LSD-like molecules counter depession without the trip
ucsf.edu
ucsf.edu
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.
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!
Griffiths' research is all high quality. He is the pioneer in making this field of scientific research palatable to the mainstream medical establishment.
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.
"unpack the meaning of a word"...this makes sense?
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).
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.
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.
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.
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"
Imagine a chronic obsessive cellphone gazer. One day he lifts his nose from the screen. Sun! Clouds! Birds and squirrels!
Except moreso.
So no deities but spiritual like what you said.
Are you saying that SSRIs trigger changes in the brain? What changes? Why do they trigger these changes?
Genuinely curious.
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
Edit to add: Downvotes even though in 2015 the FDA required "black box" suicide warnings on SSRIs because what I'm saying is true?
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.
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.
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.
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...
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.
but obviously nobody can make a fortune with these simple advices.
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.
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.
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.
Insurance likes low variance outcomes because they’re easier to model accurately
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.
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.
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....
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.
1. https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD...
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.
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.
"According to existing literature there is an inverse relation between magnesium and depression. " https://johs.com.sa/admin/public/uploads/187/46_pdf.pdf
While you N=1000-reddit-teletubbises try to hold back humanity the N=1 change the world.
Giving pills to these people is a crime
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
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...
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 :)
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.
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.
The common theme is that all these things change perspective, and none of them are entirely safe.
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.
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.
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.
Instead of selling xxx tonnes of xanax&co per day worldwide and make absolutely outrageous profit doing so ? Doubt
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.
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.
So that number was probably 10x off. That doesn't change the conclusion though.
I learned all this from Scott Alexander. All details here: https://slatestarcodex.com/2019/03/11/ketamine-now-by-prescr...
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.
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.
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.
I would even classify this realization as an exception to your "is not useful" rule.
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.
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"
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.
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. =)
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?!
Some pedant has to say it: shouldn’t that be “pedantry”?
Are you thinking of machine learning?
Yes alluding to something illegal makes it clickbaity.
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.
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.
See this diagram on wikipedia for LSD binding affinities (lower means more affinity): https://en.wikipedia.org/wiki/Lysergic_acid_diethylamide#/me...
Don't worry. You're in the right place :-)
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?
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.
Brilliant! I'm going to steal that for a datacoms lecture to hammer home 'layers'.
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_...
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.
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.
Who said "look"?
You're being pedantic about your own interpretation.
I wonder how they look like compared to serotonin and some tryptamines
https://i0.wp.com/sitn.hms.harvard.edu/wp-content/uploads/20...
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`
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.
So I don’t think this is actually proof of the trip being needed
"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."
https://ec.europa.eu/research-and-innovation/en/horizon-maga...
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.
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.
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.
I don’t think the GPs informal synopsis characterizes the gist of that paper in any meaningful way.
It seems to me like the “trip” aspect is at least worth some investigation.
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.
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.
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)
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.
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.
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.
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.
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.
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.
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?
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.
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 :)
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.
With the risk of lifelong HPPD
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.
No. Standardization, rigorous testing, and FDA approval are good things.
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.
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.
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.
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.
(Picturing people lying on a lawn taking turns looking through a cardboard telescope)
But making big pharma insanely rich - once again.
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.
So basically like antidepressants and psychotherapy, both work but some people get more out of one or the other.
The forced swim test is used in animal models of depression: https://en.m.wikipedia.org/wiki/Behavioural_despair_test
I'm a layman, I don't know what the scientific basis is for using the test to model depression. I personally find it pretty cruel.
This research direction is an example of "cargo-cult science" [1] as Feynman understands the term. (That does not mean that the hypothesis is necessarily wrong.) There is a reason for "in mice" being an internet meme [2].
[1] https://calteches.library.caltech.edu/51/2/CargoCult.htm
They don't do anything such as iso-dmt for example