Compass Pathways' Phase IIb psilocybin trial shows reduced depression symptoms | Hacker News Reader

Compass Pathways' Phase IIb psilocybin trial shows reduced depression symptoms

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82 pointshentrep119 comments

There was a great interview between Peter Attia and David Nutt on the research and effectiveness of psychedelics on various disorders https://peterattiamd.com/davidnutt/

He touches on the history of governments banning various drugs through junk science and propaganda (mostly from the US which influences the rest of the world). The scheduling system for drugs is a joke.

Also interesting that the inventor of AA credited LSD for his ability to quit drinking.

Edit: David Nutt authored this study in the NEJM https://www.nejm.org/doi/full/10.1056/nejmoa2032994 which pitted psilocybin against lexapro for the treatment of depression and it showed the same effectiveness (more nuanced than that but you'll have to read or listen). Peter talked about how he is very familiar with Lexapro and it's side effects (libido, a blunting effect on life) in his patients and remarked that what was most exciting about that study is that it showed it could be as effective as Lexapro with less side effects.

I wasn't aware of the credit the AA inventor gives for his fixing drinking problem to LSD - that's certainly an interesting story, From what I understand the connections one might make considering the religious tones AA has, the common idea of what a high dose LSD experience might entail and the fact that LSD and other psychedelics have proven effective against addiction all together match the science so far - tied together by the interesting fact that for people suffering with depression or addiction who seek out help through psychedelics, religious or spiritual experience, not necessarily dose, is what associates with life improvements including long term. Those who did not have what felt to them a deeply significant experience did not reap the same benefits.

I think though the psychedelic community can be somewhat pseudo-sciency (they were of course driven out of main stream science), the reference to psychedelics as a healing tool is apt. It is not the mere ingestion of psychedelics which helps people, but the intense and vivid realizations, visions, and feelings they come to experience which deeply affects them. Its a subtle difference - but I hypothesize that if you put people under anesthesia and gave them a high dose the long term results would be measurable weaker than those who were lucid for the experience.

The shrooms community has known about this for a long time, and now it's just about recreating the knowledge in peer-reviewed studies. Although there is a lot of "woo woo" on shrooms usage in the online communities, I do hope that researchers can extract the useful bits.

This isn't like an SSRI. 25mg psilocybin isn't something you can just pop at the beginning of a workday. Your setting and "head space" matter a lot for how your "trip" (which we will now rebrand as "treatment") will go. This needs to be accounted for in future studies.

> This isn't like an SSRI. 25mg psilocybin isn't something you can just pop at the beginning of a workday. Your setting and "head space" matter a lot for how your "trip" (which we will now rebrand as "treatment") will go. This needs to be accounted for in future studies.

This is what I worry about. It's likely great, when done in the care of a licensed and trained therapist. It's not the mystical panacea many will make it out to be, and I worry that people will do it when they're not with the right people and it'll be a mess.

The Huberman Lab podcast episode on depression touches on this. According to Dr. Huberman the quality of the trip is not important, the chemical changes the brain function regardless.

But is it solely the chemical changes in the brain that "fix" the depression, or does it also have to do with integrating what you've seen and experienced into your worldview?

Apologies in advance for the formatting, copied and pasted from YouTube transcript:

https://youtu.be/Xu1FMCxoEFc?t=5928

99:33 But one of the things that came up

99:35 and is a fundamental question that I had,

99:37 that I think probably many of you are asking,

99:38 is does the experience that one has on these compounds

99:43 make a difference for whether or not somebody gains relief

99:46 from depression, from these psilocybin journeys or not?

99:50 In other words, does it matter what they talk about?

99:52 Does it matter what they think about?

99:53 Does it matter if they have a good trip or a bad trip?

99:56 And I don't want to hold you in too much suspense,

99:58 I'll let Matthew provide the more thorough answer.

100:00 But what's really interesting

100:02 is there are some common themes to psilocybin administration

100:08 and experience that lead to relief from depressive symptoms,

100:11 but they are subjectively very varied,

100:17 meaning that whether or not people feel

100:20 they had a good experience or a bad experience,

100:22 whether or not people thought about their parents

100:24 or thought about the color of the ceiling,

100:27 doesn't seem to have too much of an impact

100:30 on whether or not they receive relief

100:32 during these studies in these clinical studies.

100:37 It seems like different people can have

100:38 lots of different experiences and still receive benefit.

100:42 And that points to something deeper.

100:45 It points to the fact that these drugs,

100:48 which is really what they are,

100:49 are rewiring neural circuitry in a common way

100:53 despite a diversity of experience while on the drug.

100:57 And that itself is really interesting.

100:58 And it takes us back to a place that we've been before

101:01 in this discussion, which is layer five of the cortex.

101:04 This area that ketamine seems to impact as well

101:06 by generating rhythms of the,

101:08 I mentioned one to three Hertz activity

101:10 in layer five of certain areas of the cortex.

Anecdotally, I've also noticed the most profound lasting positive effects on my mood after the worst trip I ever had- an absolute nightmare for no good reason (same people I'd tripped with before, familiar places, etc), but the following couple weeks I was on cloud 9. There are so many confounding factors, but at the time I was completely convinced the trip was responsible for the following positive period.

The experience was sort of like an extremely intense workout, or emerging from a sweat lodge- it was painful, but led to a sort of rebirth. It may be simply, when you're already in good spirits prior to tripping, the results are just less noticeable afterward.

Did you see lasting changes? Or they were mostly temporary.

I've never made it enough of a habit to feel like I've had long-lasting changes, but I do have one friend with serious life-long depression, who has approached psilocybin use methodically, as a means of treatment along with periodic ketamine dosing, and it seems to be working quite well. However, I'm not sure about long-lasting effects after quitting these drugs entirely. There are so many life-factors influencing 'depression'.

Everything is just strange when tripping, from the things you see to human interactions to life in general- whether the strangeness is beautiful or terrifying depends on the trip, but afterward it can have a lasting (at least long after the drug has worn off) child-like appreciation for things that might've been mundane, boring, or tedious. How long this break from monotony, or revitalization lasts, is hard to say.

~70% of people who have "bad trips" don't regret the experience.

The terminology is actually being phased out, especially in the medical community. "Good" and "bad" might be appropriate descriptors if you're just trying to get high and have fun, but they're not quite right if you're trying to work on yourself and your mental health.

Some trips are easy, some trips are difficult, and just like in real life, it's often the difficult journeys which cause us to learn and grow most.

I wonder if the mental health benefits require consciousness. Would be interesting to study if tranquilized or anesthetized subjects get the same effects.

From personal experience treating mental issues with psilocybin, this isn't a dose you need to do frequently. Think 1/year.

> It's likely great, when done in the care of a licensed and trained therapist.

As someone with a lot of experience with psilocybin, there's all this mysticism around it. People act like you're injecting fentanyl. If someone doesn't have a license and training, you're going to instantaneously see flying demon dragons and go schizophrenic.

It's actually fairly tolerant over quite a large range and I know a lot of people who have used over the last year and they are all in spectacular shape.

It reminds me about all that nonsense on HN last year about how if you weren't tested and trained on wearing N95 masks, you wouldn't be able to use them effectively. People over-rate licensing.

Translating a dose in mg to the equivalent amount of dried mushrooms you would likely come across recreationally is quite difficult, but I believe 25mg equates to something like 4-5g of dried mushrooms which would be a full on trip beyond surfaces flowing like water :sweat-smile:

I did some brief googling on the topic earlier, and the best I could find was "anywhere from 5-20 milligrams of psilocybin per gram of dried mushroom". Which is very unhelpful for working out whether these people took a strong dose by recreational standards. :D

It's more or less impossible to know the psilocybin content of any one specific mushroom offhand, and it can vary greatly even between mushrooms from the same batch, thus microdosing with actual shrooms is an inexact science. You can grind them up into powder and mix it together to average it out, but the total psilocybin will still be an estimate at best.

There is 4 aco dmt, which is supposedly gets converted to psilocin just like psilocybin and I don't believe is illegal in the US, however it degrades very easily into psilocin if stored incorrectly so can be dicey to have since psilocin itself is still illegal.

Erowid dosage pages can be helpful: https://erowid.org/plants/mushrooms/mushrooms_dose.shtml vs. https://erowid.org/chemicals/psilocybin/psilocybin_dose.shtm...

Isn't uptake through digestive tract unreliable? Mental disorders require extremely precise dosing, therefore probably should administer intravenously.

Most psychiatric medications are applied through eating pills, mind you, so this seems like a criticism that applies to a vast field of medications...

> 25mg psilocybin isn't something you can just pop at the beginning of a workday.

I would disagree. For many, 25mg is sub-perceptual.

Source: have done this over several year.

3-5 grams of mushrooms?

I want to work where you work. I hope it doesn't involve heavy machinery.

it depend on your weight, and potency of batch.

I have settled on 2g every 3rd day. 1g dose seems to work only on empty stomach and I have to pay attention to feel difference in my mood.

I can easily see a big guy taking 3-5g and not feeling much beyond mood boost.

20-something mg of 4aco dmt was pretty wild, psilocybin must be somewhat similar

I am guessing the 25 mg does here is of pure psilocybin, which is about 2.5 g of dried mushrooms.

I think you're confusing 25mg of psilocybin with a microdose of 25mg of dried mushrooms. 25mg of pure psilocybin is anything but sub-perceptual.

Ahhh - yes, missed this.

Holy hell, yeah that'd blow the roof off for sure.

I am pretty prone to depression and I definitely feel it lifting for a while after microdosing or taking a larger dose. Unfortunately I have never experienced a life changing trip that solved all problems as you may want to believe when you read some of the latest articles about the miracle of psilocybin and other psychedelics. Same for Ayahuasca. It seems to help a lot of people but for me it was more just a very interesting experience.

For example I think a lot of film makers are/were taking psychedelics. During my trips I noticed so much more detail in my environment and different light reflections which you often see in movies.

It’s a pretty well established fact that creatives have to use some mind altering substances to be productive, but it’s hard to believe that claim if you’ve never experienced them personally.

When I meditate hardcore then after a session, I also look differently at light.

I’m a believer in the potential value but think placebo or blind studies of psychedelics are absurd. You know full well of you’ve eaten an eighth of cubensis.

I think to be fair, they should compare psychedelic treatment to other therapies like ECT or a weeklong vacation to Hawaii.

To someone who has done mushrooms before, sure, they can tell. But for people with no psychedelic experience, niacin (a common stand-in) causes flushing and some other effects which a patient can tell "is doing something."

IIRC, the famous "Good Friday" psilocybin experiment had some people from the control group believe they were not in the control group.

> IIRC, the famous "Good Friday" psilocybin experiment had some people from the control group believe they were not in the control group.

I can find a few people right now that believe that Lord of the Rings is a historical account of medieval Europe.

Right but when it comes to questions of placebo, the belief is what matters.

9 weeks of TMS should be tried before ECT. ECT is just one away from a lobotomy in terms of brutality and risk.

ECT is not as brutal or risky as it used to be. You can now opt for unilateral treatment (only shocking one hemisphere) rather than bilateral for the same outcome with lessened side effects. I agree TMS should come first, but I think the comparison of ECT to lobotomy is misguided.

That's your opinion. The point of ECT is to induce a seizure. Seems damn barbaric.

This does at least show a difference between 10 mg and 25 mg dosage.

One way to do this — and I don’t know why it isn’t done — is to use a general anesthetic and then administer drug/placebo and record effects.

Not clear that it works when not conscious

Then run that experiment, too:

Psilocybin + anesthetic

Psilocybin + nothing

Control + anesthetic

Control + nothing

There is a specific belief here around something which changes under these substances, around memory, recall, ideation, I'd use the word "plasticity" but thats not what I mean. Taking these drugs (or MDMA) and undergoing some kind of guided psychological engagement, appears to have lasting effects on how mood is mapped over experience, for people suffering negative ideation/PTSD.

I'd love to poo-poo this because I believe in (and do) CBT and have a continuing high level engagement with somebody which is strongly anti-drug: the SSRI are a weapon for a problem which are being over-used. Its classic hammer/nail analogy stuff.

There was interesting, good science being done on these drugs before the "war on dope" took everything offline.

Consider the work on its effect on timor mortis. If we can ease people's passage into an inevitable end, Isn't that net-beneficial overall?

I had to look it up to put it in perspective. 25mg pure psilocybin could be around 5g of dried p. cubensis if they are .5% (which varies considerably...) point being this is no microdose. These patients are really tripping! So they are saying a psychedelic experience, which could reconstruct your entire ego, really can be a significant life-changing event.

Terence McKenna called 5 grams an heroic dose.

As somebody who sometimes "treats" severe multi-decades-long depression with psychedelics, I'm not surprised that they'd have a positive impact but the news seems too unclear to my simple mind to make sense of a few things:

1- why is a private group on the stock market doing this, instead of public research & universities? vested interests in seizing a market of illegal drugs in a legal way worry me, because it's easy to completely forget the humans in the process when there's billions to be made

2- is 1mg declared a placebo with enough proof? I'm personally not receptive at all to any kind of "micro-dosing" but I've also seen equally anecdotal comments going exactly the opposite direction and loving that. Is there a study that thoroughly compares the 1mg dose to a fake product looking similar but with no psychoactive substance?

3- as someone keenly aware of an "afterglow" that can happen on psychedelics, I also don't see a proper discussion about (1) the potentially ephemeral nature of the benefits when taking a single dose, as well as (2) the difficulty of taking psychedelics along with pretty much any other treatment for mental health issues (SSRIs, MAOIs, anti-psychotics and so on, which all have their own counter-indications)

I very much love all the psychedelic experiences I've had in life, from simple doses to "heroic" and intensely crushing trips, and I've always tried to extract some long-term benefits from them during and post-trip, but even compared to a psychiatric treatment that doesn't help me quite enough (doesn't get rid of anhedonia, brain fog, suicidal ideation, etc etc), I have still come to see those trips as more of a targeted temporary relief for the soul that one should ideally leverage in the window of time post-trip - and not so much as an ongoing treatment in and of itself like what's offered by my meds.

At least from my limited perspective it hasn't been so much a treatment for a depression but a temporary relief from it, which offers a window of time to discuss anchoring constructive habits ("job search for an hour every morning", "clean up your house", ...) and having empathy for the self in pragmatic and measurable ways post-trip (cook yourself a meal, get a haircut, commit to physical activities again, etc). I'm not really convinced that we'll turn those substances into long-term treatments, but I could see them becoming a "shock therapy" of sorts.

I guess the hope is, by figuring out how it helps, the effect can be prolonged?

1. Pharmaceutical studies are extremely expensive so usually done through private sector. In this case compass has a patent for a certain way to synthesize psilocybin, but not a patent on psilocybin itself. However, the results of the study will generalize to psilocybin of all sources. Win win in my view.

2. There are many studies in the literature that compare "psycholytic" (which tend to accentuate pre-existing mental states) to "psychedelic" (which can trigger mystical/insight experiences) doses of psilocybin. I'd say it's reasonable to treat 1 mg as placebo.

3.i. The study followup is ongoing. One of the remarkable aspects of psilocybin treatment is that one dose can lead to lasting (ie >6 mo) effects on mood. See the john hopkins studies.

3.ii. Although the studies all have folks weaning off, concurrent SSRI, MAOI, and anti-psychotic use is not an absolute contraindication. They do not cause serotonin syndrome with psilocybin. But clinically I think this won't be a huge issue as most patients will only be trying psilocyin if 1. their ssri has failed or 2. they are opposed to trying ssris. cheers!

Thanks for replying to all those points!

I agree that all news is in principle good news for psychedelics, but the private interests still have a bigger reason to exaggerate the positives for any treatment for financial benefit. We even see this with how prevalent the "latest" SSRIs are vs. treatments that have existed for a long time. New research with fancy articles isn't always better than old research, especially when the people prescribing it to you fall prey to the market pressure of prescribing the costly solution to you vs. older solutions for a tenth of the price, for which on the other hand we'll exaggerate the side effects...

Do you happen to have any interesting link regarding what you mention as being psycholitic and how it relates to a placebo? Because from every page I've been finding on the subject, none seems to indicate that the substance acts specifically as a placebo but only that noticeable psychedelic effects aren't present, which is slightly different. I've done some digging to find something[1] supporting the idea that "microdosing == placebo" but given that there's pretty much only studies that have self-reported data in that domain, I'm not sure I've ever seen anything conclusive regarding microdosing being a placebo, nor at what dosage one can consider each psychedelic substance as microdosing/placebo. I might have very much missed something big in the domain and you seem to know your stuff, so if you happen to know something to link I would happily take a look :)

As for long-term positive effects, are you referring to this study [2] ? It certainly looks interesting for significance over long periods of time, but not necessarily to alleviate depression. I have a few DMT trips in my life that are amongst the most significant moments of my existence, yet I'm into my third decade of debilitating depression - those things don't necessarily have to overlap.

I also agree about concurrent treatments not being absolutely contra-indications, but I think we're being particularly kind to whatever is the new kid on the block and unfairly harsh to old treatments in comparison. I had the chance to meet a psychiatrist who's been doing their job since the 60s, and they were the first to offer trying a RIMA (moclobemide) which significantly helped compared to multiple SSRIs, and had less negative side effects than SSRIs and even some positive ones (libido) - despite a truly horrible reputation everywhere you look, and in young psychiatrists' minds.

I believe there's a good place for psychedelic treatments to contribute to the well-being of a suffering person, but as a pretty experienced "psychonaut" I've always remained keenly aware of the potential for these substances to induce a certain degree of collective delusions too -- even more so if we're talking about a multi-billion dollar new market opening up.

[1] https://www.imperial.ac.uk/news/216134/citizen-scientists-sh... [2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3050654/

I too have treated MDD with psychedelics along side CBT therapy (not in official conjunction) and found that my suicidal ideation and anhedonia subsided for about a year after my first big trip. Since then, I've done heroic doses and microdoses and found that the most beneficial to me was infrequent large doses combined with integration in therapy afterwards. I agree with your take that it's more akin to a "shock therapy" than a regular medication.

I'm curious, do you work with a talk therapist? If so, do you feel like the therapy + psychedelics is better than either alone?

I have had limited opportunities to have ongoing talk therapy, but I've done a lot of the heavy lifting of CBT on my own throughout the years (both during psychedelic trips and in my day-to-day life).

For me the psychedelic trips have been an opportunity to focus on a subset of CBT (challenging negative thoughts + behavioural activation), while in the day-to-day CBT I've focused more on keeping in mind the cognitive-behavioural model as well as an index of cognitive distortions to test my flowing thoughts against. It's a bit challenging to try to hold on to your flowing thoughts when under the influence of noticeable doses of psychedelics, and that's why I focused more on specific points of trauma as well as noticeable reactions (literally looking at my face in the mirror at times). I've personally noticed two different moments post-trip: the first few hours to days where clarity of mind is much higher than my baseline and I can transform the work of the trip into something tangible in the long run (like a commitment to the gym), and the next few weeks where I sense an initially sharp and then gradual fading out of any "afterglow" from the trip, which is why I've come to see those trips as shock therapy even when I can extract something positive beyond the horizon of time of that "afterglow". I've also noticed that this whole system worked less and less well with the years, the window of time going from months to weeks to days, even as I spaced apart the psychedelic trips more and more (1/month -> 3-4/year -> 1/year or less).

I used to be a bit wary of inherent bias from researchers all too eager to share positive things with the world, but with the widening of the Overton window regarding psychedelics and the success of the cannabis market in many places in the world I've also started to be wary of financial interests in the subject. Nonetheless, I'm really looking forward to the new research coming out around psychedelics because there's just so much that we don't actually know properly with science to back it up - and more teams to work on the subject will offer more chances to figure out what's going on within that expansive world.

It is because you see the experiences as false compared to the reality you are now immersed in.

If a big trip doesnt manage to completely change your belief system it has mostly failed in its effect.

It is the change in beliefs that lead to a lasting result.

If one leaves the experience denying the new experience and calling it false or calling it just a dream then it will surely fade and results will not last.

This is self evident over time. Effects should not fade but in fact should grow stronger without the further use of psychedelics. Proper integration and meditation do this.

If one takes the experience as truth, a Big trip then has the power to cure. Depression will never return.

Conviction in the experience must be there for it to really work its magic.

To have an experience like this and then to come back calling it just a dream is a tragedy. What a waste. For someone like this they have missed the point. They go back to their lives as normal. Everything is as it is. They simply feel a little better or feel relief for some time, but because they did not accept the new reality they are then forced back down into their old routines and habits. They are put right back in the reality they left and felt relief from after their Big trip. Depression sets in again. Everything goes back to the way it was, the trip becoming a distant memory.

What happens if you were to do two trips in a row, would you then have to change your mind to completely different outcomes each time? Would that one time in the middle be invalidated by the later trip? How do you go about quantifying which trips offer enough change and which don't? How many trips do you then have to do to get there? How do you qualify a new set of beliefs as being the "right" one? Are YOU the person who gets to decide that? And so on.

I appreciate that you find freedom in your personal belief system, and I'm happy for you. But you're definitely getting ahead of yourself if you think that whatever you're holding on to is a universal truth for all that is living. I've had that conversation countless times with people who've also gone through DMT breakthroughs: you're no less in a prison of your own mind when you think this way, you've only shifted your philosophical perspective into a place that anchors different beliefs in place. They appear entirely valid because you perceive less subjective suffering, but generalizing the idea that those beliefs are valid everywhere and for everyone is like believing that a singular value in a system of differential equations give the whole picture. There's a difference between solving your problems and solving everybody's problems, and thankfully the scientific work comes into place to bridge that gap (however slow the process might be).

I appreciate your intentions and I think there are nuggets of truth in what you write (re-integration helps you carry things further, meditation offers relief, a change of beliefs most often does lead to lasting results yes), however some people are allergic to blindly dogmatic thinking and I happen to be one of them. Your entire post could have been written to advocate for religion X, Y or Z btw, and people in each religion have just as valid of a claim as you do when it comes to their belief systems alleviating their suffering.

Mandating that one is bound to find the truth with a big T if one "does it right" is pretty much one of the things that as a guide for others through psychedelics I've never made the mistake of advocating for. Psychedelics are a journey, and like any journey you might come in with who you are and come out with different parts but the more you project rigid expectations the less you'll actually extract from the journey itself. Like any journey, two different people taking the same means of transportation and going to the same place, might extract two entirely different things.

It would do a lot of good to a subset of the psychonaut community to retain empathy and compassion when it comes to sharing about personal journeys.

It is precisely because I care that I commented so that another one may find it.

Just for the sake of clarity I am referring to a level 5 trip.

Two trips in row with different outcomes? This is not a question that would be posed by someone who has experienced a level 5 trip. Why? It becomes self evident. But it is not something I can 'prove' to you. You have to see for yourself.

Regarding outcomes - One has either broken through or not. One will know when they have had an ego death and OBE. It is a very distinct experience. Some will still deny this even but much much fewer can deny an experience that powerful.

I have had many trips that were below a level 5 but only one that I would classify as a level 5 trip - complete loss of ego or ego death.

I was an atheist before that Big trip.

The Psychedelic experience has many common threads. I've read hundreds of big trip reports maybe thousands. The common threads become very obvious after a while. As obvious as the sunrise.

Yes this is my interpretation and the interpretation of some very old religions like Hinduism and its offshoot Buddhism.

They are not dogmatic in that you can believe whatever you want next to them while still considering them as truth.

From One there are many. Surely this does not even escape a mathematician. You cannot deny your own existence yet Science has very little to say about the nature of consciousness. In fact Science really has no clue when it comes to the mystery of consciousness. Its view is that we are meat puppets and the sum of our parts. Nothing more than we can see with our eyes. Why is this accepted as dogma but other belief systems are not?

Science itself is a kind of dogmatic religion. It is one that many take for granted as absolute truth. Older thought systems such as Buddhism have been around for much much longer. To assume they are somehow inferior to Science because of their age is a mistake.

All beliefs are valid. One can worship or believe as they wish to find happiness. It is only that they accept Science's answer as Absolute Truth and not their own direct experience after they have had a big trip. That is the waste. The lack of conviction in their experience as being real.

It is surprising that after such an experience one can walk away without conviction! They would have to try hard to forget and make themselves believe that everything is just as it was and it was all just a dream. That is the difficult part. Believing should be the easy part but the world pulls us back in. Our old concepts rush back in.

We put our belief back in the old way of doing things and back to the world we knew before that Big trip. The world of the 24 hour news cycle and Reddit. The world of our addictions, apps, and waking life. Because we feel comfortable there. It is challenging for us to change our outlook so drastically but that is what a Big trip challenges us to do.

I can only assume you refer to "level 5" from a personal source rather than DMT-Nexus (which only has 3 levels) or PsychonautWiki (which mentions levels rather freely and goes to Levels 8+, also spreading out the descriptions into various categories).

It's going to be impossible to convince you that your subjective experience isn't an absolute truth because it seems like the entire foundation of your approach to the discussion and psychedelics is based on that assumption. What you're entirely wrong about however is regarding the definition of science: science is (1) a set of logically consistent statements for a set of givens, and (2) meant to have its validity tested constantly in order to be invalidated so that a better fitting approximation can be found. Science, down to basic axioms of mathematics, is not debating "Truths" but only relative truths, and is making statements that for assumption A,B,C one will observe logical results X,Y,Z, where it perpetually strives to refine the process such that more logical links can be established and any assumption that leads to incorrect/invalid/uninteresting consequences can be weaned out. When in fairly abstract fields, even those assumptions are usually also explored over time and utilized by people as they see fit (maths without ZFC, relatively quick acceptance of relativity in the world of physics, and so on).

If your insights about science as a whole are so off the mark, I'm frankly not surprised that your assertions come off the way they do. And I happen to disagree with the stance that takes refuge in absolute truths (unless its validity were to ever be proven somehow), and even the mightiest of psychedelic trips of dozens of kinds (including ridiculous doses of DMT, Changa, DOM and what have you) have not fundamentally changed a thing about it since I wasn't susceptible to that belief in the first place. That you can just come out and say "well it was simply not enough drugs you took buddy!" is much more likely to be indicative of your wish for personal bias to be a truth than any alternative. And much like with religions in general, I'll respect your right to dive into your personal belief system, but my perspective will be wildly different from yours (and perhaps not as fixated).

I am not looking to debate or argue. I am simply stating my beliefs. You are free to disagree or take nothing at all from it. To become critical of me or my understanding shows how little you have learned from your experiences.

Depression comes from the same place as your judgement of others.

All experience is subjective. That is my point.

You however limit your experience to the world view of your senses and what science and your cultural background have told you are true. It is as simple as that.

That is valid. But it wont cure Depression. The analytical mind has no clue. That is why. That is my belief. Take what you want or take nothing at all.

> To become critical of me or my understanding shows how little you have learned from your experiences.

That's just an attempt to shield yourself from any kind of external perspective.

> Depression comes from the same place as your judgement of others.

Glad you, on your own, have managed to solve remotely a problem that is a complex combination of multiple traumas, PTSD, neurochemical issues and psychological ones. Or more likely, you've lost all sympathy from me in this response as you've revealed just low little your personal experiences have fundamentally changed in your ability to extend and practice empathy, and therefore the very limited extent to which your experiences retain value in the bigger scheme of things in this discussion.

Have a lot of experience with microdosing psilocybin, as well as with psychedelics like Ayahuasca. My experience with both as a means to remedy depression have been significant.

It is analagous to having a lamp in a dark forest. It won't get you through it itself, you need courage, and other tools like meditation (your machete), exercise (your provisions) and intention (your compass) to succeed. But with it, everything is easier.

Err -- AMA?

With micro-dosing, doesn't your body get acclimated to the low doses taken over extended periods of time and thus rendering the micro-dose ineffective? I assume you have to cycle with it?

Are there any negative effects on your off-cycle days? i.e less creativity or feeling down

Hello!

Your body does build a tolerance. But there is a common misconception that the "psychedelic" presentation is where you find the efficacy. In most microdosing stacks, you combine Psilocybin with lion's mane mushroom and vitamin B12. It is usually 5 on, 2 off. Even if you do not feel any upwelling, it is working.

The process of neurogenesis is very subtle, and that is the mechanism which, when combined with other tools, will help you get over depression when microdosing. It takes time, it is a gradual, slow, re-wiring. The affect of the psychedelic experience can provide creative and mood benefits. But I believe these are separate processes with separate benefits.

Often when speaking with folks, and I notice myself, that there are no withdrawal symptoms. There is always risk of dependency when ingesting any outside substance, but something about the experience itself is resistant to abuse.

Interesting analogy of a dark forest. I'd say the Zen realization is of value here. You can always, at any moment, realize that your sensations and consciousness is all there is. We don't need anything more than to observe what we sense at any moment. I say this because changing our mind doesn't have to be hard arduous work, Zen Buddhists realized that enlightenment is here now, if we have the will to simply see it and accept it.

Regarding machetes, wow. I'd say meditation is more like the calm and the observation of the dark forest, not a machete. A machete is a constant necessity to hack through tough issues. Meditation is the art of doing nothing, of simply noticing what is occurring. In that way, it's more like standing still and observing the jungle, not hacking it.

I like Sam Harris's analogy best. Meditation is taking a calm sail boat ride to wisdom, whereas psychedelics are like being strapped to a rocket. Both will get you places, but one is more likely to crash.

Reading a book at the moment called "Cutting Through Spiritual Materialism", which are the words of Tibetan Buddhist monk of renown Chögyam Trungpa. He also likens the development of spiritual presence to a blade. The trick with Sam's stated perspective, from this Buddhist perspective, is that it implies attainment of a desire: I meditate to be calm. Meditation can make people calm, and so can breath work. But if you say "I meditate to be calm and ride to wisdom", there are those who would say you are not meditating at all. They would say it is just "I meditate", and then "meditate", in these sort of Buddhist philosophies like Zen and similar.

I do not say this to gatekeep - but experiences have taught me that, absolutely, meditation and the path of spirit is very hard, dangerous and arduous work. Helping others through derealization and psychosis has taught me this lesson time and time again.

In my metaphor, meditation in the psychdelic context is a machete because it is the blade to cut through all the psychedelia, all the woo, all the false notions of personal loftiness from spiritual insight, all the ideas of being healed, all of the mind mess. It simply is the mechanism that you use to cut through, and then "become here and now", to allow yourself to heal beyond stories: depressive stories, happy stories, and into a state of mind that is resilient to the suffering of the times.

This is something I've been interested in for a good while now, and tried a similar LSD microdosing regimen without any exciting results. However, I also didn't pair the practice with meditation or regular exercise (some, not a lot).

My main question is, how does one get anything like a regular, precise (micro)dose of the psilocybin? Volumetric dilution with LSD seems simple, because I know how much each tab contains and can plan accordingly. Are mushrooms really that regular in compound content?

In Canada, we are very lucky.

My city produces many laboratory grade mushrooms.

Look! https://www.magicmushroomsdispensary.ca/

There would be a significant variance in potency if we were nibbling on different parts of the fruiting body when measuring a dose. But first, you grind it into powder, measure it on an electronic scale, and then take it.

If you stick to the same supplier and the same type of mushroom, this keeps things very consistent.

Powderize a bunch of mushrooms and mix well so they are consistent. Then take a specific amount and adjust for potency. You then have a consistent dose for the entire batch.

If you throw 100M people at this as a solution, do you expect to see most carefully and successfully getting through it like you or would most just become addicted and eventually lose their job and go homeless?

Addicted and losing your job because of psilocybin? I've not tried it myself, but many of my friends have, and anecdotally, none of them have (to my knowledge) ever even gotten to the point of it being a "habit".

I can't say the same for alcohol, cocaine, and even cannabis. I know people who have had problems with all of them.

Even Terence McKenna, who himself was likely part mushroom given how many he ingested, said time and time again that mushrooms are resistant to abuse. If you take a very high dose, the experience itself can be so difficult and wonderful, that the idea of doing that to yourself again starts to seem ridiculous. :)

When it comes to something like Ayahuasca, I make a point of not recommending it. I lean into the woo of it, and allow "the ready people" to help realize their calling to it through me. I know, bear with me, but advocating something this wildly, impossibly potent and transformative is something I cannot do, and so I defer to greater wisdom.

For small doses of psilocybin, it is - both in my experiences and in a lot of scientific contexts - considered very, very safe. Greater doses, 2.5 dry grams, you start to introduce risk triggering latent psycho-affective disorders.

For most people with common neurotic conditions, anxiety, depression, etc, it is very low risk. Out of 100M, I'd say .1% is at risk having a very negative experience due to significant, untreated issues like schizophrenia.

All of things things require support. Community, a guiding hand, will truly improve the outcome.

This isn't something you can really answer, but I'd be game to try micro-dosing psilocybin, but I have no idea where to get it safely (from LEOs and bad chemistry). It would be great if the local dispensary sold it.

If you are in Canada, acquiring them from reputable sources is very easy. Also, growing them is not too difficult. Depending on your location, spores can be easy to find too, and then the quality control is ultimately all up to you.

In the US, unfortunately.

microdosing psilocybin is definitely not the silver bullet.

But it helps me realise what is it like to feel normal. Depression is insidious beast. It blinds you and you forget what its like to feel normal.

I really like your analogy of having multiple tools in order to fight depression.

The trial tested psilocybin combined with therapy. This isn’t equivalent to ad-hoc self treatment with mushrooms.

They noticed a response to psilocybin+therapy in about 20-25% of patients depending on the criteria for “sustained response”:

> The protocol-defined sustained response* up to week 12 was double, with 20.3% of patients in the 25mg group

It’s also notable that about 5% of the psilocybin receivers experienced severe adverse events including suicidal ideation:

> There were 12 patients who reported treatment-emergent serious adverse events (TESAEs). These TESAEs included suicidal behaviour, intentional self-injury, and suicidal ideation

This sounds pretty crappy right? If I'm understanding the numbers, 25% response is about like what we get with a placebo in most studies if my memory is correct.

It sounds like they were tripping balls on 25 mg, so this is definitely in active placebo range.

From my memory:

Placebo is about 25%.

Antidepressants about 35% response rate.

Active placebo of something like atropine which makes you feel weird but isn't an antidepressant has about a 35% response rate.

https://blogs.scientificamerican.com/cross-check/are-antidep...

I’m not sure if it makes a difference, but this study was conducted on _treatment resistant_ patients.

This 29.1% effectiveness is awesome considering it is a single dose that was given.

How does this get commercialized? I can't think of anything that's inherently cheap and easy to produce that you use for a few weeks and then never again that is also a financial cash cow the way most pharmaceuticals are. Disclaimer: I work for a pharma.

They figured out how to jack up the price of ketamine 100x by making it esketamine - find an analog, shove in an acetyl group somewhere, something something chiral something

The money is in the professional therapists who administer this. It's the same model that's currently working for Ketamine.

It's probably not "a few weeks and then never again" -- I'm not depressed, but anecdotes from people I know who've tried mushrooms at home for this suggest that one trip produces a noticeable improvement that fades over time.

It's possible that the full experience with a trained therapist who supervises the trip could produce longer-lasting changes, of course.

Why does it have to be commercialized?

Personally, I think the best option is it gets mainstreamed by knowledgeble guides working with individuals through the process, the mushroom growing is done by small-scale growers who do it with the passion and love this Medicine deserves, and the pill-makers are kept far and away from it.

Why does it have to be commercialized?

In general it doesn't has to be, but in this case the research is done by a for-profit company which expects to see a return on their investments.

Ah, good point.

that's why i don't get all the psychedelic stocks and stuff i keep hearing about. seems like itll be less profitable than marijuana

In Michael Pollan's fascinating history of psychedelics, "How to Change Your Mind", he explores this. It was interesting to see how governments appeared to have no issue with psychedelics until Timothy Leary came on the scene.

Having powerfully beneficial medications locked away is what happens when a law enforcement agency (DEA) decides national medical policy, instead of a qualified medical body.

Psilocybin has changed my life. It needs to be available to everyone in the world. Pharmaceutical companies will fuck it up (it's coming - very quickly) so learn to grow your own.

Legality aside, growing and consuming a fungus to me, someone who knows nothing about them outside the grocery store, sounds very dangerous.

People eat mushrooms all the time. they aren't dangerous.

Make hacker news HACKER news again. We've been eating these for thousands of years and suddenly everyone thinks they are dangerous. It's social conditioning.

Ketamine also. It's already approved.

I would prefer all drugs were legalized as in Portugal and regulated because it's impossible for a consumer of illicit drugs to verify their contents and it would cut off criminal profiteering, violence, and the police-prison-industrial-complex from some funding too.

Drugs are not legalised in Portugal, they're decriminalised.

Trafficking is still a criminal offence, and personal possession is still punishable with a fine.

Duh. The word "as" means "like" or "similar," it doesn't mean "is." Prohibition never works, and Portugal doesn't have a consistent approach yet.

Wow, 5% reported suicidal ideation or self harm, in a clinical setting. That’s pretty horrible.

Depression is a quite significant cause of death, above many other major diseases especially for younger people.

Well, participants were already on anti-depressants, and asked to stop before the trial, so causation isn't clear.

Well, how did it compare to the control group?

I had one trip where I found peace with the idea of dying. Why keep struggling with life if you can leave it in harmony? Not sure if I would call this suicidal though.

But it changed my attitude towards dying. I think if I had a hopeless disease or was close to dying otherwise I wouldn't fight it but try to die in a peaceful and aware way.

29.1% effective

Headline could be more informative by including this number.

That number is misleading without context for how effective other drugs are and in comparison to placebo. Given that placebo was ~8% effective this is a highly promising treatment.

I think that was the control group, not placebo. But I didn't read the study in depth.

Control groups are given placebos…

With the placebo group too

"Overall, 29.1% of patients in the highest-dose group were in remission three weeks after treatment, compared to 7.6% of those in the control group, "

In remission after three weeks is pretty impressive, too. There's many antidepressants which take a lot longer to ramp up to being effective, even assuming they work for you.

So more effective than antidepressants?

Great news!

Do you have a source? I don't think it is "more effective" in terms of the remission rate. That being said, in this hypothetical world where you can choose between shrooms and SSRIs, you would have to compare the side effects as well.

21% delta in remission rate vs. placebo is higher than both SSRIs and bupropion in this study [0] for example (11% for both). This is also a single dose which is amazing.

[0] https://pubmed.ncbi.nlm.nih.gov/16086611/

>Do you have a source? I don't think it is "more effective" in terms of the remission rate.

I actually look at the broader picture: https://pubmed.ncbi.nlm.nih.gov/20616621/

There's clear evidence that the antidepressant companies have inflated numbers and the actual numbers seem to suggest it's more like ~7% effective on par with placebo levels.

The conclusion made is that we need to look at alternatives.

>That being said, in this hypothetical world where you can choose between shrooms and SSRIs, you would have to compare the side effects as well.

True. SSRIs even at same efficacy would be out of the question given the risk. Mushrooms on the otherhand? Kind of recreationally used.

Flipside, we have a very clear problem. As marijuana legalizes, we are going to re-evaluate all these other psychedelics. In addition to the political situation of the losing war of drugs. We may politically seeing marketing on why we need to legalize. So we need more info.

The thing that's not clear is, how often do you have to do this? It's definitely not an everyday pill like Prozac, but it's not very effective after 6 weeks. Would you trip every 2 months? Seems like that would rapidly run into diminishing returns. No one has even tested a second dose! How is this actually going to work?

Psilocybin changed my life. It threw off the wet blanket of depression, which allowed my antidepressant to fully do its job. I can’t really explain it, but imagine if your depression was a jacket, and one day you just took it off.

> patients who were given [...] 25mg had a significant decrease in depressive symptoms

Is that enough to cause impairment?

It's a serious trip, yes. More (by far) than most people would recommend someone do recreationally for their first time - it appears that high doses accompanied by a therapist are what has shown the most promise across various exploratory trials.

Love that it’s randomized and double blinded. Will be hard to cast doubt on it.

Some quick points:

> 233 patients

Very small, can't generalize results based on such a small number. Doesn't mean the study's trash or anything, but don't jump to any conclusions here - good or bad.

> "The trial, which had all patients stopping antidepressants before participating, compared two active doses of COMP360, 25mg and 10mg, against a comparator 1mg dose."

- COMP360 was, I assume, their therapeutic psilocybin but it's unknown if that differs from raw psilocybin or not, and if so in what way.

- Did they TEST and PROVE discontinuation of antidepressants at all stages of the trial? Which kinds of antidepressants did they test for? SSRI? TCA? MAOI? How did they test? Uranalysis? Blood? Or did they just take 233 people's word for it?

> "[...] 179 patients reported at least one adverse event — the most common being headaches, nausea, fatigue and insomnia."

- Likely unrelated to the medication itself, as those can be caused by hundreds (thousands) of factors. Literally included in every possible side effect list for nearly every medication known to exist. Doubtful that the medication caused any of these.

> "There were 12 patients who reported more serious adverse events, such as suicidal behavior, intentional self-injury, and suicidal ideation."

- Do we know how many experienced which specific "serious adverse event"? Was it 11 ideations and 1 behavior that could be interpreted as self-injury, for example?

- Do we know for certain that none of these 12 had any of those adverse events occur in the last few months prior to starting the medication?

---

Again, I'm not crapping on this at all here, but folks should take it with a grain of salt and realize there's more to this, that only 12 adverse events isn't a significant concern unless we can show with high confidence that it was caused by the therapy, and at only 5%, even then it sounds like manageable risk as long as a prescriber would know the patient's history before hand.

The announcement - not the study data itself just the press release - is here: https://ir.compasspathways.com/news-releases/news-release-de...

> Very small, can't generalize results based on such a small number.

This comes up pretty often, but how many subjects do you need to know getting punched in the face hurts? It's absolutely possible to get statistically significant data from 233 patients, what matters is how the study is designed.

Yeah For surveying large populations I think you only need around 270 samples to get 90% acuuracy. Something like that, might have mixed up at word it's been awhile since I did stats.

> Do we know how many experienced which specific "serious adverse event"?

From the topline data [1]:

- 3 Suicidal behaviour

- 5 Self-injury

- 4 Suicidal ideation

- 1 Drug withdrawal (from codeine?)

- 1 Adjustment disorder with anxiety

- 1 Adjustment disorder with mixed anxiety and depressed mood

- 1 Hospitalisation

[1] https://compasspathways.com/knowledge-navigator/pdf/COMP001%...

For me, I get depressed when I feel "stuck" in my circumstances (mostly a directionless project, bad boss, or cancerous working environment, or all of the above). I suppose going on a "trip" would alleviate that significantly, at least for a while. Then you'll get used to it and you'll be back to square one you can't escape without fixing the root cause. So any enthusiasm for this is going to have to be tempered by long term studies and outcomes. Any significant change in one's circumstances can _tactically_ alleviate depression somewhat.

Do you have clinically diagnosed treatment-resistant depression?

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