>The methodology is also kind of strange, the psilocybin group got a total of 20 hours of in-person therapy during their 'treatment' and 6 follow-up skype calls, whereas the SSRI didn't get anything other than the 6 month questionaire.

They got 'matched' support, which reads to me as 'equivelent': "Patients were randomly assigned (1:1) to receive either two 25 mg doses of the psychedelic drug psilocybin administered orally combined with psychological support (‘psilocybin therapy’ or PT) and book-ended by further support or a 6-week course of the selective serotonin reuptake inhibitor (SSRI) escitalopram (administered daily at 10 mg for three weeks and 20 mg for the subsequent three weeks) plus matched psychological support (‘escitalopram treatment’ or ET)."

>They also measured results by a self-administered 16 question "quick inventory" depression survey. To enter the study they had to be officially diagnosed with major depression by a doctor, but the results of the study were based completely around a self-reported 16 question questionaire?

This is only the follow up portion, and as secondary measure at 6 weeks. The original study (https://clinicaltrials.gov/study/NCT03429075) says the primary measure was; "Change in blood oxygen level dependent (BOLD) signal during fMRI in response to emotional faces during an emotional faces paradigm done inside the fMRI scanner." at 6 weeks vs baseline.

>The results are based on a grand total of 25 people in the psilocybin group and 21 people in the SSRI group.

Statistical significance is based on sample size, and is independent of population size. Let that sink in, doesn't matter if your population is 100K or 8 billion, when you sample you are trying to understand the probabilities in your sample, not in the population.

Therefore, (think about the birthday paradox, doesn't matter how many people in the world, a few dozen in the room with you is an adequate sample), it should not surprise you that statistical significance is achieved through a much smaller sample size than most non-statisticians have intuition for.

If that's true, I'm confused how this is a "double-blind, randomized, controlled trial"?

Also, what's up with drug studies always having such a low sample size? Is it really that hard to find people who'd volunteer to get free drugs?

Therapy is such a wash statistically that I'm not particularly confused or concerned by that, and everyone that has ever taken psylocibin knows the results are typical.

The article states that both groups received psychological support though. The only mention of 20 hours I find in the article is as an option to psilocybin. Does the original research article say something else?

Thanks for sharing this, you’re not the only one. I have a close friend who tried LSD as a last resort to get the best of his severe depression and suicidal thoughts (after being on SSRIs for his entire life) and just one session completely removed his suicidal thoughts for months. After this experience he repeats this whenever he feels the dark thoughts are coming back and it always curbs them down almost completely. It’s mind-blowing how well it worked for him.

Same. I came to them as an older person (late 40s) who basically had only tried pot a few times prior, and nothing at all before late thirties. I don't drink.

My few experiences, the first few times, over the course of a year, spread apart by 3-4 months, went from extremely dark to .. just positive, except the last one, where I had no visuals, no bliss at all, and just came to terms with something else in our lives that was going wrong.

The dark ones were rage and anger, and now it seems just gone, like there's nothing there. Like a weight lifted, and seemingly long term.

I'm want to try them. I figure growing them myself is the safest way to go. Got 10 bags of Uncle Ben's brown rice growing mycelium right now.

Is it something that you still take here and there or was it a time limited therapy ?

Congrats on finding a cure for your ailments

Can you share some info on how much you took, and in what setting you took them, what you did on the trip, etc? I have a bunch of shrooms sitting in my cabinet but I havent had got any life altering effect out of them.

Psilocybin has always made me not want to drink for extended periods of time after use. Always saw that as a great benefit.

SSRIs did the same for me.

That sounds great. How can I try it?

That is so wonderful to hear!

Same. Grew them myself. Microdose regularly. Take big trips once in a while. It completely changed my life.

Its not the medical professionals making these decisions. That's like soldiers choose what tanks they drive. They don't. These decisions are made by the hospital/insurance company "complex"

There are plenty of medical substances out there that are chemically similar to recreation drugs. Particularly in the fields of painkillers and anaesthesia.

Unfortunately it's hardly possible to do proper case control studies with psilocybin, since the psychedelic effects cause unblinding.

This is a problem with SSRIs as well; studies have found most people can correctly guess if they’re in the study group or control group.

A true double blind study would require a drug that has similar side effects via an unrelated mechanism, but nobody has attempted that as far as I’m aware.

There was this interesting one though where they deceived patients into believing they were taking an “active placebo” instead of an SSRI, and found that the benefits went away, which is very interesting and raises a lot of questions about the true efficacy of these medications: https://www.nature.com/articles/s41398-021-01682-3.pdf

If there is a medical question that double-blind studies cannot answer, that doesn't mean the question is unanswerable. It means we should be more skeptical of non-blinded studies (or worse studies that pretend to be blind), and we should look for alternative ways to address biases.

You could compare against other psychedelics. I’d be interested in that.

Hardly an issue. When people do similar studies measuring say the effects of prescribed exercise vs not they are also unblinded but we still get good data.

I've never found it compelling that blinding isn't possible for drug-naive patients. There are other drugs that could induce a "trip" and an unfamiliar individual could mistake for a minor psychedelic experience.

> we do not know, really, what goes on in there when you take a drug like Psilocybin

FYI, same goes for SSRIs. The scientific consensus is that the serotonin deficiency theory of depression was wrong. When SSRIs actually work, we still don’t know why.

I’ve had bad trips, too. Very bad, but I still think that psilocybin (in a controlled, supportive setting) is a better bet. My bad trips were all due to being in bad settings and being completely unprepared for what could go wrong. I was young and dumb and just fucking around. But tripping in positive supportive settings was incredibly helpful. And if we do find a way to do this right, then people don’t have to take drugs for the rest of their lives. Psychiatric drugs are generally lifelong sentences, and negative side effects tend to compound over time, which often leads to polypharmacy, and more side effects.

For folks that are interested in anecdotes about psychedelics, I recommend reading Erowid expertise vaults as what gets volunteered here is very narrow and not representative of the population as a whole.

I would know, as my psychedelic mega dose stories are very different from this and also completely unique to me.

I’ve done 500ug of LSD and it was great fun. I scheduled a day off to rest ahead of time and was back to normal after that.

250ug of LSD + 1 full ounce of golden teacher psilocybe cubensis and had a somewhat spiritual experience, took a couple days before I wanted to resume normal life.

+ a dozen or more similar stories

There is a reason why “set and setting” is repeated so heavily when instructing people on how to use these substances. Any discussion of potential subjective benefits or harms of a psychedelic in the context of an experience without specific accounting for that is fundamentally incomplete.

That being said, if my experience sounds ridiculous to you, that’s because it’s unique to me, just as others’ are unique to them. There isn’t really much to be gained by talking about individual experiences other than it’s an entertaining topic of discussion. It gets everybody exactly nowhere closer to establishing the objective clinical value of these things, though.

I did various journeys - initially alone, then with an experience guide. Mostly to explore a childhood trauma - mild, but traumatic enough to leave me with a stutter.

There were indeed some "bad" trips, although I really do not like the term "bad". IMHO there is no bad journey, it is stuff that needs that wants to be seen.

Nor is the journey itself what counts, one cannot expect a quick fix from a 4 or 5 hour journey. What really counts is the preparation (4 to 8 weeks) before, and integration afterwards (again 4 to 8 weeks). In my case I also paired it with years of therapy and meditation.

It takes a lot of courage, especially to continue after an unpleasant experience (fear, grief and loneliness in my case). In my case I kept coming back and allowed myself more and more to let the bad experiences happen. Finally I just learned to be with what is, and accept things and myself the way it all is. With that came a measure of peace and insights I had not experienced before. Along with visions about the structure of existence.

But I'll stress again, just popping a mushroom won't get you there :)

Did you take it in a controlled environment like the study suggests? Every time serious conversation of medical progress comes up, it's polluted by naysayers with anecdata about how they took it while raving beside a live volcano.

We need to give psychedelics a fair chance, and sure after we can discount them. The article suggests at scale there is potential

Why did you take a very high dose?

As someone who was experienced with psilocybin some 20+ years ago, I always took fairly consistent doses (roughly 3 grams), as I could sense taking much more would be playing with fire. This was pretty much a given amongst my circle of a dozen friends who experienced these trips with me… hero doses were almost never a good or healthy idea. Fun to read about on Erowid though, mostly as cautionary tales.

My time with the substance ended after two bad trips (after a few dozen great ones over a period of 5 years), but neither produced any sort of even minor lasting effect.

Anyone who has ever tried to fine-tune medication for psychological issues knows how challenging it can be to get the dosages and combinations just right. In my experience, even medications within the same class can have different effects on different people, especially when combined with drugs from other classes.

The interactions between medications, as well as the patient’s individual response, are hard to predict. These reactions can change over time, too, as bodies and brains adapt, and lifestyles shift.

Yet, you often hear oversimplified statements like "depression means you have too little serotonin," "feeling sluggish means you lack noradrenaline," or "difficulty focusing means you have too little dopamine." These explanations are so reductive that they barely make sense.

The more I read about drug trials, the more I realize how little I — and even many professionals — truly understand about how these medications work and the best way to make informed treatment decisions.

> Ok like most of you I’ve taken psychedelic drugs.

I would like to see some actual data because my assumption has always been that most people have never tried any. I personally have not had any. I have always subscribed to the slippery slope theory of vice.

>Thoughts came out of nowhere, I had no control over them; often the constant, unceasing flow of thought was distressing and uncomfortable.

I want to touch on this. "You" never have any control of your thoughts, because "you" isn't really a thing. Psychedelics and meditation teach us this if you pay close attention. The thoughts arise from nowhere and we - the imagined, but illusory - self are mere observers along for the ride that is consciousness.

I can imagine that using a substance such a psilocybin could cause your thought patterns to have both short and long term changes in quality (in terms of substance, not of superior gradation), however. It's also possible that your experience led to your paying greater attention to the thoughts that did arise, and over time the feedback loop of consciousness along with taking better care of yourself led to greater moderation of their genesis.

I'm a little ambivalent about this response. It sounds like you're describing invasive thoughts of some kind, though your description is vague. At any rate, despite the perceived negative effects, by your own account, it apparently spurred you to lead a healthier life; in other contexts, this is precisely the thing that is praised when it comes to psilocybin.

> Ok like most of you I’ve taken psychedelic drugs. I’ve had bad experiences sure, but I’m fine now.

I guess people with really bad experiences don’t talk about them as readily as the lucky ones. I don’t know the scale, but there must be some selection bias at work here.

Had a very similar experience. Took ~2y to fully go away.

This is a real risk I see overlooked and minimized often. People should not assume it can't happen to them.

I had a profoundly difficult trip that affected me deeply. It felt eternal, and when I emerged, I could feel it in my head like some antimemetic parasite that fed off disgust and terror. I can still remember the feeling, twenty years later, if I try, so I don't. I had to learn how not to be influenced by it, and in doing so, learned about myself. And as I changed, because I was aware of what I knew, I knew when I'd changed.

Our selves are not immutable, steady states. Our experiences shape us. It's a lesson learned to guard that carefully and jealously.

Yeah, maybe don't take "very high doses". I've not done that. And not had any seriously bad experiences. Maybe like everything else is all about moderation?

“Like most of you”

“Objection, assuming facts not in evidence”

Taking psychedelics is a bit like trying to fix a Swiss watch with a sledgehammer: it might just work, but that's not the way to bet. Therapy and well-guided meditative practice can be a lot gentler than that.

The 2018 Hemp Farm bill gave the balls back to the citizens that the 2013 Analag act neutered.

Seeing mushroom extracts with all the alkaloids included besides psilocybin at gas stations may be a temporary point of stability until I can go to the "21+" store in 2030 to get my preferred arylcyclohexylamine and phenylethylamine variant.

Geneva is home to the only Swiss hospital offering psychedelic-assisted therapy. [0]

Also, Peter Gasser, a Swiss therapist acquainted with LSD during the 1988-1993 window, was granted approval to carry out the first controlled study of LSD-assisted psychotherapy in more than 40 years. [1]

[0] https://www.swissinfo.ch/eng/science/can-psychedelics-therap...

[1] https://theswisstimes.ch/lsd-and-magic-mushrooms-how-switzer...

I'm taking a prescription med that is basically a schedule 1 drug that's been very slightly modified and declared schedule 3 and prescribed through a tightly controlled program. I'm even taking a generic version.

It's already being used in therapy. Oregon is giving licenses.

https://www.oregon.gov/oha/ph/preventionwellness/pages/psilo...

I doubt about everywhere, as shrooms are sold in shop around here.

How do you even go about proper dosing and frequency of psilocybin use? Just random guess?

Good for you. I'll just add that there is a non zero chance that getting checked out or mentionning at least to your closed ones about what you noticed would be a net benefit in plausible futures, as thyroid issues, bipolar disorder, various endocrinoloical disorders etc could also cause what you perceive as benefits.

> A more holistic approach to health care would be beneficial.

I've commented on this elsewhere, but with psychedelics in particular we wind up in a weird space around our normal approaches to health - for instance, there's a lot of effort right now on finding the chemical mechanisms by which psychedelics affect mood, with the goal of creating substances which have the same impact on depression without the phenomenology of the trip. My suspicion is the trip is the treatment, or at least part of it - that the experience of being in an entirely different mindstate, of reacting to the world in a fundamentally different way using different mental pathways for several hours - is a core part of the treatment. Medicine has a bad habit of ignoring the patient's lived experience - to look at the patient broadly as a mechanism, and particularly as a collection of mechanisms, and to see things like hypertension* as something to be treated with a chemical offset and not a reflection of the full factors of a person's life. My hope is that the psychedelics will help us recognize a paradigm shift here (like, in data leading to changes in practice, not just in their normal way), but I think they've still got too much of the taint of the hippie on them to really be taken seriously.

* I'm using hypertension as just an example of a particular ailment, I'm not making a statement on the treatment hypertension in particular.

> A more wholistic approach to health care would be beneficial.

Maybe. My personal experience has been that those "negative symptoms" were in fact the entire disorder. I didn't need purpose or depth. I needed to not be so sad that I couldn't function. I needed to be able to hold a coherent thought for 5 minutes without getting stuck into a negative spiral of self loathing.

I want "purpose" and "connection", but those things are what everybody on earth are looking for. The search for those things is the _stuff_ that life is made of. I needed help to get back to a place where I could pursue those things. Pursuing them is my life.

> I often hear people talk about the risks of psychedelics, which are to be considered, but what’s the risk of doing nothing or withholding the best treatment?

The risk is to make things worse.

And I know that I am preaching to people that are of the opinion that they know better than the FDA, scientists and doctors and are all for self-medicating based off of the echo chamber here and a few cherry-picked, limited and flawed by default (like in the case of this one) studies on the first page of Google.

The article discusses the risks of treatment:

> 'He added a word of caution for therapists that "psilocybin requires active confrontation of painful, negative emotions and people who take this drug need to be open and prepared for the idea that they are going into a state where they may probably end up crying and confronting whatever they are maybe running away from in their lives. Not everyone may want to do this."

The long-term consequences of trying to avoid such issues seem considerable, e.g. it might lead to schizophrenia if people try to wall off parts of their memories they find intolerable, though that's just speculation at this point.

> Psilocybin seems to help reconnect people with a part of themselves they only dimly remember

Is there science behind this statement?

From what I know, we understanding psychedelics work. We don’t know precisely how.

> I don’t know how you account for the intense placebo effect of a psychedelic experience for six hours though.

If what they discovered is a particularly powerful way of applying a placebo effect, that could be just as clinically useful. Maybe more so since it could apply to more conditions.

> I don’t know how you account for the intense placebo effect of a psychedelic experience for six hours though.

You don't need to. It doesn't really matter whether it's the trip itself that works, the belief that a trip will work, or some other aspect of the molecule. The drug category it's being compared to also has its own placebo effects. It is entirely reasonable to compare the complete holistic experience of taking each.

This is true of most if not all drugs / studies. That is, the drug gets "credit" for the placebo effect. Sure they took the meds, but that's correlation in at least some. That is, in some the drug did not actuay work but they still get to benefit from the placebo effect.

I rarely see this discussed. I'm not sure why (short of actual cellular test showing it was the drug that did triggered the success some of the success even in the group taking the real meds is still the placebo effect).

This might not be ethical, but given a psychedelic naive population, I wonder if the control could be given a non-serotonergic psychedelic such as salvinorin A. There would definitely be a noticeable effect, but for someone who hasn't studied the effects of psilocybin, they may not realize it. The downside is that in order to keep the duration similar, you'd probably have to administer the salvinorin using an IV drip, and a six hour salvia trip could quite possibly be too traumatic.

For obvious reasons you probably can't put a patient under general anaesthetic before giving them either the placebo or the drug, but I wonder what would happen if you did. Does a patient have to be awake to see the antidepressant effect? How do sedation and sleep differ?

I think a major criticism of how this study is designed is that it is not truly "blinded". I doubt many of the participants were unsure if they received psilocybin vs escitalopram.

This is already a problem for most psychiatric drug trials; studies have found that most people can tell if they’re on an SSRI or in a control group, since the side effects are pretty noticeable.

There is evidence that this skews study results, to the point that some scientists believe that SSRIs may only be “effective” because the obvious side effects make them a good active placebo.

Being blinded isn’t some gold standard. For example we know exercise leads to good health outcomes from unblinded studies. Every study on fitness ever done is unblinded and we consider these results to be a ground truth.

How would you effectively blind a study on a drug with such obvious "side effects"?

I can see such unreasonable objections being used to prevent it's approval though.

Having tried all the drugs, Ketamine and its cousins are very "preppy" - the idealization and ruminating seem to be more side-steppable; as if they were intrusive thoughts that were a minor annoyance.

With the after-glow lasting weeks however, it seems to facilitate/allow a period of self-reflection (using whatever else possibly as an aide) that is notably absent of self-pity.

The doses of psilocybin being used were so low as to be barely perceptible.

> There's no one to trust more than a good friend to be there for you when the ride gets bumpy, not some guy in a suit doing it for the money.

I couldn't disagree more.

Your good friend most likely doesn't have the slightest idea how to handle things if your trip goes south. Especially when they're on their own "ride". That's not to disparage anyone, but just to state the fact that there is training around these things that comes from lots of experience.

And therapists are not "some guy in a suit doing it for the money". You don't get rich doing psychotherapy -- you do it because you genuinely want to help people. And never in my life have I seen a therapist in a suit.

This isn't to say that every therapist is great or that every friend is terrible -- just that the relative success rates of being able to help someone on a bad trip, both during and after, are going to be a lot higher on the side of trained therapists. Because of the training.

Thankfully it’s just mushrooms. It must be one of the easiest drugs to grow yourself after just dropping a cannabis seed in the ground. As long as spores are accessible it’ll be “democratized” and even in places like California where they’re illegal to ship, they’re still easy to get.

It’s a lot harder to accurately dose in its natural form though.

As an outside observer, I have to notice that doctors and "the system" have lost such trust that people prefer self-medicating with illegal drugs.

Within a few hours of taking zoloft I lost all sensation in my genitals and it's stayed that way for years

I've since gotten all my hormones tested (normal), and doctors are suggesting I cycle between TRT HCG & Clomid + Dopamine Agonists

I don't have ED. My symptoms are purely genital numbness/anorgasmia/failure to finish.

I submitted a complaint to the FDA last year. I understand they're currently being sued over this.

I don't understand how SSRIs aren't classified as reproductive toxins.

Can psilocybin restore the mojo, or are you just commenting on the downside of SSRIs?

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"Funny, psilocybin has been largely detrimental to the mental health of everyone I know."

This statemwnt is true for the people I know who have used it in a recreational manner. This statement is also false for the people I who who have self-treated with it in a controlled setting.

I've have done a lot of drugs and know a lot of people who have done a lot of drugs, and psilocybin is far and away the substance that is most loved and gets the best reviews. It's not even close.

As someone who has personally dealt with mental health issues I attribute to use of cannabis, I agree with the underlying sentiment here.

The people in this thread saying things like, "they wear off" or dismissing clinical treatment for depression as "suits ripping people off" are delusional and embodying bad stereotypes. Just because you and your bros took mushrooms, had a few laughs and carried on "working hard on saas" or even had a beneficial, religious-type experience doesn't mean that there aren't also risks or that everyone will have a similarly beneficial experience. It's been known for decades -- both empirically and scientifically -- that psychoactive substances can surface latent or bring about psychological issues (e.g. cannabis and schizophrenia) in some people.

Now, I'm not against use of these substances medicinally or recreationally but to pretend like there is no risk and that they're a one-size-fits-all miracle cure is reckless, naive and dumb. As mushrooms and cannabis become more widely available and more powerful (in the latter case), I suspect we'll be hearing a lot more about this class of issues in the coming years.

Agreed with a caveat: SSRIs and other antidepressants are far worse.

sometimes it amplifies preexisting issues and forces you to deal with them, at least that's what they did for me

In what way were they using it? In what dosages? Was it pharmaceutically pure or bought from some dude?

Overdosing on SSRIs or using them haphazardly could be pretty detrimental too.

my experience has been very different for everyone I know

Where are you that fentanyl is legal in a way opium is not? In the US both are schedule II and approved for medicinal use.

This is surely no surprise to anyone who's ever had a good trip. I'd love to do this in a proper, controlled therapy setting, I suspect it would do me the world of good.

If you don't mind my asking, what about the experience was so bad? Did it take time or work to process the experience for it to have its beneficial effect?

Yeah that's just society absolutely wants to label/categorize behavior that appear to fall outside of the normal, most of the time failing to understand that those behavior have roots in the genetic makeup of the person as well as his personal experience. Most of the time there is nothing really wrong with the diagnosed perso but capitalist/productive society push for normalized behavior so that individuals have less difference and more exploitable/interchangeable.

Funny thing is that you can make the arguments that many of those behaviors are actually adaptation to the environment and may sometimes be the future of humanity. That do not please the productivistes who want to extract as much value of every individual as possible, like we do with cattle.

Now they are some very crazy people out there but it's a very small part of the population and you can often trace the problem back to genetics or physical impairement (environmental or else). Solving that sort of thing with drugs or therapy is basically wishful thinking, but it makes money so I guess that's ok...

As far as I can tell the whole field of psychology/psychiatry is basically just one step removed from full on charlatanism. We can learn some stuff about people's behavior, take some moral judgment about what's good or not (changes with time as well as political viewpoint) but the drive to specifically categorize is a bit crazy in itself...

> ... burnout-related depression (person worked normally their whole life but is suddenly just empty of energy and does not look forward to anything with joy) ... existential depression and anxiety that is driven by pathological self-focus (not egotism, but inability to stop focusing on one's own inner states)

Is there any rigorous operationalization of these concepts, that might be explored in further studies? Unless one can be found, these fuzzy, heavily qualitative descriptions are unlikely to be helpful for future researchers.

Psychiatry seems to be very symptom based, depression is an umbrella term for many completely different problems that show as "big sad".

Maybe it would be more productive to base diagnosis on some kind of brain imaging.