard people also make similar comments to the LSD or psylocibin experiences as well. In my personal experience, that's purely a matter of dosage. Sounds like an obvious thing, but not everyone knows how a particular dosage will affect them. Any particular dose that is just a fun time for one person might be 1:1 meeting with a higher power for someone else.

        This is where I hope honest legal regulation would help. Rather than having to think about how many stems/caps you can eat from SourceA vs SourceB, you can just take a capsule that is accurately measured at X mg. Maybe you need to take half or take 2, but at least it would be the same each time.

    • lm28469 58 days ago
      > If pharmaceutical companies can deliver a pill that cures depression and gives life meaning without forcing users to face their angels and demons, then the FDA would give approval before the ink on the submission form had dried

      Instead of selling xxx tonnes of xanax&co per day worldwide and make absolutely outrageous profit doing so ? Doubt

      • ceejayoz 58 days ago
        Xanax has been generic for decades. This happens to all medications. Pharmacy loves newly patentable venues like this. It’d be another new, expensive pill or infusion to market.
        • parineum 58 days ago
          It's almost like the patent system is meant to spur innovation and development of new things.
      • jasonhansel 58 days ago
        You do know that these new psychedelic-like drugs are going to be patented and probably quite expensive, right?
        • fragmede 58 days ago
          That's not even hypothetical either. Ketamine was proven to have great anti-depressant effects so Johnson &Johnson came out with their own patentable formulation of it called Spravato.
          • BurningFrog 58 days ago
            Not exactly.

            Ketamine is well known to have great anti-depressant effects, but since it's long out of patent, no one has the incentive to spend $1B to get the FDA approval for it.

            So J&J invented the chiral twin molecule (the mirrored version), got it approved, and it's now sold as Spravato.

            To me this is 100% a regulation bug rather than some misfeature of capitalism or corporate greed.

            • avidiax 58 days ago
              I don't think it's a regulation bug to require a study to approve a drug for a certain use.

              The bug is that we don't incentivize funding expensive studies to discover unpatentable (i.e. cheap) treatments.

              The minimum "patch" would be that the governments of the major drug markets decide that effort and discovery of applications count as a basis for patents. Then a drug maker could fund their studies based on which drug candidate is the most promising, not which is the most promising but also novel and thus patentable.

              Much better, would be to have the governments presiding over the major drug markets get together and create a proportional fund to cover studies for the public's benefit. The economics of that would be similar to private companies, but at least the profits would go towards further research.

              • BurningFrog 58 days ago
                > I don't think it's a regulation bug to require a study to approve a drug for a certain use.

                That's actually not how it works.

                When a drug is FDA approved for a certain use, doctors are free to prescribe it for anything the think it's useful for. This is called "off label" use, and is ~20% of prescriptions in the US. This "loophole" cures a lot of people!

                And there are some clinics who do use regular Ketamine for depression. The main problem for them is that insurance will not cover this usage.

                > The bug is that we don't incentivize funding expensive studies to discover unpatentable (i.e. cheap) treatments.

                This I agree with. Though I'd expect some philanthropic billionaire to get to that long before any governments would.

            • Natsu 58 days ago
              Normal ketamine is a mix of both antiomers. Spravato is only s-ketamine in an inhaler.

              Also, while some see the trip as the point of this, I woke up at knife point due to psychosis caused by that. Yet it also really does basically cure depression, if not accompanying anxiety, and it is known to cause new psychosis.

              So I hope this works out and can be used on people who really need to avoid the psychosis caused by ketamine.

              • mmsnberbar66 58 days ago
                tbh never heard of ketamine psychosis
                • Natsu 58 days ago
                  It can apparently trigger them in susceptible people. I got to see it first hand.
            • kennedywm 58 days ago
              $1B? Is that an exaggeration? I can't seem to find anything close to that number anywhere. Perhaps you're mistaking the low-end cost of developing a new drug (around a billion, but it can be three times that) with the cost of FDA approval.
            • heavyset_go 58 days ago
              J&J didn't invent esketamine, they patented the use and formulations of esketamine for certain conditions.
            • feet 58 days ago
              They didn't invent anything, they just made a specific enantiomer
            • fragmede 58 days ago
              Alright we can call the FDA-regulations-on-top-of-capitalism thing Americaism, and say there's something wrong with that then. Because whatever part you want to blame it on, regulation bug or capitalism or corporate greed, something has gone wrong. Here's a medical technology that improves people's lives, but it's being held back from dying patients (an estimated 7% of men with depression go on to commit suicide) because they couldn't make enough money from it. I guess the real question is how could you structure regulations so as to incentivize getting FDA approval for unpatenable life-saving medicine?
      • yodsanklai 58 days ago
        Xanax is available in generic form and costs almost nothing.
      • sixQuarks 58 days ago
        Exactly. Very naive thinking.
    • pgt 59 days ago
      Something Huberman said on his podcast about alcohol is that the anti-depressive effects of SSRIs are not due to serotonin, but due to neuroplasticity.
      • jnovek 59 days ago
        Can you elaborate on this, please? I’ve never heard this hypothesis and I don’t totally understand what it means.

        Are you saying that SSRIs trigger changes in the brain? What changes? Why do they trigger these changes?

        Genuinely curious.

        • snek_case 59 days ago
          Yes, SSRIs trigger change in the brain. That's why the effect is not instant when you start taking the pill, the change needs some time to start to happen. In particular, it's believed that depressed people have lower levels of neuroplasticity. Their brains are less able to adapt to their current circumstances and they're stuck in negative thought patterns. SSRIs help increase the brain's ability to grow new connections and help the brain adapt, which helps you get out of negative thought patterns.

          If you're interested enough to watch a whole talk about this (you can jump to around 26 minutes): https://www.youtube.com/watch?v=k2AdebIbx5Y

          • loceng 58 days ago
            Leading also to an increase in rate of suicide compared to placebo, and arguably increased homicide as well; guns being the misdirection narrative.

            Edit to add: Downvotes even though in 2015 the FDA required "black box" suicide warnings on SSRIs because what I'm saying is true?

            • snek_case 58 days ago
              There's this narrative going around that antidepressants bad because medication bad, psychiatric industry evil, modern medicine bad, yadda yadda yadda.

              The problem is, everybody's brain chemistry is unique and different, because our genetics are different. Some antidepressants work for some people and not others. I've personally tried 5 of them. Only one of them worked on me, and it had some unfortunate side-effects (messed with my sleep). My ex-girlfriend used a different antidepressant (Zoloft). Personally, I've tried Zoloft and all it did was make me sleepy all the time, but I've found Lexapro was quite effective and useful for getting my life back on track.

              The way efficacy studies are done right now is, we measure the average effect on a group of people. That's doesn't really make sense when you think that everyone's genetics are unique and the antidepressant could be making some people better and some people worse, right? Maybe half the group feels better, but a quarter of the group becomes suicidal. Then on average, you see scores going up, you see the drug is beneficial on average... It would be kind of like giving everyone in a group a prescription for eyeglasses, all with the same prescription, and measuring that on average, participants can read better with the eyeglasses than not.

              In some ways, modern medicine is still very primitive. Flooding the whole brain with a chemical and hoping that it interacts with the right receptors and has a beneficial effect without too many side effects if you have the right genetics is very primitive. It's the best we have right now though, and antidepressants in general are probably more helpful than not, but yes, people SHOULD be aware that they might very well not work on them.

              • loceng 58 days ago
                "It's the best we have right now though, and antidepressants in general are probably more helpful than not, but yes, people SHOULD be aware that they might very well not work on them."

                MDMA, for example, seems far superior than anything else on the market - and what it does is simply causes the brain to release more serotonin than it normally would; SSRIs (etc) don't do that, they change how the brain actually functions.

                Your argument that "in general are probably more helpful than not" also then means you are okay that MORE PEOPLE kill themselves taking the SSRIs than would have otherwise - so you're okay with people dying, when rather there are alternatives - they just aren't mainstream because they haven't been promoted and marketed to doctors, nor advertised to manipulate people via ads by the pharmaceutical industry; I don't think that's acceptable or reasonable.

                • snek_case 57 days ago
                  As someone who's almost certainly used MDMA longer than you have, just no... MDMA is know to commonly cause depressive crashes. It's no panacea, it's a drug with it's own tradeoffs just like antidepressants. Do a google search for "suicide Tuesday".
                  • loceng 57 days ago
                    As someone who uses the very shallow metric of "length of use" - thinking it is somehow a strong argument point, I'm guessing my judgement, critical thinking, understanding is greater than yours.

                    The "tradeoff" is MORE PEOPLE die of suicide with SSRIs (et al) being prescribed than if they weren't allowed to be prescribed.

                    "MDMA is know to commonly cause depressive crashes" is another shallow-narrow scope counter argument you put forward. A "depressive crash" - and arguably, in the right container with the right guidance can be avoided, and in fact is underlying depressed state that a person is connecting to - is not akin to people literally killing themselves from SSRIs.

                    '"Suicide Tuesday" is the nickname given to the trend for people who use xtc all weekend committing suicide when they fully come down from the high on Tuesday.'

                    You're bringing in abuse, an excess of something, as a supportive argument point? People also accidentally or purposefully recklessly drink too much or take too many opiates - perhaps in hopes they die.

                    You also put forward a straw man argument - I never said MDMA was a panacea.

                    Are you aware of the MAPS.org FDA approved clinical trials for MDMA-assisted psychotherapy for veterans with an average of 17.5 treatment resistant PTSD, where after just 2-3 sessions, in 1 year time 80% no longer qualified for a PTSD diagnosis vs. the placebo group where 80% had no improvement? Using therapeutic doses of 100-120mg.

                    Do you know what the efficacy of SSRIs are, what the tradeoff your arguing and in support of? 3-7% better than placebo depending on the research you look at - and you kill people (through suicide and homicide) that otherwise wouldn't have died; and this happens at prescribed doses, not abusing the medications.

            • heavyset_go 58 days ago
              I've written about this in the past a lot[1], but 5HT2C activation is the primary cause of suicidal ideation when starting SSRIs. Once 5HT2C is downregulated after a few weeks, the feelings and akathisia caused by 5HT2C activation dissipate, as does suicidal ideation.

              5HT2C activation can be very, very uncomfortable, and can exacerbate depression, anxiety and suicidal thoughts. Downregulation results in an equilibrium where those feelings and symptoms are relieved over time, however.

              [1] https://hn.algolia.com/?dateRange=all&page=0&prefix=true&que...

              • loceng 57 days ago
                So your argument is, if your claim is true - and if it's true in all cases or not - that those excess, unnecessary suicides, will happen within the first "few weeks" - and then that's acceptable to you that more people kill themselves on SSRIs (etc)?

                And there are other options - far better, far less harmful options do indeed exist - but the medical-pharmaceutical industrial complex hasn't made them widely known or available because getting people dependant on (due to severe withdrawal in most cases, another thing they lied about; like how it was lied about the new opiates weren't addictive to get them mass prescribed) medications that are patented allows pharma to make an increasingly large recurring revenue stream; and who cares if X% of MORE people kill themselves than otherwise would have if you're now making many $ billions per month - and as a doctor all you need to do to "help" someone, and the only competency and knowledge you need, the most shallow complexity you need to understand, is to write a prescription for someone?

                And then the other side of the coin is the increased homicide, and the responsibility that people they should take on if they want these medications available - on top of being in part responsible for the increased suicides - are all of the mass shooting deaths; let alone the increased ideology and antisocial behaviour we have in society could arguably be heavily influenced by these medications as well, and the widespread harm that causes to society.

        • twic 58 days ago
          It's been decades since i studied this stuff, but i remember there being a very promising line of work on the connections of the growth factors BDNF and NGF, which promote neuroplasticity, to depression. Seems it's still being worked on:

          https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174655/

          https://pubmed.ncbi.nlm.nih.gov/30235967/

        • heavyset_go 58 days ago
          The theory is that hippocampal neurogenesis could be a factor in the treatment of depression. The hypothesis is based on the fact that effective antidepressants trigger neurogenesis, and not all antidepressants have the same mechanisms of action.
    • sallystarace 58 days ago
      I am a religious person who happens to have enjoyed LSD in my time. I have had the most profound experiences during my many trips, and not a single one that was at all like the sense of awe I get from worship.

      I love the headspace that you get into during the trip. It is great for finally addressing issues that you have set aside. After the trip however, you think that all your ideas are good, then it wears off, so either way it is not useful just by itself.

      • orange_fritter 58 days ago
        I had a friend's mother who had very profound experiences on LSD, so she wrote them down. After a few weeks, she read the diary. "I am the peanut." I think LSD is not a panacea but it can help you shake some stuck, unhelpful thoughts.
      • ipnon 58 days ago
        I made a poor choice of words. It would have been better to say “the experience of the ineffable and reckoning with intensely personal beliefs.” I meant no blasphemy with my use of religious and Christian terms.
      • mistermann 58 days ago
        Note that "you" refers to you, and some other people, but not necessarily all other people.

        I would even classify this realization as an exception to your "is not useful" rule.

    • IIAOPSW 58 days ago
      >profound religious-mystical component

      If you're meeting god on your trips, I'm willing to bet you believed in god to begin with, and possibly believed you would meet him before your trip started. You see what you were expecting to see. To say that there is a religious-mystical component of the psychedelic experience, well, if its real it for sure isn't universally felt.

      • hawaiianbrah 58 days ago
        Not universal, sure, but I thought I recalled in “How to Change Your Mind”, they talk about studies done with psilocybin that definitely result in people of all walks of life experiencing a sort of super spiritual trip, even atheists.
    • loceng 58 days ago
      They're looking for a pill they can patent, and then will demonize and do a fear campaign on the non-patentable options.

      If the supposed anti-depressant effect of whatever specific molecule they claim doesn't induce relatively rapid nerve generation, opening up previously closed or blocked off pathways - that pruned off arguably due to trauma and lack of use - then they likely aren't as powerful as where the mystic effects come from; it's the temporary turning off, removing the ego mind from the algorithm of the mind/the mind's eye - allowing you to see reality very differently then you've been formed rigidly in beforehand; some tribes give Ayahuasca to their babies to keep them open as they develop, rather than letting trauma and/or natural processes lock them into more narrow behaviour and thinking patterns.

    • feet 58 days ago
      There are other serotonin receptors at which psychedelics are active besides 2a
    • bowsamic 59 days ago
      [deleted]
      • isoprophlex 59 days ago
        The experience is highly variable between people. I'm sorry you had such a rough time, and I'm hoping that things are at least slowly getting better for you.

        About the god thing, my 2 cents. "god" doesn't always mean Christian White Old Guy on a Cloud Looking Angrily Downwards. There's a less narrow interpretation.

        If psychedelics strip away your day-to-day preoccupations, and show you life with a vastly different set of mental filters in place, many people experience a transcendent feeling of belonging to something bigger than their sober selves. A connectedness to other humans and nature that goes beyond ordinary experience. The idea that death isn't so bad, only suffering is; and suffering is the price we must pay for the ability to see its opposite, beauty.

        Which people then conversationally condense to "yeah you meet god"

        • bowsamic 59 days ago
          So they just mean a transcendent, spiritual experience?
          • isoprophlex 59 days ago
            Yeah i guess that's a lot more accurate if you want to avoid the cultural baggage of the god-word
          • swayvil 59 days ago
            It expands your consciousness is a popular way of describing it.

            Imagine a chronic obsessive cellphone gazer. One day he lifts his nose from the screen. Sun! Clouds! Birds and squirrels!

            Except moreso.

            • bowsamic 58 days ago
              But shouldn’t God be in all things, including the profound, if he’s really the Absolute? I doubt he’d be limited to our human conception of nature
              • swayvil 58 days ago
                I prefer to observe first, theorize second.
                • bowsamic 58 days ago
                  So He is more of a Kami?
                  • swayvil 58 days ago
                    That would be one of those theories.
            • canadiantim 58 days ago
              This is a really good explanation
          • avisser 57 days ago
            For me, on one of my trips, I had a profound feeling of being part of life in the universe. Like this feeling of how vast the universe is, but it's all dead rocks, except for everything on this tiny blue world (and hopefully more). I felt like a part of that.

            So no deities but spiritual like what you said.

      • PraetorianGourd 59 days ago
        I am confident the OP meant “meet God” as short-hand for “a spiritual and transcendental experience wherein the ego is destroyed and rebuilt anew with a profoundly different perspective”.

        I don’t think anyone would earnestly claim that there is zero risk to any hallucinogenic experience. One of my hopes is that through study we can better understand the ingredients that lead to profoundly positive experiences vs. profoundly traumatizing experiences. And anyone who claims we know that today is acting in bad faith.

        • ipnon 59 days ago
          Roland Griffiths’ foundational psilocybin study did not have any adverse outcomes. They used a simple protocol: no patient or patient family history of schizophrenia or bipolar, patients underwent cognitive behavioral therapy before and after the trial, patients were made to develop a warm and trusting rapport with the physicians before administration, and a physician was on hand for the duration of the psilocybin administration to coach the patient through unforeseen disturbances and administer anxiolytics in the case of panic attacks. With this simple protocol they reported no adverse affects, although they also did not report a 100% rate of efficacy. Griffiths wrote an entire separate study on this protocol, it is self-recommending.
          • PraetorianGourd 58 days ago
            This one? https://pubmed.ncbi.nlm.nih.gov/27909165/

            Terminal cancer patients, those expecting to die and “meet God” soon, are a very, very niche audience compared to a general population with non-specific major depressive disorders.

            But at the same time, I love this. The more study, the better!

            • ipnon 58 days ago
              After seeing the responses to my original post I wish I had used different terms. I did not mean "meeting God" literally, but used it more as a metaphor for "meeting your maker": coming to terms with universal human problems like mortality, our relations to our friends and family, the nature of good and evil, things of that nature. "Meeting God" I thought would sum all this up poetically, but you can always count on HN to take things literally!

              Griffiths' research is all high quality. He is the pioneer in making this field of scientific research palatable to the mainstream medical establishment.

      • Schroedingersat 59 days ago
        Meeting is just a way of describing a numinous experience. I have heard atheists, christians, pagans and sikhs alike use the term. Mathematicians often use it to describe especially profound proofs regardless of religion.
      • ruined 59 days ago
        if i were unhappy with my life after an epiphany, i would simply act to change my situation
        • naasking 58 days ago
          > if i were unhappy with my life after an epiphany, i would simply act to change my situation

          It's anything but simple if you're depressed. You seem to think that insight drives motivation, but in depressed people these are often decoupled. You can have all the insights you want but the motivation to do anything just does not manifest.

          • ruined 57 days ago
            my post is formatted after a meme, in which the joke is the speaker is ignorant of the difficulty inherent in the suggested course of action.

            it's a little tongue-in-cheek. of course changing your life is hard. but, if you are dissatisfied with your life, it is also the only solution.

        • bowsamic 59 days ago
          The only great impulse of change I had after my trips was an intense urge to kill myself
          • andai 59 days ago
            Curiously, antidepressants can trigger suicide in suicidal people because they give them the energy to act on those impulses.

            My friend was suicidal, and psilocybin was the only thing that made him go back to wanting to be alive (though the effect only lasted ~2 weeks each time).

            • parineum 58 days ago
              >Curiously, antidepressants can trigger suicide in suicidal people because they give them the energy to act on those impulses.

              As someone with somewhat first hand experience with this, it's not exactly "gives them the energy".

              The anti-depresents I started taking worked exactly as advertised. The "problem" was I wasn't just depressed, I was also just not happy with life. Anti-depresents can get you out of a depression but they won't make you happy.

              It was a bit enlightening to understand the difference between the sadness I felt and the depression but it can also make you feel more helpless when the depression lifts and you still don't really want to wake up tomorrow.

              As a result of this experience, I think it's irresponsible to prescribe anti-depresents without accompanying therapy.

          • ruined 59 days ago
            what, with no reason? you didn't have a why? fix the why.
            • bowsamic 59 days ago
              It didn’t show me a why it just showed me that I want to die. Other LSD users say I should take more at a higher dosage but that seems like a bad idea
              • chaps 59 days ago
                What dosage did you take? I've heard low doses can actually be a deeply frustrating experience.
              • ruined 58 days ago
                you keep looking at LSD for feelings you're having while sober. examine your reasons for your feelings now. if you can't identify your own motivations, how can you attribute cause like that?
                • bowsamic 58 days ago
                  I wasn’t ever suicidal before, I was after, that’s all I know
                  • mistermann 58 days ago
                    A theory / thought experiment:

                    Take "it just showed me that I want to die" and unpack every single word into an absurdly and "pedantically" complex, comprehensively and perfectly correct articulation of the(?) precise meaning in this context. In doing so, use various forms of articulation, not only paragraph/narrative form.

                    If you are doing it right, ideally you will find yourself having to fight against your own mind at several points during the analysis.

                    Work on the problem for a month or six, even just two or three minutes at a time now and then. I propose that at the end of this process, you will possess more knowledge than you did before.

                    There are various techniques to accelerate this process, but I will let you figure those out on your own along the way. As a hint: consider various topics of discussion that arise on the website you are on.

                    I should probably also note: this is not necessarily a risk-free undertaking, so maybe build some safeguards into your methodology.

                    • bowsamic 58 days ago
                      I have literally no idea what the hell you are talking about
                      • mistermann 58 days ago
                        Too much to ingest at once, fair enough!

                        "unpack the meaning of a word"...this makes sense?

                  • ruined 57 days ago
                    if you are unable to identify motivations and reasons for your own actions and desires, there is certainly a more complex causal relationship here, and you probably need some assistance to discover it.
                    • bowsamic 56 days ago
                      I am on a waiting list for therapy, as I said. I'm not sure what else you want from me. I have no idea why I want to die
            • ceejayoz 58 days ago
              Not all whys are known, and not all known whys are fixable.
    • jokoon 58 days ago
      Meeting God or finding meaning in life is not on the requirement list for the FDA. There other ways to evaluate treatments for depression.
    • Silverback_VII 59 days ago
      What about very cheap and nonetheless effective "treatments" like exercise,sleep hygiene, magnesium, zinc, fish oil, onion, galic, saffron and even simply eating edible non psychoactive mushrooms? all these have been associated with a reduction in depressive symptoms.

      but obviously nobody can make a fortune with these simple advices.

      • xen2xen1 58 days ago
        I'll take it in good faith you're not just being a nasty troll, but that's a LOT of work for someone who is depressed, enough to be a non-starter. In reality drugs should probably be seen as a way to start better life habits. The benefits of hose habits are real, but getting there is a lot.
      • 6stringmerc 59 days ago
        This is true but it’s modeled after behaviors in the big picture - you just described a lot of effort and commitment versus taking a pill, maybe doing therapy / counseling once a week or two, and just living life. I’m getting back into fitness routine and it takes time, effort, and money that typically aren’t subsidized by the corporate gigs I’ve worked.
        • nonrandomstring 59 days ago
          > you just described a lot of effort and commitment versus taking a pill

          Funny but I have come to regard the "effort and commitment" as part of the recovery mechanism. Causal or concomitant, I have no idea, let's just say 'linked'.

          By the same token I have come to regard "convenience" as, if not a great evil, some kind of joker/trickster that lures us down a dark path.

        • j-bos 59 days ago
          This strikes me so much. Exercise is a proven health booster and yet health insurance doesn't cover gym memberships or exercise equipment. Why is that?
          • michaelmarkell 59 days ago
            Treatments like exercise also have high variance - depending on the circumstance and how diligently you implement it, it may have no effect, a big effect, or even cause injury in the worst case.

            Insurance likes low variance outcomes because they’re easier to model accurately

          • msgilligan 59 days ago
            I’m not in the insurance industry and have no idea what the actual reason is.

            And I don’t know what the statistics are, but a significant percentage of people with gym memberships rarely go to the gym. I suspect the percentage of people with free (i.e. payed for by insurance) insurance who rarely go would be much higher.

            • msgilligan 59 days ago
              Further thought: Maybe insurance companies could pay, reimburse, or reduce rates for those who can reliably prove they are exercising.
              • jan_Inkepa 58 days ago
                My insurance offers reduction if you pass a basic health check each year. It's kinda nice but also sets up a slightly adversarial relationship with my doctor, which I don't like.
                • jlokier 58 days ago
                  Ideally the health checks would be done with someone else, to reduce that adversarial conflict of interest problem.

                  Maybe your doctor should even get a small reward each time you pass the basic health check, so that in aggregate they are better aligned with keeping people in shape for those checks.

              • heavyset_go 58 days ago
                I've seen plans that subsidize gym memberships.
          • parineum 58 days ago
            >health insurance doesn't cover gym memberships or exercise equipment

            Because neither of those things are necessary to exercise.

            I bet if you asked your GP for some body weight exercises you could do at home he'd happily provide some for you and insurance would cover the visit.

      • guerrilla 59 days ago
        As I've argued before, if someone can diet and exercise then they aren't very depressed, so most of that advice is useless and why people work on drugs since taking a pill daily is much easier to accomplish for someone who can't get out of bed or find a reason to do anything at all.
        • lm28469 58 days ago
          But that's the thing, a lot, if not the majority, of people getting prescribed these awful drugs aren't depressed, they just have a shitty life, a shitty job, no hygiene, no nutritional education, are going through a hard place, etc.

          Giving pills to these people is a crime

          • heavyset_go 58 days ago
            It's not your place to decide if the quality of life improvements others experience with medication are worth it or not. Sometimes life gives people circumstances that are hard to cope with, and sometimes medication helps them cope.
            • lm28469 57 days ago
              > It's not your place to decide if the quality of life improvements others experience with medication are worth it or not

              It's our place as a society to ask questions and be very concerned about the fact that more and more people need medication to operate as normal human beings, especially when these medications are dangerous and/or addictive

          • c4ptnjack 58 days ago
            all of those things cause depression, leading to a nuerobiological effect needing the treatment
            • lm28469 57 days ago
              You forget the part where the treatments can cause addiction, sexual disorders, suicides, emotional issues, cardiovascular diseases, &c.

              These things are prescribed way too easily to people who have tons of others ways to get out of their issues without relying on these potentially dangerous drugs.

              Medication definitely has a place, but the current trend of over prescription is very alarming.

              It's so much more complex than "take that pill and you'll be happy", in lots of countries these things are prescribed by general practitioners without any kind of mental or lifestyle evaluation. You just show up there: "hey I feel down and anxious" and boom you go home with 6 months of xanax. In my country (France), 25% of people consume antidepressant in any given year, 12% are regular users, several studies concluded that out of these 25%, only 1/3rd have signs of depression [0], I know it's the same thing in other EU countries, and apparently also in the US [1]

              [0] https://www.slate.fr/monde/76468/depression-medecins-prescri...

              [1] https://archive.nytimes.com/well.blogs.nytimes.com/2013/08/1...

          • guerrilla 58 days ago
            Why do you think you know this? What do you base it on?
        • Silverback_VII 58 days ago
          Magnesium, zinc and fish oil supplements don't seem very hard to take. And what about a cold shower of 2 min each day? also easy to implement without much effort if one is willing to suffer a little bit.
          • guerrilla 58 days ago
            > Magnesium, zinc and fish oil supplements don't seem very hard to take.

            Obviously people do that and it works for a handful, but rather ineffective in general.

            > willing to suffer a little bit.

            Yeah, no. That's definitely not something a seriously depressed person can do, I say as someone doing that now. People who suggest these things are completely out of touch with what depression means. You'd be lucky if they were taking shows at all.

            • Silverback_VII 58 days ago
              >but rather ineffective in general.

              Study with 22 people with major depression: "Treatment with both omega-3s was associated with a significant improvement in depression, with an average 64% drop in symptoms for the EPA group and 71% in the DHA group."

              https://www.webmd.com/depression/news/20210618/fish-oil-supp....

              • guerrilla 58 days ago
                > Study with 22 people

                i.e. worthless. DHA is being studied and has massive effects on inflammation but the science is definitely not there for depression. You need to adjust your epistemology if you are making decisions based on tiny studies like that.

                • hallway_monitor 58 days ago
                  Seems like 22 subjects is better than zero. One is better than zero so if it worked for one person that's probably worth trying for a second. I hate how people act like you can't try anything until it has had a study with thousands of people over years. Sure, that increases confidence but in most cases the study doesn't invent a treatment, it just adds trust in the effectiveness.
                  • guerrilla 58 days ago
                    No, that's not how it works at all or else we should also recommend fairy crystals at the same time. Anyway, people do try it. That's the point. It's common practice and it's known to not work for most people with severe depression. It's only a matter of time that we have strong meta-meta studies showing that definitively. For now, here's a Cochrane meta-study that reviews 35 studies [1].

                    1. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...

                • Silverback_VII 58 days ago
                  >i.e. worthless

                  Certainly not and considering the almost non-existent side effects, it is at least worth a try since it looks very promising. You are right that it is a tiny study but it doesn't mean that it has no value.

                  I have to say that I know people like you very well, I almost can hear the "go see a therapist and take your meds" or better "don't try and certainly don't think you can solve this on your own". A positive force first and foremost acknowledge people's potential and doesn't put roadblocks everywhere.

          • astrange 58 days ago
            The first two are hard to take. Almost all magnesium formulations don’t do anything, and they’ll mostly sell you those because they’re cheaper.

            If you take the wrong zinc brand it gives you the worst nausea of your life. Although I haven’t heard of even good ones helping with depression - it is a pretty strong aphrodisiac and testosterone booster, but that’d just be an additional distraction on top of being sad.

          • c4ptnjack 58 days ago
            Meta studies show those supplements in fact have little to no quantifiable impact on most people's depression out side of placebo
      • BurningFrog 58 days ago
        Those things can often work, but the depressed mind is often 100% convinced that there is no way out. Nothing you do can make a difference.

        Intellectually you can agree that all those things are worth doing.

        But some deep calculating part of your mind will see that between hard work that will not help, and doing nothing which will also not help, the latter is the rational choice.

      • okaram 58 days ago
        1. Most of those are not actual treatment, and the association is spurious.

        2. Tons of depressed people are still depressed even though they exercise, eat well and sleep.

        3. Tons of people are making fortunes peddling these and similar 'cures' to everything :)

  • isoprophlex 59 days ago
    As someone with a background in organic chemistry, I have a silly nit to pick with the phrasing "LSD-like molecules"

    These molecules look nothing like LSD! Structurally they are as different from eachother as a dog is to a flying squirrel.

    Of course they act like LSD by binding to 5HT2a. This is absolutely terribly pedantic and probably only applies to the mind of someone who wants to see the molecules first, and the rest of the research later, but I would have preferred "Molecules that act like LSD can counter depression without the trip"

    • lifeisstillgood 59 days ago
      "This is absolutely terribly pedantic and..."

      Don't worry. You're in the right place :-)

      • motbus3 59 days ago
        Don't worry Y in Ycombinator is for pedantic XD
        • arjvik 59 days ago
          Actually if we're being pedantic, it's capitalized as YCombinator.
          • kn8 59 days ago
            Y Combinator ;)
            • panxyh 59 days ago
              But Why Combinator?
        • chalst 59 days ago
          Fixpoints are too powerful a concept to be added safely to any but the most pedantic minds.
    • xdfgh1112 59 days ago
      "LSD-like" can mean "acts like" just as well as "looks like", so you're being hyperpedantic.
      • snek_case 59 days ago
        Actually, I don't think he's being pedantic at all. LSD binds to a wide array of proteins and receptors in the brain (including dopamine receptors) and the binding profile of this substance is most likely very different from that of LSD. Likely to be much more specific to 5HT2a, closer to psilocybin than LSD. IMO they just said "LSD-like" because it would make a nice headline.

        See this diagram on wikipedia for LSD binding affinities (lower means more affinity): https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#/me...

        • realce 59 days ago
          Scientists are excited about a new hotdog-like food that prevents depression without the meat: cake!
      • quietbritishjim 59 days ago
        I guess it's like the question of: could you say an SSD is "hard drive-like" even though it works totally differently? I would say you validly could.
        • boloust 59 days ago
          While you could say a drug is "LSD-like" because one of the many receptors it targets is also targeted by LSD, that would be more akin to saying a keyboard is "hard-drive-like" because they both plug into a computer.

          Biology is extremely complex, and even drugs that have similar receptor binding profiles can have very different effects.

          Most drugs will have action across a wide range of receptors. There are a multitude of drugs that target the 5-HT2A receptor, including the most common antidepressants and antipsychotics, for example.

          • jcynix 59 days ago
            Hmm, depends on the receptor, where the molecule or the hard drive docks to?

            So USB hard drives might be keyboard like (for USB keyboards), but hard drives which dock to the SATA connector aren't …

            Anyway, such comparisons sometimes limp and sometimes don't have any legs at all.

      • ekianjo 59 days ago
        or alternatively the headline is just super clickbaity by adding LSD when it was not needed.
        • alehlopeh 59 days ago
          So using LSD in a title makes it clickbaity? Come on, that’s ridiculous. Don’t squeeze the life from that term by applying it to anything you don’t like.
          • Retric 58 days ago
            The comparison to LSD is sensationalized and misleading making it clickbait even if the link is not deceptive. https://en.wikipedia.org/wiki/Clickbait
          • ekianjo 58 days ago
            > So using LSD in a title makes it clickbaity

            Yes alluding to something illegal makes it clickbaity.

    • bfung 59 days ago
      Haha, I feel ya -

      As a computer/tech person, when business people say real-time, or AI (when they just want simple statistics) I get the same annoyance and react with the pedantism (you don't need REAL-time, just sub-second latency).

      But for the non-experts and layfolk, many KNOW what LSD does, but none of us know what 5H... yup. =)

      • throw827474737 59 days ago
        Being pedantic (and a smartass) the same, "real-time" original definition is that some calculation/reaction of the system is guaruanteed to be always bounded and within the system rqequirements (usually for it not to fail). So depending in the use case and application, real-time can be sub-second, or even seconds/minutes.

        E.g. if the instagram folks require likes to happen in real-time for all users around the world that is fine to be within seconds, but a safety critical application in a car must respond within milliseconds.. "you don't need REAL-time, just sub-second latency" in general does not make much sense, sounds more like this application real-time requirements just lie in the sub-second resolution region?!

      • SirRuthven 59 days ago
        > react with the pedantism…

        Some pedant has to say it: shouldn’t that be “pedantry”?

        • bfung 59 days ago
          LOL - true, thx.
      • erikpukinskis 59 days ago
        Simple statistics can be AI. AI just stands for Artificial Intelligence. An if-statement can be AI.

        Are you thinking of machine learning?

    • kaoD 59 days ago
      I'm curious about this and someone here might know. Why do they bind to the 5HT2a receptor yet not cause trips?

      I always assumed the difference in strength between, say, DMT and psilocybin was because DMT was "more agonist" (pardon the layman terms).

      Do these molecules intrinsically not cause trips, or is this more akin to microdosing? Would a higher dose of these molecules cause a trip?

      • valec 59 days ago
        different ligands can bind to the same receptor in different ways and cause different signaling cascades. look up "biased agonism"
        • tux3 59 days ago
          It's fascinating how Nature effortlessly creates these leaky abstractions, completely opposite to how we design systems, and makes good use of the constant layering violations where we would see unmaintainable code that we can't wrap our heads around.

          When we design signaling mechanism, they deal with the layer below while presenting a simpler digital interface to the layer above. Your Ethernet PHY has to care about electrical details, but to the IP stack it's just a stream and sink of bytes. No weird side-band edge cases effects, like if the IP stack could affect DC balance by changing the mix of 1s and 0s it sends out.

          But those G protein-coupled receptors — or whatever it is — it seems like if you don't want to miss important side-band edge case signals, you really have to model them as this 3D structure that threads through the membrane 7 times, that you can jiggle on one side to change the shape it has on the other side.

          The receptor-agonist abstraction makes total sense from a human perspective (and it's a good and useful model), but at the end of the day the Wikipedia lists nine different types (partial, super-, inverse, co-, irreversible, biased, ..) of agonists, multiple of which can apparently apply to a single ligand ("can concurrently behave as agonist _and_ antagonists at the same receptor, depending on effector pathways or tissue type").

          Nature seems to have absolutely no preference for clean abstractions, and I don't know how to feel about that, but it's fascinating to me. Maybe my horrible code is actually universally optimal under a non-human optimizer =)

          Or maybe it's just intrinsically hard to make clean abstraction out of chemistry? I wonder if it _would_ be beneficial for a large system like the body to be built out of cleaner (less powerful) abstractions that don't expose all their internal details, but maybe stochastic DNA mutations with natural selection isn't a good enough optimizer to find that place in humanity genomespace?

          Death is so out of style compared to Adam and SGD.

          • magicalhippo 59 days ago
            > like if the IP stack could affect DC balance by changing the mix of 1s and 0s it sends out

            For those that don't know, avoiding DC bias due to the distribution of 0's and '1 in the transmitted data is a real concern and something that's engineered into many transmission protocols. A common choice is a form of paired disparity code[1] like 8b/10b[2], found in HDMI, DisplayPort and PCIe 1.0/2.0, and variations[3] like 128b/130b for PCIe 3.0 or 128b/132b for USB 3.x.

            [1]: https://en.wikipedia.org/wiki/Paired_disparity_code

            [2], https://en.wikipedia.org/wiki/8b/10b_encoding

            [3]: https://en.wikipedia.org/wiki/64b/66b_encoding#Technologies_...

          • kortex 58 days ago
            > No weird side-band edge cases effects, like if the IP stack could affect DC balance by changing the mix of 1s and 0s it sends out.

            As someone who started in chemistry and moved into computers, this made me laugh out loud hard. It's an absurd and absolutely perfect analogy for the weird shit biology does all the time.

            I think it is intrinsically hard to make clean abstractions out of chemistry. Biochemistry even more so. Chemical synthesis in the lab is all about the loop of: react under ideal conditions, work up, extract, purify, repeat. Biochemistry is just...fancy soup.

            You get some barrier, especially for really nasty stuff, like peroxisomes, but there is just tons of diffusion. Especially with neurochem, where usually drugs have to be the right lipophilicity to cross the BBB but also specific to targets.

          • heavyset_go 58 days ago
            I disagree. We build happy paths for our designs, but there are plenty of vectors for attack and modification outside of things like exposed APIs and other "contracts" we bake into systems. You see this all the time with viruses, jailbreaks, virtualization, and hardware hacking.

            If we had instrumentation that allowed us to poke and prod at microscopic integrated circuits, there would be a lot of attack vectors exposed there, too.

            After all, our abstractions are built upon implementation details, and if you can play with the implementation itself, those abstractions and contracts are up for grabs when it comes to modifications.

          • stackbutterflow 59 days ago
            I think that's called five-billion-years-of-trial-and-error driven development.
          • nonrandomstring 59 days ago
            > like if the IP stack could affect DC balance by changing the mix of 1s and 0s it sends out.

            Brilliant! I'm going to steal that for a datacoms lecture to hammer home 'layers'.

      • ekianjo 59 days ago
        Because not just one receptor is involved
    • sva_ 59 days ago
      Where can you see these molecules?

      I wonder how they look like compared to serotonin and some tryptamines

      https://i0.wp.com/sitn.hms.harvard.edu/wp-content/uploads/20...

    • doctor_eval 59 days ago
      Well, they are both mammals, so at some level a dog actually is squirrel-like.
      • erikpukinskis 59 days ago
        A dog is extremely squirrel-like. Compared to a fish or a fungus or a sequoia a squirrel and dog are basically the same.
    • carrychains 59 days ago
      Your preference is unnecessarily pedantic and logically reduces in specificity to the exact phrasing that peeves you.
    • gpcr1949 58 days ago
      (I have a background in organic chemistry as well)

      I somewhat disagree with this. Measuring chemical similarity is notoriously difficult, see these two interesting blog posts from a cheminformatic angle [0][1]. The molecules are not only pharmacologically similar but even chemically at least somewhat similar, perhaps in the same way a dog has much more similarities with a flying squirrel than with, let's say a church. I would argue the main active molecule [2] is relatively similar to LSD (compared to other well known psychedelics) due the presence of the tetrahydropyridine unit, which is also present in LSD, albeit connected to the 3 position of the indole in a different way. Also, there is a pharmaco*phor*ic similarity: positively charged N and 5-6 fused aromatic ring oriented in the same way with some degree of rigidity (though you could argue this is just a roundabout way to bin it in a category of 5ht2a binders). So in this way, I feel that it has something like an LSD-based design philosophy to it.

      Quantitatively, making use of one of the most common similarity metrics, the Tanimoto similarity of ECFP4 fingerprints, the similarities to LSD, psilocin, DMT and mescaline are respectively 0.17,0.15,0.18 and 0.07. In other words, the similarity is low to all compounds and the indole derivatives are about equally far removed from the compound from TFA, although a bit closer than mescaline. The numbers probably rather follow your line of reasoning.

      Finally, I'd also like to remark that I consider the fact they generated quite novel chemical matter a plus: most of the people working on generating new 5HT2A agonists are currently using quite conservative classic SAR approaches, for example creating constrained (e.g. Lophora's azetidines) or deconstructed versions (e.g. Delix's ring opened LSD variants and ibogaine analogs) of better known compounds, or even just prodrugs of known compounds (Field trip's FT104 is a 4-HO-DIPT prodrug). This will also make it easier for them to fight patent challenges if this series of compounds will lead to a clinical candidate.

      [0] http://www.dalkescientific.com/writings/diary/archive/2020/0...

      [1] http://www.dalkescientific.com/writings/diary/archive/2020/0...

      [2] The SMILES string of molecule 69 from the paper, which is the one from the cryo EM structure: `C[C@@H]1C=C(c2c[nH]c3ncccc23)CNC1`

    • tpm 59 days ago
      Or even "Molecules that act like LSD in regards to 5ht2a can counter depression without the trip". Because LSD is also active at other targets, and presumably those new molecules too.
      • ithkuil 59 days ago
        Or perhaps they don't, that's why you get some effects and not others (as desired)?
        • tpm 59 days ago
          The probably strongest and most selective currently known 5ht2a agonist, 25I-NBOMe, is a psychedelic, and also (unlike LSD, which is less strong and less selective), much much more toxic and user reports say that the effects, both on body and mind, are much worse. So this is a complicated topic and I look forward to reading user reports from these new molecules, if they decide to test them.
          • gavinray 59 days ago
            Eh, I wouldn't call the mental effects of NBOMe's objectively worse than say LSD -- just different

            Now, the body load/vasoconstriction + other physical effects, definitely. You can always tell the NBOMe is kicking in when you get shuttery cold from vasoconstriction and have a weird motor rigidity.

            Also FWIW, there are more potent agonists than NBOMe. I know of at least one discovered by Nichols' lab that they refused to publish for fear of use as an aerosolized bio-weapon.

    • amelius 59 days ago
      > These molecules look nothing like LSD!

      Who said "look"?

      You're being pedantic about your own interpretation.

    • cwkoss 58 days ago
      The article was written from the perspective of a 5HT2a receptor
    • mseidl 59 days ago
      Maybe a flying squirrel compared to a flying dog would be better?
    • 9991 59 days ago
      They didn’t say “LSD-shaped”. There are lots of ways to be “-like”, and one is acting in a similar manner. Your training is blinding your thinking.
  • GenerocUsername 59 days ago
    Doubt.

    It's maybe possible that LSD (and per the article, LSD-like chemicals) has a chemical effect on depression, but based on the fact that MANY different psycadelics exhibit similar anti depression abilities, it seems more likely that it is the actual experience of the trip that confers most of the benefit.

    • GavinMcG 59 days ago
      “It’s possible that consuming glucose (and other forms of sugar) has an effect on weight gain, but based on the fact that MANY different foods exhibit similar weight-related effects, it seems more likely that it is the actual experience of flavor that makes the body convert calories to fat.”
      • andai 59 days ago
        Wasn't there something about artificial sweeteners causing the brain to release hormones that lead to insulin resistance? So the brain is reacting to the "flavor" rather than the actual sugar (or more precisely, the neurological pathway that consciousness experiences as sweet taste is also linked to this sugar-related physiological chain reaction).
        • kolinko 59 days ago
          I think this might've been a myth.

          I wore a constant glucose monitor for a while (Veri), and drinking soft drinks filled with all kinds of artificial sweeteners caused no glucose changes. If sweeteners caused a spike in insuline, I would see glucose levels fall.

          I tried finding research on the subject once, and couldn't find anything legit.

          • naasking 58 days ago
            > I wore a constant glucose monitor for a while (Veri), and drinking soft drinks filled with all kinds of artificial sweeteners caused no glucose changes.

            It doesn't cause immediate changes, it causes long-term changes to glucose response by altering the gut microbiome. Here's a recent double-blind randomized controlled trial showing these effects that was discussed on HN a few weeks back:

            https://www.cell.com/cell/fulltext/S0092-8674(22)00919-9

            This is the first study that I think showed this pretty conclusively.

        • Etheryte 59 days ago
          Yes, it was on the frontpage of HN a few weeks ago. Off the top of my head the results were that certain artificial sweeteners spike insulin and some don't.
          • fuckstick 59 days ago
            This doesn’t pass the smell test for an in vivo result. If they spiked insulin in a physiological meaningful way without actual glucose you’d expect hypoglycemia. It’s not like insulin resistance is an acute process.
          • schrodinger 58 days ago
            I thought it was that the reduce insulin sensitivity, so you’re affected when you DO have sugar on the future?
      • sheen 59 days ago
        I heard an interesting counterploint the other day. I think the statement is completely unfounded but figured I'd share because it sounds reasonable...

        "Memories are formed by neural pathways, and it is these memories / correlations that form a basis for (some) mental illness. Taking psychedelics can help take another perspective on these memories and rewrite these these pathways / correlations."

        • phnofive 59 days ago
          This is specifically true for some phobias:

          https://ec.europa.eu/research-and-innovation/en/horizon-maga...

          • Sugimot0 58 days ago
            Wow this sheds some new light on an anecdotal experience if mine:

            I once watched a climber free climb a moderate 30 meter route me and my friends had just completed with ropes, and he mentioned his LSD hallucination was peaking as he saw us at the top.

            I considered that maybe climbers like him have exceptionally higher risk tolerance or a habituated comfort with psychedelics and climbing. However, as someone with a reasonable amount of exposure to both of those (separately), it still baffled me. This feels like a more palatable explanation in tandem with higher risk tolerances and habituation.

          • sheen 57 days ago
            Great read. Thanks for sharing!
      • jnovek 59 days ago
        While this is a completely fair counterpoint, the part that GP didn’t mention is that a patient’s subjective experience is usually ignored or minimized in psychological research, which prefers to focus on behavior and biological phenomena (because they are easier to measure).

        It seems to me like the “trip” aspect is at least worth some investigation.

      • peanut_worm 59 days ago
        Not really a fair comparison. How can you compare weight gain to a mental illness?
      • betwixthewires 58 days ago
        ...except sweetness isn't what all those foods have in common?
      • namero999 59 days ago
        Precisely. That's why the placebo effect is so effective.
    • galaxyLogic 59 days ago
      Maybe it's part of the "actual experience" that you don't feel depressed any more. The hallucinations, who needs those. Therapeutically what matters is the increased feeling of well-being that lasts for weeks if not longer.
      • puchatek 59 days ago
        A trip is more than a series of visual disturbances. It's an emotional rollercoaster. Your perception of yourself and your surroundings changes drastically and you have many insights that you perceive as very significant. This can help take your attention away from irrelevant things and direct it to more meaningful things in your normal life.

        And even the hallucinations can show you that we construct our realities in every instant of our lives. You know this already of course but knowing and experiencing are two different things.

      • Out_of_Characte 59 days ago
        The hallucinations do really help. Its very difficult to be depressed when all the trees are dancing and shining. LSD and the likes also avoids congnitive hallucinations in most people so you're perfectly aware that it's just the wind.
        • sterlind 59 days ago
          set and setting. 2C-E showed me how I was a tiny spec, on a tiny speck of a planet, in an infinitely large universe, cold and unfeeling and uncaring, loved only in a tiny way by only a couple of other tiny specs, all of whom would die in a brief instant, cosmically speaking. it was like Carl Sagan showed up to tell me how meaningless my existence was.

          also, unbearable sensory overload as the panic attack worsened, seconds took minutes to pass, and my kidneys felt like they were failing (they were fine though.)

          the ego death was more or less permanent. my "self" never recovered, I had to build a new one. uncanny experiences of feeling like I wasn't my parents' real daughter, that my phone was a dead person's. I wasn't the same person. but this person is better than she was.

          so.. worth it in the (years-)long run, but hardly sunshine and roses! bad trips are scary. 2C-E is known for being cold and analytical, but I'm sure you can have similar experiences on acid.

        • Schroedingersat 59 days ago
          Unless the thing that makes the trees dance and shine rather than loom and glow ominously is the same thing that has the anti depressant effect.

          I personally think pearl clutching about the idea someone might have fun whilst benefiting from medicine is stupid and there's no reason psychedelics should not be available to anyone who is screened for potential contraindications, but there's no reason to assert that all of the different effects are inexorably linked.

          • galaxyLogic 57 days ago
            I'm thinking that "having fun" is what cures us from depression. Fun and "goodness". Love and happiness. Spirituality. Hallucinations can be fun, which is a good thing. But I think these scientists are onto something trying to extract the "good thing" that is good even without hallucinations.
        • peanut_worm 59 days ago
          What is a “cognitive hallucination”? LSD can absolutely change your thought patterns
      • Nursie 59 days ago
        > Therapeutically what matters is the increased feeling of well-being that lasts for weeks if not longer.

        But what if that is a consequence of the 'hallucinations' changing your perspective on things? What if the psychedelic break with baseline reality for a few hours is the trigger that changes things?

        It's definitely interesting to try and understand. I also just react poorly to people trying to create 'useful' versions of a drug without the 'fun' parts. I don't dabble any more but the experience of compounds like these was well worth the time invested.

        (I put hallucinations in quotes above because I think there's a difference between the psychedelic experience and something all-out hallucinatory, read erowid reports on belladonna, datura and brugmansia for the latter)

        • galaxyLogic 57 days ago
          It is "fun" to get out of depression. Things start feeling fun again. But depression is a mind-set, how you see things. I'm not saying hallucinations couldn't change your mindset, for the better.
    • heavyset_go 58 days ago
      I agree with this. There are novel tryptamines that exist that bind to 5HT2A but don't cause a trip. I've tried a couple of them. They do have effects upon mood, generally positive, but they are distinctly different than the effects on mood from an actual trip.

      I think the difference comes from the meaning and significance that come from the experience of the trip itself. The meaning is logically and emotionally interwoven with your perspective, effectively changing it. I believe experience is required for that profound perspective shift, and non-psychedelic 5HT2A agonists don't provide that experience.

    • tpm 59 days ago
      I am also doubtful, but the new molecules look quite a bit different to both LSD-like and tryptamine psychedelics, so it will be interesting to see what will the test subjects say, if it gets that far.
    • ipnon 58 days ago
      There are also primarily dopaminergic psychedelics like ibogaine that have even more potent therapeutic benefits. This suggests it is not sertonergic effects that are the primary therapy.
    • dqpb 59 days ago
      Maybe the only reason you associate positively with the trip is that it's paired with anti depressant effects.
    • desro 59 days ago
      [citation needed]
      • rippercushions 59 days ago
        There is significant evidence that MDMA, LSD and psilocybin, which are all psychedelic drugs but wildly different chemically, have a significant impact on depression.

        https://en.wikipedia.org/wiki/Psychedelic_therapy

        • waffleiron 59 days ago
          Every single one of these has an effect on serotonin receptors, there are a lot of clinical antidepressants that don’t make you trip but affect serotonin.

          So I don’t think this is actually proof of the trip being needed

          • rippercushions 59 days ago
            The difference is that antidepressants have a temporary effect on serotonin levels and thus need to be taken continuously, while a "trip" on psychedelics appears to actually be able to rewire your brain, so a single dose can have permanent or at least much more long-lasting effects.
          • eurasiantiger 59 days ago
            There’s also some evidence that those serotonergic antidepressants actually worsen depression and make it chronic.
  • pfkurtz 58 days ago
    LSD:

    Multiple times I did it with others and profoundly deepened my relationship with those individuals.

    Another time I did it by myself and saw the face of evil and I've never been so terrified, but I survived and wouldn't change a thing.

    I don't think any of that can be captured by whatever neuro-binding effect is being mimicked by these designed molecules.

    I also took antidepressants for awhile once and it was diet and exercise and commitment to changing my life and talking to a therapist that was what helped; but I know others who need to take pills every day or things go bad. I wish there was a short treatment for people who need that.

    • Synaesthesia 58 days ago
      The effects used to be classified as a "model psychosis" in the 1950's by psychiatrists. That classification was simply dismissed by the government as it implied LSD had useful research properties: allowing individuals to experience the effects of mental illness for 8 hours and then sobering up.

      The government was adamant that LSD and psychedelics had to have no legitimate medical or scientific value, and they had to be banned. To be fair they had escaped controlled use and were being used as "party drugs".

      But anyway, it sure can be a hella scary and strange experience, and not always pleasant. Handle with care.

    • teawrecks 58 days ago
      > I don't think any of that can be captured by whatever neuro-binding effect is being mimicked by these designed molecules

      Agreed, it sound like they do not cause any hallucinations, so you would likely not "see the face of evil".

      > it was diet and exercise and commitment to changing my life and talking to a therapist that was what helped;

      Speaking from my armchair, from what I understand about clinical depression, these are the things that someone who is not depressed can do because they "crave" them. For people who are depressed, there is a (possibly intermittent) neurological imbalance that is preventing them from craving these things which would otherwise keep them functioning normally. While it may be possible to power through the depression, and do these things until the imbalance is resolved, I would argue that this is only due to a temporary break or recession of their depressive symptoms, something that an effective antidepressant should aim to do.

      I'm not claiming my view is true, I'm looking for feedback on how correct/incorrect my view is.

      • logicchains 58 days ago
        https://www.nature.com/articles/s41380-022-01661-0 this paper was published recently, shows there's actually a lot less evidence for the "depression is caused by a neurotransmitter imbalance" hypothesis than people tend to believe.
        • teawrecks 57 days ago
          That study seems pretty focused on serotonin. I guess you're suggesting that most of the science tries to link depression to serotonin?
      • pfkurtz 58 days ago
        There's a wide range of symptom-clusters called "depression" and other mental health issues that pair nicely with feeling terrible.

        If it's not that bad, and/or if you have sufficient willpower or support you can change your life. But I wouldn't describe it as powering through. More like finding the capacity to grow and change; depression is neither monolith nor destiny.

        Other people NEED modern pharmaceuticals to live full, functional lives.

        **

        Interesting that people seem to focus on the hallucination claim, not the deepening of interpersonal relationships claim, which is the much more important result, from my perspective, and the part really not replicable with a pill, because it requires an intense shared experience.

  • captainmuon 58 days ago
    OK, now make a molecule which gives you a trip without the psychological effects. It would be cool to have a sober mind and at the same time see completely realized halucinations (not pressing-on-the-eyebulb I see weird colors, but fully formed people and things undistinguishable from reality, like when you are dreaming). I'm not sure that's even possible.

    But I think you could invent a lot of interesting recreational drugs in theory, alas nobody is developing them because there is no incentive and they would be illegal. Soma? Cigarettes that are safe? Aphrodisiacs? Drugs that let you tweek your personality?

    • Synaesthesia 58 days ago
      I think there's a limit to what can be achieved with drugs, still a lot awaits to be discovered out there. Did you ever read Shulgin's PIKHAL and TIKHAL?

      LSD doesn't so much give you those kind of hallucinations (seeing people that aren't there etc), in fact it's effects are pretty hard to nail down, all kinds of things can happen on a trip.

      But the closest analogy is still a "model psychosis", in other words you will experience what people have when they have psychosis, for about 8-10 hours.

  • acchow 59 days ago
    Uhhh, why would you do this? You can learn so much during a trip to solve some of the fundamental issues/trauma behind your depression.
    • scaramanga 59 days ago
      As someone who has enjoyed tripping, and is generally positive about the benefits of the experience, there are a number of reasons that spring to mind.

      You may not have the luxury of time for that. Or even a save place to do it. What if you are in a vulnerable and insecure housing situation? Living on the streets? etc.

      You may not feel ready for that. For example if you feel anxious and avoidant about having a raw and truthful "conversation" with your self because of what you might find there, then it probably means that it isn't a great idea.

      Perhaps you don't have the access to talk therapy, supportive friends and family, and the like, to trip-sit you, or to discuss and process your experiences with after the trip.

      I don't think it would be fair to take options off the table because you (we) think one is better. I mean, why drink a can of PBR, when fine whiskey exists? Why masturbate when you can have sex, which is clearly superior? The fact that one proposition exists does not take the other one away.

      That said, with the way the laws are, one proposition IS taken away by prohibition so really it's a question of why put one of them through FDA approval to enter widespread usage while the other one sits in a weird limbo where the vast majority of those seeking it are forced in to an illicit drug trade which endangers them. But that question has a lot more to do with the moral and political failings of our society.

    • comboy 59 days ago
      It may be that somebody depressed does not feeling like exploring unknowns, or brave enough to lose himself and experience something completely different.

      Also, I don't think it's necessary wise to suggest somebody depressed go on such trip. It can take you different places. Sure, it may be fine 9 out of 10 times, but if somebody gets stuck in some negative positive feedback loop (heh) he may end up with a trauma.

    • fsloth 59 days ago
      Perhaps a depression drug that does not induce a psychedelic experience is psychiatrically safer than one that would?

      One would need some background in psychiatry and/or pharmacology to answer this I think. I'm guessing such talent is present on this site :)

    • yieldcrv 59 days ago
      Not everyone has 14 hours of trip time and another half a day of shock

      With the risk of lifelong HPPD

    • bananamerica 59 days ago
      I don't do recreational drugs, but don't LSD trips make you pretty useless for a while? If my morning psych medication required me to be non-productive for 4 hours, it would be hard to find a place for it in my daily routine.
      • tsukurimashou 59 days ago
        LSD isn't for daily routine unless you microdose (and even then you don't take it everyday) a trip is more like 8-12h
        • bananamerica 51 days ago
          I understand. Maybe a "no trip" LSD can be useful for people who require larger doses of the substance for therapeutic effect.
      • yieldcrv 59 days ago
        4, thats cute
    • int_19h 59 days ago
      It's not an either-or. You can't be tripping all the time, either.
    • jasonhansel 58 days ago
      Not everybody wants to hallucinate.
    • InfiniteRand 58 days ago
      As someone with a chronic mental illness, I am personally reluctant to try psychedelics because I am often struggling to control my mind and it seems like a psychedelic experience would feel like a loss of control of my mind. Not sure if my impression is misinformed
  • c7DJTLrn 58 days ago
    Pharma really will do anything to find a depression drug they can sell for huge markup when LSD, ketamine, and psilocybin are already known to work effectively.
    • jasonhansel 58 days ago
      I can imagine someone saying the same thing about aspirin. "Pharma will do anything to sell you aspirin pills, when you can just get salicylates the natural way from willow bark."

      No. Standardization, rigorous testing, and FDA approval are good things.

      • heavyset_go 58 days ago
        > Standardization, rigorous testing, and FDA approval are good things.

        But that's what we aren't getting with existing substances, instead what gets tested, standardized and approved are substances that are patented and immensely profitable.

      • zwkrt 58 days ago
        it would be nice if the standardization could come from using the substances that we already have, even if just as a sensible start. I can understand mushrooms being iffy because they comlpex and vary (even between mushrooms of the same species), but LSD is a single molecule already!

        I would love to see a future where I can get a government-standardized tab of acid. Of course this will never happen. The reason they are investigating how to get the 'good' effects without the 'bad/uncontrollable' effects is because of who is deciding what 'good' and 'bad' are. 'Good' = Allows people to continue functioning at a high level with the current power structures in place. Put in other words, it is only worthwhile to cure someone's depression if you can do it without the cure involving that person realizing that their current government isn't working for them.

        • chevman 58 days ago
          That's literally what they did. Started with their knowledge of LSD and went from there using a similar chemical.
        • jasonhansel 58 days ago
          Personally, I wouldn't want to take a medication that would permanently change my political views.

          I seriously doubt there's a drug that reliably makes your political opinions more correct and truthful, but I'm sure that there are drugs that impair your judgment so much that you cannot tell you are impaired. So I would suspect that LSD falls into the latter category, not the former.

          If the changes are irreversible, I certainly wouldn't want to take that risk.

      • mmsnberbar66 58 days ago
        I would like to hear why this person is being downvoted
        • 5co 58 days ago
          undefined
  • ianbutler 59 days ago
    Someone who isn’t me had long lasting, maybe permanent, positive impacts with regards to depression the one time they did LSD. They did it in a very safe environment with very close friends, but hopefully we can understand the mechanism and isolate how to better help people without the stigma attached.
  • kayodelycaon 59 days ago
    Interesting. It has the opposite effect of antipsychotics and antidepressants that act the same receptors.

    Makes me wonder if studying LSD could help with the treatment of schizophrenia and bipolar disorder.

    My personal experience is the brain becomes very plastic during manic episodes, especially when they border on or cross into psychosis. In a way similar to stories I’ve read about LSD.

    • wise0wl 58 days ago
      That was one of the original purposes for LSD---it was billed as a "psychomemetic", in that it mimicked the state of psychosis and made it so therapists could better study and treat the disease in isolation.
    • Synaesthesia 58 days ago
      Yes my friend who had a psychotic break told me it was "just like an acid trip", that didn't end. I've had all kinds of delusions on LSD, it's interesting because afterwards you can reflect on the odd thoughts you just had (if you don't take them too seriously!) It sure can be insightful, in the right space.
    • SamoyedFurFluff 58 days ago
      Generally schizophrenia and schizophrenia spectrum disorders are an instant no-go for hallucinogenic drugs like LSD. It’s been known to trigger psychotic episodes and mental health crisis. Schizophrenia and manic episodes aren’t necessarily the same or behave similarly, and where they overlap is via schizoaffective disorder.
  • swayvil 59 days ago
    Common cardboard tube generates all the joys of astronomy without magnifying any heavenly bodies.
    • isoprophlex 59 days ago
      Combining common cardbord tube - astronomy with real LSD might eventually get you what you need wrt. inspection of heavenly bodies.

      (Picturing people lying on a lawn taking turns looking through a cardboard telescope)

    • taylorius 59 days ago
      Very good! :D The whole endeavour does have a rather an air of "keep the worker drones functional and content".
  • westmeal 59 days ago
    I just saw an episode of the Simpsons where Lisa finds a flower that makes scorpions in the desert docile, so she makes an extract of the flower to test that theory for her school science fair only to find that it makes old people bearable to be around. Long story short, a pharmaceutical company finds out and before long they synthesize a pill that does the same - with the side effect of the patients eyeballs popping out of their sockets.
  • benevol 59 days ago
    This sounds like "Nutella - without the chocolate flavor".

    But making big pharma insanely rich - once again.

    • avidiax 58 days ago
      Yes. Let's work around the moral panic that some people might enjoy tripping for a few hours under medical recommendation and supervision by not even investigating whether existing psychedelics are a viable treatment, and instead assuming that the trip needs to be removed.

      It would be one thing if psychedelic treatment for mental health were widespread and the time off from work or the experience was distressing to patients. But we've skipped step one there, and it has absolutely nothing to do with how unprofitable effective psilocybin, ketamine or LSD treatments would be.

  • neuroma 59 days ago
    Maddening paywalled article; https://doi.org/10.1038/s41586-022-05258-z Honestly why bother doing the science for public good on public money if the information can't be disseminated freely.
  • heap_perms 59 days ago
    That's just missing the point completly.
  • macrolime 59 days ago
    It could perhaps also be that it would work without the trip for some people, for example if the depression was more like metabolic/chemical or something in nature, while for other people the depression was caused by their life situation or other issues and working through it through a trip would help.

    So basically like antidepressants and psychotherapy, both work but some people get more out of one or the other.

  • classified 59 days ago
    I'd much prefer it _with_ the trip, but then that's only possible if you don't have to work the next day, let alone the same day.
  • simonebrunozzi 59 days ago
    Typo in the title: depession -> depRession
  • mizaru 59 days ago
    *in mice
    • yellow_lead 59 days ago
      Can anyone tell me the standard for determining if a mouse is depressed? Or anxious? Just curious
  • knodi 58 days ago
    Does this worry anyone that this drug will be abused? Doesn't everyone like to feel good no matter the day. What if your employee gives this to you because you hate your work?
  • enviclash 59 days ago
    What food types contain something like that? Anything healthy?
    • puchatek 59 days ago
      Those molecules were engineered IIUC. They don't exist in nature
  • akimball 58 days ago
    Extraordinary claims require extraordinary evidence.
  • danielunited 58 days ago
    Don’t mushrooms treat depression as well?
    • mmsnberbar66 58 days ago
      The key thing in the title is "without the trip"
  • armatav 58 days ago
    Can’t possibly let people go on any sort of subjective journey, can we?
  • jokowueu 59 days ago
    I have tried most of these non psychadelic analogs

    They don't do anything such as iso-dmt for example