[reubenmorais]

I see so many studies trying to somehow distill trippy drugs into an isolated, side-effect free, take a pill and get back to work treatment. Maybe there's something to be found there, would be huge, but my hope is that we don't waste all the will and funding down this path without more fully exploring the path where we admit that yes, the trip helps, and we'll just need to deal with the lack of blinding.

[PragmaticPulp]

The problem is real, though. Drugs with overt recreational effects very frequently distract the patient from the therapeutic effect in unproductive ways. The recreational effects generally disappear quickly as tolerance develops, which can give patients the false impression that the medication “stopped working”.

A common example would be ADHD stimulants, where the early stimulating and mood-boosting effects disappear over time while the concentration-enhancing effects mostly remain. This leads a lot of patients to assume the medication isn’t working because it doesn’t feel like those first few doses, which can lead to discontinuation or abuse.

Ketamine has a similar story arc. The antidepressant effect doesn’t require full blown dissociation, but so many headlines and fame-seeking authors have hyped it as “psychedelic medicine” that some patients assume it isn’t working until they disassociate/hallucinate. This can create a sort of nocebo effect where patients may actually be improving but they think they’re not because they didn’t have the wild hallucinations they read about in some exaggerated internet article.

[vasco]

I took LSD twice in my life only and it changed my outlook ever since. It's been almost 10 years. I wasn't depressed and had other benefits from it, but I can see how that experience could've fixed depression, and know of people who say it did for them even though I'm not in any hippy-like community or whatever.

I think a possible reason why medical research prefers a pill that works forever for continued use is that if you buy something cheap twice in your life and it fixes whatever needs fixing the pharma industry can't make money off of you the same way they can put you on antidepressants for life. I'm not in the medical field so I'm just speaking out of my ass based on personal anecdotes though.

[ativzzz]

Or because it's not really medicine and person specific? I've taken LSD several times in varying doses and it's never been anything more than "a really really fun time". Nothing profound, but damn fun times, the same effect as any fun memorable party

Perhaps if you are looking for something profound or want a change of mindset, psychedelics might be able to help you reach it - similar to how shamans used psychedelics to talk to their gods or whatever - but if you're just looking to have fun that's what you'll get

[efields]

Last time I remember taking LSD I was on a bus going from NYC to Boston and I guess I was either bored or knew we were going to have a longer than usual trip home because of traffic. I wind up talking with the guy behind me for hours who describes something to me he was working on that sounds like modern day Spotify (this was circa 2005ish?). We get into spirituality at some point. We have a 7 hour trip and get home early morning before the subway is running. We walk around the Commons a bit. He had a cane but didn't need it… just used it as a fun prop in life. He had me believing his name Joshua or in Hebrew Yeshua aka Jesus. (edit: copy pasta)

Anyway if you take drugs to party and then go to a party, you'll party. If you take drugs and do therapy you'll do therapy. If you take drugs just to see what happens and you're open to whatever happens, things will happen. Maybe you'll just have an oddly memorable time and you ponder what it means, slowly altering how you think about other things for the rest of your life.

[lcnPylGDnU4H9OF]

The anecdotes you give don't necessarily suggest this is person-specific. They don't refute that, in the general case, there might a good chance for a person who is depressed to have their symptoms alleviated by an LSD trip. Were you depressed (in the DSM-5 sense) any of the times you took LSD and had "a really really fun time"? A person who is not depressed obviously won't notice the mindset shift which alleviates their depression.

[ativzzz]

I've been "depressed" if you want to call it that based on the DSM-5 definition both before and after the LSD trips. And no not during - that's one of the benefits of fun events - you forget about depression because you're too busy with other things, at least I do anyway

[klyrs]

I did LSD once in the depth of grief where I was having trouble processing the loss of multiple family members. I went in with a "roll up your sleeves and clear out the garbage" mindset and it had an incredibly profound effect. Other times it was just fun, though I've also found elusive solutions to problems I've been working on, similar to dreaming.

[jcranmer]

> I think a possible reason why medical research prefers a pill that works forever for continued use is that if you buy something cheap twice in your life and it fixes whatever needs fixing the pharma industry can't make money off of you the same way they can put you on antidepressants for life.

Drug discovery is difficult enough that the pharma companies don't have the ability to make a meaningful choice between fix-once-and-you're-set-for-life versus manage-symptoms-forever.

[thomastjeffery]

It's not just about money.

How do you test a medication that only needs to be taken once or twice? This is very challenging to study scientifically.

Psychedelics bridge the gap between medication and therapy. A trip is not guaranteed to be therapeutic, but a trip with proper guidance it's more likely to be.

How can we know which aspects of that guidance are useful, and which are superfluous?

It's going to take a lot of work to get to the level of certainty that our medical system expects for medication.

[vasco]

> How do you test a medication that only needs to be taken once or twice? This is very challenging to study scientifically.

Most vaccines you only take once, you can still test if they work or not. Same with poison antidotes and things like that. Like I said, I'm not a doctor, but the fact that it's only once doesn't seem like the problem.

[thomastjeffery]

Yes, because you can measure the amount of antibodies as many times as you want; and you can be pretty certain they are the direct result of the vaccine.

How do you measure depression? How do you know what changed it, or how much?

[jimnotgym]

That seems to be their objection to mushrooms, can't charge a lot for something that grows in your lawn. Turn it into a pill with some chemical tweak and you get a patent.

[thomastjeffery]

Continuing your ADHD example, the mood-boosting effects may very well be secondary, not directly caused by the drug itself. It feels great to finally have the balance of stimulation you always needed, but never had. The experience also has novelty, which is known to be very important to ADHD brains; because novelty is stimulating.

After some time, the novelty of the experience wears off, and you start to get more familiar with the limitations of medication. That's disappointing. Disappointment feels bad. Again, this is not caused by the drug itself, but by the surrounding experience.

ADHD itself is riddled with secondary experiences: they make up the name itself! People with ADHD do not struggle to pay attention, we struggle to direct it. Hypoactivity is a reaction to living without enough simulation. Neither is a direct symptom of the disorder, but they are ubiquitous enough to

People who live with undiagnosed/untreated ADHD are likely to end up with a lot of trauma. That trauma is unaffected by medication.

So if you start taking ADHD medication, you need to know what it does and doesn't help with. Medication can't make up the entirety of treatment, just like cognitive behavioral therapy can't replace medication.

[zamnos]

> The antidepressant effect doesn’t require full blown dissociation

I'm not sure, isn't that kind of what's being shown by this study? Or like, is there levels of disassociation that you're distinguishing between? Are you able to enumerate those levels for those of us who are unfamiliar with disassociation?

[naasking]

> Drugs with overt recreational effects very frequently distract the patient from the therapeutic effect in unproductive ways.

How are you quantifying "frequently"? Does that necessarily mean that the recreational effects cannot themselves be therapeutic?

[tokai]

Literally the last line of the article:

"Future studies of novel antidepressants with acute psychoactive effects should make stronger efforts to mask treatment assignment to minimize the effects of subject-expectancy bias."

Instead of pondering if their method is at fault for their negative result, the conclusion is to double down and working even harder at masking the effects.

[mtlmtlmtlmtl]

Well, what they're trying to do is provide better blinding. Doing proper blind studies of ketamine is quite hard because its subjective effects are far too noticable.

That line just says people should do better at this in future to get more accurate results. It's not a statement about the ultimate form the treatment should take.

[tokai]

yes ofc, but if the treatment is the trip it will never work blinding it like this. If anything they should be looking for drugs that give comparable trips, with no potential for depression treatment.

[mtlmtlmtlmtl]

I agree in principle, though having tried most of the various types of trippy substances, I've yet to encounter one that hasn't showed potential for a short term antidepressant effect. I guess I haven't tried those weird delta opioid ligands(salvia divonorum). I guess deliriants(like diphenhydramine) would have about zero antidepressant effect too, but that would have possible negative effects, even being liable to cause trauma.

I believe benzodiazepines have also been tried as an active placebo but I don't remember what the results were.

[oaktrout]

Small correction, the active ingredient in Salvia is a kappa opioid agonist.

[mtlmtlmtlmtl]

You're right, thanks for the correction! Really should check more of these things and not just do it from memory.

[tpm]

Diphenhydramine as a first generation antihistamine acts on a large number of receptors and can even be used as a mild anxiolytic, so I'd guess it could very well have antidepressant effect.

No idea about deliriants like atropine/scopolamine, but in low doses, they were traditionally used to spice up beer (hence Pilsen named for Bilsenkraut, black henbane), so I could imagine short antidepressant effect there too.

[natechols]

> Diphenhydramine as a first generation antihistamine acts on a large number of receptors and can even be used as a mild anxiolytic, so I'd guess it could very well have antidepressant effect.

It does, and this observation led to the development of dedicated antidepressant drugs. There are several such cases where interesting side effects turned out to open a world of possibilities, including an anti-TB drug that also led to antidepressants, and of course Viagra.

[Spivak]

You basically can't do science like this and prove anything useful outside of group A is the more effective than group B. And that's assuming your test subjects can't tell the difference. That would tell you that at minimum either A or B has a non-zero effect because they both can't do nothing and be different. But proving that A is an improvement over not A is the important bit. A and B could both be worse than nothing but A is just less bad.

"find something that has a similar trip but does nothing" is actually equivalent to the original problem.

[naasking]

> That line just says people should do better at this in future to get more accurate results

But it's also doubling down on the assumption that the subjective effects aren't the source of the benefit.

[SiempreViernes]

One of the objections against the improvement observed that is mentioned in tfa is precisely that you can get "trips" from general anaesthesia:

'Schenberg points out that people often report dreamlike and visual, auditory, and affective experiences under anesthesia. “Maybe people who had dreamlike experiences during the anesthesia had more improvement than the people who didn’t,” he says.'

So maybe the trip does indeed help, but evidently it is not necessary to be able to remember if you had one to get the reported benefits.