Single-Dose Psilocybin for Major Depressive Disorder: Randomized Clinical Trial | Hacker News Reader

Single-Dose Psilocybin for Major Depressive Disorder: Randomized Clinical Trial

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108 pointsbookofjoe87 comments

My take on these studies -- either read the whole study or don't take it as evidence of anything. If you aren't motivated enough to read 20-30 pages, then you probably shouldn't be willing to risk your health around it.

For example title is great, but there's a bunch of other stuff to be aware of in there. E.G. "the most common solicited AE was headache in 33 of 50 participants (66%) receiving psilocybin and 13 of 54 participants (24%) receiving niacin."

Also this study was only 6 weeks. I think the obvious question is "Then what, do you redose, or hope it lasts?"

Lastly, anecdotally, I know a lot of people who recommended hallucinogens personally, and many/most of them seemed believably happier, but perhaps had other negative side-effects that a study like this wouldn't measure (e.g. do you friends think you're acting kinda weird now?). Some of these people seemed overly invested in convincing me in a way that made me uncomfortable and uncertain of their objectivity.

There's an interesting reply-all episode about microdosing LSD. https://gimletmedia.com/shows/reply-all/2oh933

People with depression probably don't care about headaches.

Studies say they feel them more intensely.

Some of the RC psychedelics can be brutal, I remember 2C-E being super fun and visual, but it also felt like having a dammed ice pic jammed into your head.

> do you friends think you're acting kinda weird now?

From psilocybin mushrooms? I have never met anyone that's encountered this

I've adopted a personal faith due to mushrooms. We're all just dreams of soil made manifest. All of life is connected in a giant network of consciousness. It's truly wild.

Any details about this personal faith of yours? Is it like pantheism?

For me it is almost exactly this. I was not a heavy indulger, but that’s what I came away with. It has stuck with me for nearly 20 years since.

I don't share that faith, but I appreciate you sharing your experience. I imagine you've found your faith an overall very positive force in your life (like most people do with most faiths), no?

One thing I'm curious about - what happens when lovers/friends/family hear about your faith? Do they laugh it off? Or just accept as valid as any faith? Or do you not feel the need to tell them?

For context, I was not raised religious at all and kind of thought a bunch of it was hokum.

But then I did a heroic dose, and I went to the church of engineering where I saw the entire construction of the machines use from the transistor all the way up to the platform I'm building.

My faith is more a faith that humanity is worth it, and I've come to see "The Lord" as an appropriate metaphor for the collective conciseness of several billion people living their lives.

At core, I'm rejecting nihilism as a valid way to live, and I'm writing an essay to outline the way.

In this, I also reject cynicism, and this is because it offers nothing.

The way forward is to embrace the responsibility that comes with great knowledge and to build an organization that helps push technology forward. This is why my platform is open source ( https://www.adama-platform.com/ ), and I'm working very hard to get my handful of clients in a good place.

> e.g. do you friends think you're acting kinda weird now

Obviously there are bad/maladaptive versions of this, but also it would be odd if you healed a major psychological ailment and your friends didn’t notice a change in your behavior.

A common, very sad meme among artists, for example, is that they ought not get better psychologically because their art will suffer. Do people say they’re “acting kinda weird” as they heal? Yep. Is that worth putting any weight into at all? Nope.

In my experience psychedelics changed my outlook so thoroughly that I needed to get different friends.

> but perhaps had other negative side-effects that a study like this wouldn't measure (e.g. do you friends think you're acting kinda weird now?).

I have a couple friends who got in early on the microdosing and psychedelics-for-depression trend. One of them has become progressively more detached from reality over the years. Previously a rational person, he started picking up various pseudo-religious ideas over time.

At one point he believed he was capable of a type of telepathic communication, for example.

Every time I tell this story people try to discount it, downplay it, or explain it away as an underlying medical condition, but the changes were clearly triggered and worsened by psychedelics.

I don’t think it should be all that surprising, anyway. The history of psychedelic research is full of stories of people who started out with a curiosity and then descended into psychedelic-induced irrationality as their lives went on. Maybe the effects are negligible for someone taking a single or couple trips under the guidance of a therapist, but I think the internet psychedelic fans have taken these isolated studies as a license to ignore some of the risks of extended use or accumulating a lot of trips over a lifetime.

A therapist should be able to spot an undiagnosed case of something like bipolar or BPD from a mile away though. Young adults messing around with psychedelics for fun may not be so wise. It's not fun when you and your friends are all coming down except for the one person in the group whose been launched into the mother of all manic episodes.

> A therapist should be able to spot an undiagnosed case of something like bipolar or BPD from a mile away though.

These are very difficult to diagnose. At the very least, they’re inconsistent between therapists. Latent schizophrenia is also, by definition, not something you can see from a mile away.

>uncertain of their objectivity.

How do you deal with something that is objectively therapeutic?

If you ask me about the benefits of isometric exercises, you're going to get something that will make you question my objectivity, because I'm not at all objective about it. I had chronic upper back pain for a decade, that got so bad at one point I could barely get out of bed. An osteopath gave me "super ibuprofen" and isometric exercises, and the isometrics literally, over night, cured my back pain. In the 25 years since, whenever I've started getting a little sore, I've done them again and been back to normal.

>Some of these people seemed overly invested in convincing me in a way that made me uncomfortable and uncertain of their objectivity.

What am I supposed to say? Psychedelics have the biggest gulf between how effective they are vs how effective people think they are in mental health. Going both by the scientific evidence and anecdotes they’re nothing but net (abliet with a significant backfire risk). Psychadelics also get you high which further biases one towards advocating them, enjoyable drugs are more viral than boring drugs.

Most people overestimate how effective pretty much every mental health treatment is except for psychadelics. It encourages one to proselytize even if psychadelics are moderately dangerous drugs.

One sentence in and this already completely ignores that the vast majority of people the vast majority of the time rely on a trust system instead of “reading the paper” for medical treatment they receive. Hell, “reading the paper” is itself almost entirely a trust exercise of its own. Most people, including most of this hellsite, aren’t capable of making sense of this stuff. It’s just that this site probably has a higher incidence of people that falsely assume that they can.

This paper also mentioned that other studies checking after 12 weeks found greater reduction of benefits, so subsequent treatment looks to be somewhere between those two time frames.

> Results A total of 104 participants (mean [SD] age, 41.1 [11.3] years; 52 [50%] women) were randomized (51 to the psilocybin group and 53 to the niacin group). Psilocybin treatment was associated with significantly reduced MADRS scores compared with niacin from baseline to day 43 (mean difference,−12.3 [95% CI, −17.5 to −7.2]; P <.001) and from baseline to day 8 (mean difference, −12.0 [95% CI, −16.6 to −7.4]; P < .001). Psilocybin treatment was also associated with significantly reduced Sheehan Disability Scale scores compared with niacin (mean difference, −2.31 [95% CI, 3.50-1.11]; P < .001) from baseline to day 43. More participants receiving psilocybin had sustained response (but not remission) than those receiving niacin. There were no serious treatment-emergent AEs; however, psilocybin treatment was associated with a higher rate of overall AEs and a higher rate of severe AEs.

AE=adverse events

Most of the AE were headaches either during or after.

Interesting that so many people in study have taken psychedelics. I wonder how that compares to general population?

“ Mean (SD) participant age was 40.4 (10.9) years in the psilocybin group and 41.8 (11.7) years in the niacin group; half were men and the majority (89%) were White. Ten participants (19.6%) in the psilocybin group and 13 (24.5%) in the niacin group reported previous lifetime use of a psychedelic”

I think US Americans generally take a lot of drugs.

Half of US adults have tried cannabis.

https://news.gallup.com/poll/509399/fully-half-americans-tri...

This poll suggests one in four have tried some psychedelic, at least once.

https://today.yougov.com/society/articles/43267-one-in-four-...

So, about right. Maybe slightly low.

I could not get the links to load.

"Americans"? Are Canadians included? (They are part of "America" being half of the North American continent and weed is legal there) Including Canada probably skews the results. Also a breakdown by age/region would be interesting.

By population Canada is 1/10 the size of the US. And when does American not refer to people from the USA? Do people outside the US ever really identify them selves as Americans?

Many Spanish speakers do use 'Americano' to refer to the Americas as a whole.

Not 1/10th. 1/8.3th.

Both say they’re discussing US adults, in particular.

Thanks. Didn’t realize ecstasy was in there.

People suffering from mental illness tend to self-medicate with drugs at a much higher rate than those without.

I saw God's face once while tripping super hard on truffles in a hotel room in Amsterdam. Changed the trajectory of my life pretty substantially. I still read the notes I took during the comedown every now and then.

Sounds intense. What did it look and feel like? How did it change your life? You've left me a bit on the edge of my seat.

They’re doodles right? I wrote my amazing thoughts while on psychedelics and to my dissapointment they were just meaningless doodles when I was sober. Not to discredit the expetience at all which was positive and fruitful.

The problem with studying psychoactive substances is that they can't realistically rule out a placebo effect. Psilocybin has strong side effects, but niacin (the placebo for the control group) has no side effects, so people know whether they are in the treatment group or control group. The apparent positive impact of psilocybin could just be a placebo effect.

A better idea would perhaps be to test two different psychoactive drugs with similar effects, like LSD and psilocybin, so people don't know which they got.

Great point, and the study even admits that point

"Limitations: First, the success of allocation blinding was not assessed, and it is likely that the acute psychoactive effects of psilocybin produced some degree of functional unblinding that may have contributed to the observed effect in psilocybin-treated participants and the increased dropout rate in niacin-treated participants."

Unblinding = participants figure out if they got the real thing

I think a recent ketamine study found a lot of the clinical effect went away if participants weren't awake/aware of the treatment. Wonder if that could be used here.

It’s also possible that the conscious experience of the effect is part of what makes it work. I’m not sure how you would test that out.

I don’t think you can.

But if a certain action routinely produces sustained change, that can also be fine.

Eg, you can’t blind participants to whether they receive real therapy or a conversation about the weather, but we’ve concluded that therapy is useful. And you can’t for a similar reason, in that the experience is itself the treatment.

Yeah, though perhaps it is the trip itself that causes the antidepressive effect, so if you prevent the trip via sleep, the effect goes away.

Exactly my thought. It's often reported that the antidepressant effect came from the increased ability to look at your problems from a new perspective.

If this new perspective isn't experienced, it seems highly unlikely this would work.

Thinking about the mechanism of classic anti-depressants like SSRIs, you expect a boosted effect of the happy chemicals to make people more happy.

With anything that is few or single-dose you expect changes in thought and behavior patterns to have the antidepressant effect. These lasting changes must come from something that is not happy chemicals, but a new perspective on life.

I missed that study and that is a brilliant way of blinding participants for this sort of thing.

>they can't realistically rule out a placebo effect.

Kind of like every other treatment for depression? Not being funny here but I don't think we gave the control groups in clinical trials for MAOIs brutal kicks to their blood pressure every morning.

Most common first line treatments for depression don't show any effect for weeks so this is a valid criticism. Things like Xanax for anxiety have an immediate effect though so it's not like we don't deal with this sort of thing.

They may have chosen niacin for its mild flushing effect, which can be quite noticeable, but usually at a higher dose than given here.

At some point a treatment is effective enough that it stretches the credibility of placebo effect. And even if you hold onto the placebo effect, that’s just the mechanism. It doesn’t make it any less effective. If you have a treatment that has an extremely strong impact on depression, it seems worth continuing to study and to also distribute it more broadly. Whether it’s because of psychedelics or the thought of them, people are getting helped.

Your suggestion would only see the difference between the drugs. They both could be wildly more effective than antidepressants but similar to each other, and that study wouldn’t show it.

Yeah. If the psilocybin effect was merely a placebo effect, that effect would probably wear off after a while, and it would stop working. So this is detectable, though not in a short term trial.

The proposal with using both psilocybin and LSD is based on this assumption: If both substances yield a similar outcome, it is more likely that they both don't work rather than that they both do work (to a similar degree). Presumably the prior probability that two hallucinogens treat depression is rather low. Because most substances don't treat any disorders, let alone depression in particular.

It has been the best antidepresant in the history of life, just legalize it.

Depression is a complex disease that can be caused my many factors. It's actually more a whole class of illnesses. As a consequence, there is no such thing as "the best antidepressant"; some antidepressant work on some of the cause and some other work on some other cause.

The whole "antidepressant don't work" feeling is caused precisely because we expect them to work on all cases and finding the right molecule - and dosage - is hard. But make no mistake, the drugs we have right now sometimes work amazingly well, for some people.

Psilocybin - if it actually shows long term improvements under double blinded studies - will just be more tool in the arsenal, but will not be the miracle cure some predict it to be.

Thank you! This 100%!

It may not be the miracle cure for all depression but it can be an absolute miracle for the individuals it does help. I was depressed, in a bad place mentally, going deeper into alcohol/drugs, letting relationships slide, etc. I spent 4 days in the woods drinking mushroom tea and just reflecting on my life and the path I was on. I came out of that experience instantly reinvigorated for life. I completely turned my life around from that moment.

That was 15 years ago now. Most of it has been good. Some mental health issues popping back up lately, but I think it’s more of a mid life crisis/loss of youth thing, that feels a little unavoidable.

I’m not advocating it as the super cure, but it can absolutely be a super cure for some. I think it’s reasonable if you haven’t experience this sort of darkness and subsequent transformation to not understand it at all. It’s not stuff some couldn’t also do without therapy and medicine. But if you have trust issues and can’t open up to a therapist, it can help you open up to yourself in a productive way.

I have friends who work in the ER who have plenty of stories about people taking mushrooms at home and ending up in very, very distressed mental states. It’s not a simple drug that cures depression for everyone.

A researcher over here at UNC has identified a marker for folks who don't get potential therapeutic effects from psilocybin https://news.unchealthcare.org/2022/07/unc-research-reveals-...

There is a fantastic interview of David Nutt where they talk in depth on the subject: https://youtu.be/UWhk2LMDwCc

How does the 25 mg used compare to what average non-research users are ingesting?

Probably about average? An 1/8 has around 35mg according to this website https://pabcounseling.com/how-to-dose-psychedelic-mushrooms/

Woof, those charts say to me that recreational dosing amount is probably all over the place. Variability on species + drying + stem vs cap percentage + accuracy of consumer scale = no consistency between doses.

Yes, this is completely true. IMO, the best option for consistency:

1. Grind up a big batch for uniformity.

2. Have someone more experienced take some, or do it yourself and start at a quarter dose.

3. Get an idea if it’s weak/medium/strong and adjust accordingly.

Not perfect, but reasonably close enough for mushrooms since the impact seems to be logarithmic (with weird jumps of effect as well).

Option 2. Go online and buy 4-aco-dmt and a decent scale.

Participants taking psychotropic agents who otherwise met inclusion/exclusion criteria were eligible following medication taper.

I have heard that people who are currently on an anti-depressant have to take a larger dose of psilocybin. It was not surprising to see that they'd want to taper the medication to maximize the effect of the psilocybin.

Not just a larger dose, most people on SSRI’s won’t trip no matter how much psilocybin they consume.

I'll make a guess that SSRIs act by inhibiting or even destroying connections between neurons, creating the effect of dullness, while mushrooms activate connections that were previously dormant.

If it keeps people off poison like SSRIs, I'm all for it.

What makes you say SSRIs are poison?

dependency, changing of brain chemistry ... lifestyle changes can manage depression, drugs are a band aid and the ultimate way to kick the can down the road.

There are concerning risks: https://en.wikipedia.org/wiki/Hallucinogen_persisting_percep...

How does the paper address this? Haven't checked.

[EDIT]

Ctrl+f on "HPPD" and "disorder" found nothing relevant.

I doubt the number of people experiencing this is anywhere close to what Wikipedia says it is. I know a lot of people who have used a lot of psychedelics from their late teens to 30s/40s and none of them have had HPPD

Only one of the studies Wikipedia included had concerning results, and it was a survey of users. Such studies are good indicators of where future research should be done, but only demonstrate a loose correlation between psychedelics and HPPD. There’s no differentiating users who are “self-medicating” the issue from psychedelics causing the issue.

AFAIK this is not something that's seen with psilocybin, maybe with frequent high dose LSD... Anyway, I wish people didn't even bring this up because it'd be a shame if that dissuaded anyone to try psilocybin.

While I do hope these issues are researched, I’m not sure why you find them “concerning.” According to Wikipedia only 1 of the 2 studies really seems well done, and that one reported no HPPD.

Since SSRIs are extremely widely prescribed already and seem capable of causing HPPD as well, I’m not sure what’s making you find them concerning for psilocybin in particular.

That's mostly a risk for recreational users I'd say. Anecdotally, from people with psychedelic experience I know, only massive multidrug abusers experience this sort of issues.

Most HPPD is just floaters or tracers, and SSRIs can cause them too.

The magnitude of HPPD and the frequency/prevalence need to be studied, but I think seeing some extra floaters in exchange for having a will to live is a trade most would take.

Not all depression is "I have no will to live".

No, but the one that does take away your will to live is the one you most want to treat.

It addresses it as such "Visual perceptual effects (assessed following resolution of acute drug effects) were reported by 22/50 (44%) psilocybin participants on the day of dosing and by 3/50 (6%) after the dosing day, all resolved by study conclusion (See Table 3 for details)." [table shows it resolved by day 9]

However the study also shows 2 people in the experiment group (1 in the control) had an adverse effect that required psychiatric attention. Unclear what that means (admitted to a hospital or a phonecall with the therapist?)

I mean even "bad trips" are an important concern?

Anecdotally I've had good experiences with psilocybin, but a bad trip induced a 6month long depression in a friend of mine.

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