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Something that's going to be interesting with psychedelics and psychedelic research is that a lot of this sort of research seems to try to "control for" the phenomenological experience in favor of focusing on the biochemical mechanism of action - I think it's possible that the phenomenological experience _is_ the mechanism of action for these substances, that the actual experience of the trip is what makes the difference.

> I think it's possible that the phenomenological experience _is_ the mechanism of action for these substances, that the actual experience of the trip is what makes the difference.

I was really confused about the entire concept of blinding a study like this until I read your comment... Now I realize they are indeed proceeding from the assumption that the phenomenological experience is somehow distinct from the mechanism of action.

That seems really unlikely to me- these drugs are unique because of the phenomenological experience! It seems self evident that this experience is the reason for therapeutic effects.

Imagine the absurdity of trying to design a study blinding the effects of meditation for example. Meditation has measurable benefits, but what are the chances those aren't caused by the psychological effects of experiencing meditation?

It's self evident to you that there's no effect on brain chemistry that accompanies the experience? A change that could have an impact on the condition?

You might be right, maybe you're even probably right, but it's not self evident to me.

“Chemical imbalance” antidepressants take weeks of ~100 milligram tablets to take effect. (Nobody can quite explain what the imbalance was to begin with, and what the ideal levels are…)

Psychedelics have an impact at the microgram range, with a single dose. They could be hundreds of thousands of times more potent, or, it could be the experience.

With MDMA the doses studied aren't that different than the amounts needed for some SSRIs. Not sure what you're going for with the mass of the ingredient.

The point was that they need to be taken for weeks before there’s any improvement. Not so much the size of the dozes.

They have a good point. The whole “chemical imbalance” thing has come under significant scrutiny as of late.

could they give the control group other psychedelics in some of these studies to see if they are differently effective? That could be blinded right?

That would be further down the path.

In this design, I have to imagine both groups' sessions were very much affected by thoughts of "am I about to trip or is this just allergy relief?" To be honest, I am uncomfortable with the thought of a participant being unsure if they had been given a psychedelic.

Consider that a non-trivial number got it wrong! To me that signals some of the control group participants may have been quite agitated.

I wouldn't mind seeing a self-controlled design where participants are randomized to receive either psilocybin with therapy or non-psilocybin therapy first, but ultimately end up receiving both. As others have noted it's not just the drug, it's the drug and the experience of therapy so I think the two ought to be packaged.

Ultimately though, what I am most curious about is the long term sustenance (and/or repeatability) of any effects and also whether any negative effects appear later.

The first wave of psychedelic research also showed some promise, but their utility faded. Have we gotten any better? Six months of alcohol use disorder or depression relief is great and useful, but the goal ultimately is long term relief.

It takes some tens of grams of sodium chloride to significantly alter my body chemistry. A few milligrams of cyanide will alter my body chemistry enough to be measured by the existence of a pulse.

well at least occham's razor is definitely calling buttshit

...or try to study the effects of a university education with a double blind study.

There are probably rules demanding blinding for these studies. Let's hope they don't hold back the research for too long.

Yea ... it's weird to talk to some types of neuroscientists who speak as though a particular neurotransmitter is an actual psychological phenomenon (beyond just short hand, IMO).

So focused they are, it seems, on the therapeutic development angle (receptors, agonists, drugs, etc), that they've forgotten that the brain/mind is a processing network of neurones that can exhibit phenomena of multiple levels of complexity. Sure, a particular neurotransmitter or receptor may be involved in a particular pathway, but that's just signalling, not the process itself, let alone its totality.

https://xkcd.com/1462/

It’s worth trying because it could be that there is a chemical mechanism rather than it being the trip. For example ketamine can ‘cure’ people of alcoholism and depression at doses that do not produce ‘profound’ experiences or at doses that do. Having said that I accidentally had a ‘therapy’ session while completely off my tits on LSD and it helped with things that I’d not previously been helped with on other trips.

The issues at hand are complex, it’s worth trying to control just to find out what the mechanisms are.

Also apologies for all of the air quotes in this ‘comment’

I’ve heard this theory before but wouldn’t that mean you could take these substances while anesthetized and derive the same benefits without remembering any of the “trip”?

I think that this is correct. I don’t remember the name of the person, but he explained that MDMA is useful for treating PTSD because it lets the patient have enough mental “energy” or wherewithal to revisit the trauma and not be overwhelmed. So it’s the—in some sense—safe revisiting of the trauma that is therapeutic.

Or it could be something like the Hawthorne Effect where the effectiveness is because the group knew they were receiving an experimental treatment.

Yeah it seems like the closest you can do to “blinding” in this case would be to take people who haven’t been on psychedelics at all, and give the control group something that elicits a “trippy but not psychedelic experience” that is new to them, so you rule out merely “experiencing something trippy and new” like that as being the mechanism of action.

There are some psychedelics (maybe 2CB, 4-Ho-Met too?) that give trippy visuals but are known for being less “in your head”.

Popular with ravers because they’re easier to handle on the dance floor.

It would be interesting to identify drugs that behave in this way and use them as comparators.

> and give the control group something that elicits a “trippy but not psychedelic experience”

The doses of benadryl they were giving them as an "active placebo" are approaching levels where you do start to get some... Interesting (and often extremely distressing) deliriant effects.

0/10 would not recommend tripping on benadryl,

Studies often use amphetamine as a control. Many psychedelics have a stimulant nature to them.

Because psychedelics = 'getting high' and (by implication) having a good time, which will be unacceptable to puritans. The idea pharmaceutical changes your behavior without making you feel any better. I will not be the least but surprised if some slow news day in Congress is filled by a Rand Paul type complaining that people are becoming alcoholics to trick doctors into giving them party drugs.

I agree with your point about puritanism, however the following bit doesn't make sense to me:

> I will not be the least but surprised if some slow news day in Congress is filled by a Rand Paul type complaining that people are becoming alcoholics to trick doctors into giving them party drugs.

Rand Paul is a doctor by trade, I'd find it strange if doctors didn't have something to say about that, or if doctors that became politicians had nothing to say about it. Should doctors not care that people are abusing the system and lying to them in order to get prescriptions?

This is Paul's position on cannabis[0]:

> you ought to be able to pretty much do what you want to do as long as you don't hurt somebody else

and "has supported efforts to legalize in Kentucky"[0].

All in all, I don't follow your point there.

[0] https://en.wikipedia.org/wiki/Rand_Paul#Cannabis

Though he professes to be libertarian I don't think he's very sincere. By all means substitute him with someone else, though. He was just the first person that sprang to mind when I thought of 'politicians making specious arguments'.

I wouldn't have thought that "you ought to be able to pretty much do what you want to do as long as you don't hurt somebody else" was a specious argument but there you go.

I'm pretty sure the (hypothetical) specious argument referred to was "people are becoming alcoholics to trick doctors into giving them party drugs".

And in addition to that, anigbrowl believes Paul isn't sincere when he professes to believe that "you ought to be able to pretty much do what you want to do as long as you don't hurt somebody else", which is why they chose him as an example, but that wasn't the important part.

Fair enough, though since anigbrowl is continuing their absurd argument regardless of any opposition, I think replacing “hypothetical” with “straw man” would be more appropriate.

You're reading way too much in what I already told you was an offhand remark. I replied to your other posts out of courtesy, not to win an argument.

A straw man does not need to be intentional, it's easily done through ignorance. I do wonder why you'd be bothered about having an off-hand remark that is clearly wrong corrected? If it was truly offhand I'd think it would be easy to accept such correction.

Maybe you'll tell me more about your belief that Paul is insincere but I don't count mind reading among my beliefs, so we'll just have to agree to disagree and - hopefully - agree that wilfully ignorant offhand remarks add nothing to HN. Perhaps take the time to find a non-libertarian, non-doctor from the Republicans to use in future and the tribalism will at least be less blatant and egregious.

Your offhand remark pulled the thread off-the-rails pretty quickly and easily.

Look at his questioning in COVID-related oversight hearings, there's a lot of grandstanding - given that he has a medical education it's disappointing that he leans so heavily on rhetoric instead. I would not be at all surprised to see him vote against a cannabis legalization bill, citing some obscure technicality or averring that it doesn't go far enough. We might even find out this session.

This is an odd criticism. What do you mean rhetoric? I mean, it’s a senate hearing, we’re you really expecting no politics?

His questions were certainly valid - why were we pushing a jab on kids who don't need it, of which we don't know the long-term effects, for a "vaccine" that's rendered mostly ineffective after 4 months, against a disease that almost never kills kids (less than 100 in the U.S. who had serious health problems).

The rushed rollout and forced mandates of these products across the country invited much criticism. If that's a tough pill to swallow, maybe you'd be happier in Canada or Australia, or China, for that matter - their COVID policies are basically the same in abnegating personal choice and freedom for bodily autonomy.

Careful, your opinions might be considered heresy by some.

It's been shocking to observe how quickly society descended into "trust the science", when time and again the public has been betrayed for trusting these institutions, the pharmaceutical companies, the politicians and even scientists.

I'm not saying I agree with one side or the other completely, but it's a relief to see the tide of public opinion turning toward critical thinking. (Maybe not though, the manufacture of consent is as powerful as ever.)

Rand Paul is a libertarian supporting legalization. He's pretty much the opposite of a Puritan.

How many bills has he introduced to legalize currently illicit drugs at the national level?

Exactly.

Look to a man's actions. Ignore his words.

https://www.marijuanamoment.net/cory-booker-and-rand-paul-bi...

Plenty more than most politicians it would seem?

What puritans are you talking about? You can do ketamine-assisted therapy for depression in how many states now?

I would prefer random trials compared to "guessing" the action. Our understanding of human body is still very primitive at best and we just don't know the mechanism of action of many frequent things like headache or hangover, where we could get data from millions of people. Even in pharmacy, the mechanism of action runs backward. We get many candidates for drugs, do animal testing, and see if something changed in them, and if it works, we later try to come up with some mechanism, which a lot of time in history was completely wrong.

that the actual experience of the trip is what makes the difference.

Possibly. But until you can control for it, you'll never know if it's real or just a placebo effect.

How on earth can you control for that? The only thing that comes to mind is holotropic breathwork, which reportedly brings about similar experiences without introducing a drug. That…might constitute an informative study, now that I write it out loud.

People who swam naked in ice water reported feeling "cold", but 95% could identify if they were in the treatment group. We'll never know if it's the placebo effect or not!

You can't do double-blind psychedelics trials. Researchers should stop wasting their time trying.

If you can't do a proper controlled trial, then you can't ever prove it's not a placebo effect.

That's basic science.

If a substance can reliably produce a strong placebo effect that helps a lot of people with minimal serious side effects, probably just start offering/administering it anyway!

Doing science that answers just that question would be valuable on its own. Knowing why/how it helps would be nice, but if it definitely helps…

Why not just give a placebo instead of an actual drug then? A sugar pill. No side effects.

If you can reliably solve the problem by doing that then why not.

I guess saying “this is just a sugar pill but it might help” and “this is a psychoactive substance that might make you trip a bit but also seems to measurably help some people though we’re not sure if it’s just a placebo” might have different placebo effects. Or maybe it actually works and it’s just hard to know.

The point is if it measurably works better than other substances, including definite placebos, why not use it?

We should want the outcome with sufficiently high probability and within whatever risk tolerance we define. Not the outcome in a way that satisfies a specific group of scientists. That’s not to criticise the scientists or their science, it’s important to do it, and knowing is better than not, but not knowing everything shouldn’t necessarily stop us if the risk/reward is there.

That is not basic science. Randomized, double blind, placebo controlled trials are the gold standard of trials. Doesn't mean they're the only option. And, frankly, trials aren't that great as far as science goes. Physics seems to get by without them.

And "prove"? What does that mean? (Big epistemology rabbit hole).

I'll make the same point I did in my other comment more literally. I have a hypothesis that giving a 5k jog, three times a week to sedentary but otherwise healthy individuals will lower resting heart rate. I get my study population and randomize between treatment and control. Treatment does the running program for six weeks. Control does nothing.

Treatment has a mean reduction in resting heart rate of 4 bpm. p = 0.01. n = 200.

Have I proven anything? Do you think this was placebo? If it was debated if jogging reduced resting heart rate, was this study useful?

There are non-chemical ways to achieve a psychedelic experience. Holotropic breathwork could be one way. So perhaps you could do holotropic breathwork + placebo versus holotropic breathwork + psilocybin.

Possibly not practical, would need a lead in phase where people practice breathwork, then selection of people able to have an experience, then actually running the trial.

This has been borne out in studies so far. They have seen data that one of the highest correlation factors measured for positive outcomes has been the degree to which the participant had ‘mystical’ experiences! [0]

It’s hard to convey why that would be or even what a ‘mystical’ experience is, but speaking as someone who has been profoundly helped by this modality in my own journey, that finding tracks pretty well with my experience.

Obviously take studies of new findings with a grain of salt, and n=1 anecdotes even more hesitantly, but before psychedelic medicine, I was stuck in a deep depression that no psychological, psychiatric, or medical treatment could budge.

I wanted desperately for anything to help, begging for even a placebo effect I could hang my hat on!

After beginning treatment utilizing psychedelic medicine, I have been given a life I could have never imagined before. I’m not cured by any means and it’s not all sunshine and roses, but I went from virtually being a shut-in, sometimes incapable of showering even once a week, to enjoying being around people, hanging out with old friends and making new ones, and easily handling a 40-hour work week at a retail job, within 6 months. After being stuck for four and a half years before that, unemployed and numb inside.

And that’s only the quantitative, objective measures. I’ve also gained a richness in my emotional being that I was shut off from before that I’m so incredibly grateful to have received.

To be clear, this has been the most difficult thing I’ve ever done in my life, but without a doubt it has also been the most rewarding.

One more earnest warning, I’m not advocating you or anyone else pursue this treatment. While I do believe it represents a major step forward in the treatment of many forms of mental illness, it is not a magic pill or a quick fix.

It should be regarded with the same seriousness as any surgery or other major medical intervention. This stuff can be very disruptive to your life in the short and medium term and there are very real risks involved that you can’t simply hand-wave away. There are a lot of advocates in the field who I feel are too overzealous and push people towards it hard and bill it as a panacea. Do your research and be cautious, and don’t take lightly the decision to pursue this form of treatment. You are the one who must make these decisions for yourself, in your life.

If you are interested in learning about psychedelic medicine, one very helpful resource I’ve come across for beginners is “The Beginner’s Guide to Psychedelic Medicine” [1] by Tucker Max.

Best of luck to you in your journeys, all of you. And no matter what’s happened to you or what you’ve done, or what you’re going through right now, I want you to know that you matter! You deserve to have a wonderful life, and I hope that every day brings you a little closer to that lovely place, and with it a little more hope! “Remember, I’m pulling for ya! We’re all in this together!” [2]

[0] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707356/

[1] https://www.tuckermax.com/beginners-guide-to-psychedelics/

[2] https://youtu.be/Orjbwv8H9zM

> If you are interested in learning about psychedelic medicine, one very helpful resource I’ve come across for beginners is “The Beginner’s Guide to Psychedelic Medicine” [1] by Tucker Max.

Please please please remember this point. If you are going to start a psychedelic journey, do some prep work first!

The focus on the molecular mechanism of action is of course typical for this kind of study. Ignoring the phenomenological aspect can seem odd however there is a rationale behind it. I don’t think that it stems from a denial that the phenomenological experience has an impact on the results. It’s stems from the complexity of the experience. Culture, personal experience, setting, etc. all play a role in the phenomenon. It’s likely impossible that we will br able to control for the many parts that influence the psychedelic aspect of therapy and at the very least it’s something that will have to be investigated further down the road.

Yeah, this was what I was thinking as well, but I think researchers should just accept that blinding is fundamentally impossible in studies like this:

1. With a high dose of shrooms, you're definitely going to know whether you were tripping or not.

2. If they can find another agent that mimics the effect of tripping, well then it's not really a placebo anymore.

Good point. I can see the normal approach being valuable if studying microdosing, but regular dosing is going to go from 'hmm I wonder if anything will happen' to 'woohoo space llamas' in no uncertain terms.

One wonders why even tried this approach, other than satisfying funding and review bureaucrats that prefer not to think.

You absolutely cannot blind a psychadelic study unless you are testing psychedelics against each other or different doses. No more than you could test someone’s performance while drunk against a sober person. The effects are just invited to everybody.

It's going to be incredibly hard to blind a study on psychedelics due to their unique and powerful effects... the best might be some sort of VR experience with a dissociative to mimic a psychedelic experience, but even that seems unlikely to be an effective control.

Especially when dealing with addiction. In other contexts, a fairly strong sedative is frequently used as the control, which is going to be a lot less subtle.

Reminds me of the 1962 “Good Friday Experiment”

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

There's still a difference between "guessing" correctly versus actually knowing the truth. It's different from an actually unblinded study even if participants can "guess" correctly.

Looks to be a vanishingly small difference if they guessed correctly, the first time they were asked, 94.7% of the time with 90% confidence.

In order to understand the difference, you'd have to have a blinded and unblinded study, and compare the results. Then you could understand the difference between a guess with 90% confidence and actually knowing what treatment you received with certainty.

It seems reckless to presume the difference (between blinded and unblinded) is small. The numbers you cite (94.7% and 90% confidence) have nothing to do with the question you're trying to answer.

For example, an important difference may be with respect to expectations. If you're told you're receiving a psychedelic treatment, you may go into the experience with different expectations than if you were unsure about what treatment you were getting.

I didn't see it in the paper, but I wonder what the difference was in people who correctly guessed their treatment assignment between the different arms.

I would imagine that everyone who got psilocybin guessed correctly.

if the intention is to have a blind test, is there a reason it's not administer while the patient is asleep?

If you stay up for 48 hours, go to sleep, get a random injection after an hour or two, wake up ~10 hours later. I would think you'd probably cut that ~90% down significantly