21 ms·

Psychedelics are challenging the standard of randomized controlled trials

144 points by chapulin 2y ago

ThePowerOfFuet 2y ago
https://archive.ph/l3GtQ https://archive.ph/l3GtQ
- neonate 2y ago
  https://web.archive.org/web/20240603195140/https://www.theatlantic.com/health/archive/2024/06/psychedelics-mdma-ptsd-fda-placebo/678588/ https://web.archive.org/web/20240603195140/https://www.theat...
s4mw1se 2y ago
LSD was expected to be the holy grail of mental health treatment in the 40s and 50s before it was made illegal by the U.S. and the rest old the world following in the united states foot steps. I’m very grateful that we are starting to see research really pick up steam and public companies like MindMed pushing for FDA approval with MM120. It’s bittersweet though because it also is proof of how much progress we lost over those decades. Not to discredit PTSD and Mental Health research, but just to expand on how much we don’t know about our mind and what these chemicals really are… DMTx had its first round of clinical trials, where participants have extended experiences in DMT hyperspace and all share common hallucinations (i.e talking to other lifeforms). What’s interesting is that these experiments are showing us how our brain models the world. Unlike freebase N,N-DMT which is a short lived rocky experince. These patient reported and the data showed that after the first few minutes on DMTx things started to normalize (the brain started modeling their world better) One of Strassmans patients years ago said on DMT that these entities could share more with us if we learn to make extended contact. Albert Hoffman the inventor of LSD also said he had contact with external entities on a trip (eyeball with wings) and said that it told him that they chose him to discover LSD for the sake of humanity. The DMTx participants all reported that these entities knew about their life and their traumas and helped them process these all in different ways. They all reported that these were beings of a higher intelligence and felt that they were external. Psychedelics are 100% challenging the gold standard. Whatever the that is lol.
- r2_pilot 2y ago
  And people experiencing DTs from alcohol withdrawal say nonexistent entities are present too. The brain is merely capable of processing its inputs based on the laws of physics, and considering the complexity of a functioning mind, we shouldn't be too surprised when abnormal inputs cause abnormal outputs, nor should we necessarily hold much stock in the matter. Certainly, though, the tales are interesting if nothing else.
  - BriggyDwiggs42 2y ago
    We don’t have any way of determining whether these experiences are purely generated by the brain, and it’s not smart to claim it’s one way or the other without further evidence.
    - JumpCrisscross 2y ago
      > it’s not smart to claim it’s one way or the other without further evidence It's perfectly smart to claim Hoffman did not make "contact with external entities on a trip (eyeball with wings)" with zero evidence because the status quo is not having conversations with eyeballs with wings. Herego, the burden of proof is on the eyballs-with-wings guy.
      - mistermann 2y ago
        Anyone who makes a claim has a burden of proof. If I'm on The Truman Show, could someone please spill the beans?
        deepvibrations 2y ago
        Yet we still work on the assumption that consciousness arises within space-time... Disappointing the burden of proof is not deemed necessary in this case!
        r2_pilot 2y ago
Animats 2y ago
That's been true of other drugs with strong noticeable effects. Not a new problem.
- Kenji 2y ago
  [dead]
jseliger 2y ago
RCTs are fine but the obsession with them is overwrought and counterproductive. My own drum to beat on this is regarding clinical trials for fatal diagnoses like cancer: https://jakeseliger.com/2024/01/29/the-dead-and-dying-at-the-gates-of-oncology-clinical-trials/ https://jakeseliger.com/2024/01/29/the-dead-and-dying-at-the.... We have Kaplan-Meier curves for fatal diagnoses. We know what happens (the tumors grow and metastasize. One doesn't need elaborate phase 3 RCTs to figure out if there's a good shot that a treatment is working; one can see it in tumor response and comparison to known KMCs. The existing system raises costs and causes people to die while waiting a decade or more for exciting treatments: https://atelfo.github.io/2023/12/23/biopharma-from-janssen-to-today.html https://atelfo.github.io/2023/12/23/biopharma-from-janssen-t... Moderna's mRNA-4157 is a current example of this: https://jakeseliger.com/2024/04/12/moderna-mrna-4157-v90-news-for-head-and-neck-cancer-patients-like-me/ https://jakeseliger.com/2024/04/12/moderna-mrna-4157-v90-new..., although it may be held up by lack of manufacturing capacity as well.
- david_shi 2y ago
  100% agreed. "RCT's are the gold standard" doesn't make them gospel.
- Aurornis 2y ago
  > RCTs are fine but the obsession with them is overwrought and counterproductive. My own drum to beat on this is regarding clinical trials for fatal diagnoses like cancer: RCTs for mental health conditions are a completely different situation. The short-term placebo response rate for cancers is not high (obviously) though the influence of unblinded trial operators making subjective analyses can be a problem. Many mental health conditions, on the other hand, have unbelievably high placebo response rates over the duration of a short trial. The magnitude of the placebo response is almost hard to believe in certain studies. The placebo effect can be a problem for approving new drugs as some times the placebo group improved so much that there isn’t much room left for the active drug to improve beyond that. This is a problem of study design and rating systems that is difficult to solve. Unfortunately, some study operators use this fact to their advantage by omitting placebo group. Without a placebo group, it’s not obvious that the drug is actually doing anything better than placebo, of course.
omginternets 2y ago
A while back I posted a moderately popular comment, which I think is equally relevant here. https://news.ycombinator.com/item?id=37949336 https://news.ycombinator.com/item?id=37949336 Beyond the importance of controlling the placebo effect, I am worried that a lot of the drug-depression research is overlooking an important possibility: that the thing about ketamine/psilocybin/etc that is helping with depression is not some latent property of the molecule, but rather the actual transcendent experience of the trip. In other words, the trip is the point, not the mechanistic neuro-tinkering [0]. Importantly, this tracks with what we know about the protective effects of things like religiosity against depression. As such, the qualitative experience of the drug might not be something we can (or should) do away with. I would even go as far as suggesting that an absence of transcendence in one's life is precisely what causes a large segment of people to become depressed in the first place, and that perhaps drugs are helpful only insofar as they produce a transcendent experience. This isn't to say we can't take a scientific approach to treating depression, but that has to be balanced with something profoundly metaphysical: the actual qualia of life experience. Wellness isn't the absence of disease; it's the presence of thriving, and that includes within it a component of things like hope, inspiration, and elevation above the ordinary. We used to have various ceremonies designed to turn us towards the numinous, but we've pretty systematically dismantled those in favor of a grounded hyper-rationality [1]. As a scientist, I can't really object to rationality on its own, but it may be worth considering non-rational, transcendent experience as a fundamental psychological need. [0] If you're a materialist, you might object that neurological machinery is not differentiable from qualia. Fair enough! I even agree! My point is simply that medicine needs to consider qualia as a major parameter in the treatment of depression. Fixing depression is not like fixing a car. [1] I suspect most people here are familiar with Nietzsche's "God is dead quote". Many people in my entourage are floored to discover that he correctly predicted the dramatic increase in anxiety, depression, neuroticism and nihilism that is present in modern life.
- panagathon 2y ago
  Your intuitions are on the mark. https://link.springer.com/article/10.1007/s00213-017-4771-x https://link.springer.com/article/10.1007/s00213-017-4771-x This study finds that: > No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. I think there's another out there with similar findings, that the stronger the mystical-type experience induced, the stronger the impact on the pathology. I haven't been able to dig it up though.
kaashmonee 2y ago
The title seems a bit misleading. I thought they were talking about LSD or psilocybin. But this is referring to an MDMA-based therapy which I feel is more of a stimulant, or at least is used as one more often than it's used as a psychedelic and it's an amphetamine.
- neom 2y ago
  LSD acts as a direct agonist at the 5-HT2A receptors, effectively pretending to be serotonin, whereas MDMA increases the release of serotonin and other neurotransmitters, affecting several receptor types, but not primarily acting as a direct agonist to 5-HT2A receptors. https://en.wikipedia.org/wiki/5-HT2A_receptor https://en.wikipedia.org/wiki/5-HT2A_receptor
nico 2y ago
Really hope at some point the healthcare industry starts trying to figure out how to harness the power of the placebo effect to enhance healing, rather than trying to do away with it I mean, is the goal healing people? Or is it to only heal them if they get better by the direct effect of a (patentable/sellable) chemical? Whose interests is the healthcare industry serving or protecting?
- tsimionescu 2y ago
  You are conflating two things: medical research and the practice of medicine. During the normal practice of medicine, most doctors do everything they can to harness the power of the placebo effect: they reassure the patient, they speak calmly and warmly, they encourage religious people to pray, etc. Doctors care about a positive outcome, and will take any help they can get to achieve it. In medical research, we are interested in figuring out if a particular drug helps for a particular condition. We already know that for some conditions, even giving patients a drink of water helps a bit. We need to understand if the drug is better than that, or if it only appears to help. The placebo effect is a baseline of noise in this case, and we need some way to filter it out to understand if there is some signal from the drug itself. If not, then you might as well give the patients some water rather than waste their money on an expensive hard to reproduce potentially poisonous substance.
- eviks 2y ago
  There is nothing to harness, it's just noise. But also homeopathy exist, so the broader healthcare industry is happy to feed anyone gullible enough with sugar pills to harness this power
- lukas099 2y ago
  Pretty much every intervention that a doctor prescribes does "harness the power of the placebo effect". It just also is effective beyond that effect.
- aredox 2y ago
  Oh, it's already done, it's called homeopathy. And it's a striving business, don't worry, the patients'needs are ignored just as much.
mannyv 2y ago
It's amusing that the placebo effect is so strong that they needed to create a standard that eliminated it. Instead, they should figure out a way to induce it more consistently.
- lukas099 2y ago
  When you perform a medical intervention that is effective beyond placebo, you are also inducing placebo. Drug research is just trying to find the most effective treatments, not trying to get rid of the placebo effect. Also, I think most doctors are happy to let patients have their placebos of choice (crystals or herbs or what have you), as long as it doesn't interfere with the rest of their treatment.
- aredox 2y ago
  They figured it out, it is called homeopathy and it racks millions each year.
- Dylan16807 2y ago
  People do try to figure that out. But the benefit of removing placebo effect in a study is that you find things you can add on top of placebo effect.
spacetimeuser5 2y ago
>>By striving to cleave the drug’s effects from the context in which it’s given—to a patient by a therapist, both of whom are hoping for healing—blinded studies may fail to capture the full picture. The amount of monkey types amongst these researchers is spectacular. In the current AI boom, with various RAG and prompt engineering, everyone is striving to maximize context, and no-one would deny that modern AI emulates parts of human mind/brain. And context sensitivity of quantum systems is also pretty much obvious. Modern astronomy, for example, can pretty much as well challenge the standard of randomized controlled trials: no one uses experimental planets and galaxies to test their null hypotheses. No engineer would strive to falsify the objects they are developing by deliberately designing non-working engines etc. And this is pretty much considered science. While these "social scientists" are still full of medieval bullshit, so that it is more optimal to commit suicide than use their evidence-skewed medicine, which under the hood by default considers the subjects are either rocks or dead.
- nathan_compton 2y ago
  I don't really get what you are saying here. RTCs are designed precisely to allow one to draw statistical conclusions which would be untenable due to confounding effects that would be impossible to disentangle otherwise, particularly in regimes where effect sizes are small and results are sometimes difficult to quantify. I'm having trouble understanding what you are even getting at with comparisons to astronomy, where the absence of controlled experiments isn't some grand innovation astronomers cooked up but a basic constraint imposed by studying stuff that is light years away. Any decent epistemologist would tell you that the character of knowledge generated by astronomical observations is of a lower quality than that of a RCT. I'm sure some astronomers or cosmologists would give their left arm to do a randomized controlled trial!
  - spacetimeuser5 2y ago
    With astronomy, where the data are mainly derived from observations and simulations, no one is spreading alarms that it is not science. While with RCTs - and specifically RCTs in the filed of human cognitive neuroscience and psychedelics - there is all this monkey circus regarding whether placebos or psychedelic experiences are real. In human neuroscience ~80% of data is derived as well from observations and is effectively non-reverse-engineerable, while the hype regarding pseudoscience is much higher. You buy aspirin in a pharmacy and the drug's instruction label lists tons of adverse effects - this is obviously a seemingly high quality of knowledge resulting from hard work in RCTs. Yet, there's absolutely no information predicting which exact adverse/beneficial effects will manifest in a specific person in a specific state of consciousness - and this is the actual empirical level where RCT derived information should actually matter and where it is ~50% useless (due to lack of context in RCTs themselves).
CogitoCogito 2y ago
> How do you study mind-altering drugs when every clinical-trial participant knows they’re tripping? Are there really no protocols for research in which participants can tell whether they have received a certain drug or not? I mean sure I think that double-blind is best for research, but are there really not other cases in which they deal with the patients knowing? Edit: > By striving to cleave the drug’s effects from the context in which it’s given—to a patient by a therapist, both of whom are hoping for healing—blinded studies may fail to capture the full picture. Okay I see the issue is that patients not being blind to the treatment is (thought to be) necessary for the treatment to work. Okay yeah so that means it's hard to make the participants blind in anyway. Still I'm surprised there aren't approaches to deal with this. Of course it might mean by definition double-blind trials aren't possible, but then again maybe that's not always appropriate. I can see the pandora's box being opened by allowing drug studies to bypass these restrictions though so I guess I see why people don't like it. Later in the article: > In an email, an FDA spokesperson told me that blinded RCTs provide the most rigorous level of evidence, but “unblinded studies can still be considered adequate and well-controlled as long as there is a valid comparison with a control.” In such cases, the spokesperson said, regulators can take into account things like the size of the treatment effect in deciding whether the treatment performed significantly better than the placebo.
- jerf 2y ago
  Yes, there are, which honestly makes this entire article premise a bit bizarre. Double blind and all that is an ideal, not a requirement. It can't be a requirement, because whether we can run double-blind or any other kind of study is not always a matter of how good we are or how much effort we are willing to put in, but a characteristic of the thing we want to study, as it is here. It's hardly the only drug where the participants can have a pretty good guess whether they're on a placebo or not. As just an example off the top of my head, I doubt there were a whole lot of chemotherapy testers who thought they were vomiting for days and losing their hair due to a placebo. Contrary to frequently-expressed opinion online, we are not in fact constrained to running only super-massive-sample-size triple-blind preregistered peer-reviewed gold-plated scientific studies and only permitted to say we might have an opinion if a metanalysis of multiple of those concurs. It's nice when we can do that, but the universe is not always so accommodating.
hereme888 2y ago
The title itself is hilarious if you think about it. But in an important note, I don't like that I never read of the warnings for psychedelics, like triggering schizophrenia.
- deleted 2y ago
  [deleted]
- freeqaz 2y ago
  I actually spoke to a doctor about this once during a psych eval. You can get screened if you're worried about schizophrenia and there are strong indicators that you're likely to develop it. (Which would mean to probably avoid psychedelics) In general though it doesn't seem like they will cause it. Just accelerate the onset.
  - hereme888 2y ago
    Good to know, thanks!
- observationist 2y ago
  Numerous studies have shown that the overall rate of occurrence in drug users is the same as the rate of occurrence in non drug users. Drug use causes schizophrenic breaks to happen earlier in susceptible individuals. The nature of schizophrenia makes the situation a "when" and not "if" question; around 1% of the population will have a schizophrenic episode and break from reality, regardless of whether they abstain from drugs or not. Almost any psychoactive drug can trigger early schizophrenic breaks; even caffeine or extreme stress and social trauma can be the trigger. Drug use can result in other forms of psychosis. Psychedelics can result in pathological derealization, when the individual begins to question everything about their life up to that point, becoming vulnerable to any potential model of the world that offers plausible answers. Persistent use can detach someone from reality, making it hard for them to integrate with normal society and maintain a normal, responsible life. Any drug use should be done responsibly. Harm reduction sites and drug safety activists and influencers have provided a huge wealth of information. Things that should be taught in school can nonetheless be found online, giving you the necessary health, use, preparation, and other harm reduction information necessary to be a responsible user. It's awesome that mainstream academia and the medical establishment are allowing this research. A better informed society will be a safer, healthier society, without the misinformation and stigmatized gossip that passed for "drug safety" in recent history.
taeric 2y ago
This is the second narrative I've seen recently where folks seem to think they have a strong argument against RTCs. Just, what? Yes, there have been advancements in statistical tools. And we actively know some causal pathways. More, sometimes the expensive randomized trials are just not worth the standard ROI calculations... But, to think that you have found some magic bullet against RTCs shows you don't really appreciate why they are so vital. And is usually a sign that you are reading the narrative of someone invested in an outcome.
sowut 2y ago
when i was 17 i found out about mushrooms and would take 1/8th ounce once a month for about 6 months which culminated in me absolutely convinced i was jesus for about 6 years. good stuff
- deleted 2y ago
  [deleted]
- mythrwy 2y ago
  If you are Jesus, maybe skip the crucifixion part this time?
  - sowut 2y ago
    turns out everyone is their own personal jesus
deleted 2y ago
[deleted]
fl0ki 2y ago
It looks like I get to be the one to comment a classic criticism of RCT absolutism. There have been no RCTs on parachutes or bulletproof vests. Volunteers welcome.
- pmyteh 2y ago
  They found some volunteers and did the study! This is one of the classics from the Christmas BMJ: https://www.bmj.com/content/363/bmj.k5094 https://www.bmj.com/content/363/bmj.k5094 The study has... let's just say "other methodological problems". But they did do an RCT of parachute use! (The open peer review correspondence is quite fun, too).

144 points by chapulin 2y ago

ThePowerOfFuet 2y ago

https://archive.ph/l3GtQ https://archive.ph/l3GtQ

neonate 2y ago
https://web.archive.org/web/20240603195140/https://www.theatlantic.com/health/archive/2024/06/psychedelics-mdma-ptsd-fda-placebo/678588/ https://web.archive.org/web/20240603195140/https://www.theat...

s4mw1se 2y ago

LSD was expected to be the holy grail of mental health treatment in the 40s and 50s before it was made illegal by the U.S. and the rest old the world following in the united states foot steps. I’m very grateful that we are starting to see research really pick up steam and public companies like MindMed pushing for FDA approval with MM120. It’s bittersweet though because it also is proof of how much progress we lost over those decades. Not to discredit PTSD and Mental Health research, but just to expand on how much we don’t know about our mind and what these chemicals really are… DMTx had its first round of clinical trials, where participants have extended experiences in DMT hyperspace and all share common hallucinations (i.e talking to other lifeforms). What’s interesting is that these experiments are showing us how our brain models the world. Unlike freebase N,N-DMT which is a short lived rocky experince. These patient reported and the data showed that after the first few minutes on DMTx things started to normalize (the brain started modeling their world better) One of Strassmans patients years ago said on DMT that these entities could share more with us if we learn to make extended contact. Albert Hoffman the inventor of LSD also said he had contact with external entities on a trip (eyeball with wings) and said that it told him that they chose him to discover LSD for the sake of humanity. The DMTx participants all reported that these entities knew about their life and their traumas and helped them process these all in different ways. They all reported that these were beings of a higher intelligence and felt that they were external. Psychedelics are 100% challenging the gold standard. Whatever the that is lol.

r2_pilot 2y ago
And people experiencing DTs from alcohol withdrawal say nonexistent entities are present too. The brain is merely capable of processing its inputs based on the laws of physics, and considering the complexity of a functioning mind, we shouldn't be too surprised when abnormal inputs cause abnormal outputs, nor should we necessarily hold much stock in the matter. Certainly, though, the tales are interesting if nothing else.
- BriggyDwiggs42 2y ago
  We don’t have any way of determining whether these experiences are purely generated by the brain, and it’s not smart to claim it’s one way or the other without further evidence.
  - JumpCrisscross 2y ago
    > it’s not smart to claim it’s one way or the other without further evidence It's perfectly smart to claim Hoffman did not make "contact with external entities on a trip (eyeball with wings)" with zero evidence because the status quo is not having conversations with eyeballs with wings. Herego, the burden of proof is on the eyballs-with-wings guy.
    - mistermann 2y ago
      Anyone who makes a claim has a burden of proof. If I'm on The Truman Show, could someone please spill the beans?
      - deepvibrations 2y ago
        Yet we still work on the assumption that consciousness arises within space-time... Disappointing the burden of proof is not deemed necessary in this case!
        r2_pilot 2y ago

Animats 2y ago

That's been true of other drugs with strong noticeable effects. Not a new problem.

Kenji 2y ago
[dead]

jseliger 2y ago

RCTs are fine but the obsession with them is overwrought and counterproductive. My own drum to beat on this is regarding clinical trials for fatal diagnoses like cancer: https://jakeseliger.com/2024/01/29/the-dead-and-dying-at-the-gates-of-oncology-clinical-trials/ https://jakeseliger.com/2024/01/29/the-dead-and-dying-at-the.... We have Kaplan-Meier curves for fatal diagnoses. We know what happens (the tumors grow and metastasize. One doesn't need elaborate phase 3 RCTs to figure out if there's a good shot that a treatment is working; one can see it in tumor response and comparison to known KMCs. The existing system raises costs and causes people to die while waiting a decade or more for exciting treatments: https://atelfo.github.io/2023/12/23/biopharma-from-janssen-to-today.html https://atelfo.github.io/2023/12/23/biopharma-from-janssen-t... Moderna's mRNA-4157 is a current example of this: https://jakeseliger.com/2024/04/12/moderna-mrna-4157-v90-news-for-head-and-neck-cancer-patients-like-me/ https://jakeseliger.com/2024/04/12/moderna-mrna-4157-v90-new..., although it may be held up by lack of manufacturing capacity as well.

david_shi 2y ago
100% agreed. "RCT's are the gold standard" doesn't make them gospel.
Aurornis 2y ago
> RCTs are fine but the obsession with them is overwrought and counterproductive. My own drum to beat on this is regarding clinical trials for fatal diagnoses like cancer: RCTs for mental health conditions are a completely different situation. The short-term placebo response rate for cancers is not high (obviously) though the influence of unblinded trial operators making subjective analyses can be a problem. Many mental health conditions, on the other hand, have unbelievably high placebo response rates over the duration of a short trial. The magnitude of the placebo response is almost hard to believe in certain studies. The placebo effect can be a problem for approving new drugs as some times the placebo group improved so much that there isn’t much room left for the active drug to improve beyond that. This is a problem of study design and rating systems that is difficult to solve. Unfortunately, some study operators use this fact to their advantage by omitting placebo group. Without a placebo group, it’s not obvious that the drug is actually doing anything better than placebo, of course.

omginternets 2y ago

A while back I posted a moderately popular comment, which I think is equally relevant here. https://news.ycombinator.com/item?id=37949336 https://news.ycombinator.com/item?id=37949336 Beyond the importance of controlling the placebo effect, I am worried that a lot of the drug-depression research is overlooking an important possibility: that the thing about ketamine/psilocybin/etc that is helping with depression is not some latent property of the molecule, but rather the actual transcendent experience of the trip. In other words, the trip is the point, not the mechanistic neuro-tinkering [0]. Importantly, this tracks with what we know about the protective effects of things like religiosity against depression. As such, the qualitative experience of the drug might not be something we can (or should) do away with. I would even go as far as suggesting that an absence of transcendence in one's life is precisely what causes a large segment of people to become depressed in the first place, and that perhaps drugs are helpful only insofar as they produce a transcendent experience. This isn't to say we can't take a scientific approach to treating depression, but that has to be balanced with something profoundly metaphysical: the actual qualia of life experience. Wellness isn't the absence of disease; it's the presence of thriving, and that includes within it a component of things like hope, inspiration, and elevation above the ordinary. We used to have various ceremonies designed to turn us towards the numinous, but we've pretty systematically dismantled those in favor of a grounded hyper-rationality [1]. As a scientist, I can't really object to rationality on its own, but it may be worth considering non-rational, transcendent experience as a fundamental psychological need. [0] If you're a materialist, you might object that neurological machinery is not differentiable from qualia. Fair enough! I even agree! My point is simply that medicine needs to consider qualia as a major parameter in the treatment of depression. Fixing depression is not like fixing a car. [1] I suspect most people here are familiar with Nietzsche's "God is dead quote". Many people in my entourage are floored to discover that he correctly predicted the dramatic increase in anxiety, depression, neuroticism and nihilism that is present in modern life.

panagathon 2y ago
Your intuitions are on the mark. https://link.springer.com/article/10.1007/s00213-017-4771-x https://link.springer.com/article/10.1007/s00213-017-4771-x This study finds that: > No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience. I think there's another out there with similar findings, that the stronger the mystical-type experience induced, the stronger the impact on the pathology. I haven't been able to dig it up though.

kaashmonee 2y ago

The title seems a bit misleading. I thought they were talking about LSD or psilocybin. But this is referring to an MDMA-based therapy which I feel is more of a stimulant, or at least is used as one more often than it's used as a psychedelic and it's an amphetamine.

neom 2y ago
LSD acts as a direct agonist at the 5-HT2A receptors, effectively pretending to be serotonin, whereas MDMA increases the release of serotonin and other neurotransmitters, affecting several receptor types, but not primarily acting as a direct agonist to 5-HT2A receptors. https://en.wikipedia.org/wiki/5-HT2A_receptor https://en.wikipedia.org/wiki/5-HT2A_receptor

nico 2y ago

Really hope at some point the healthcare industry starts trying to figure out how to harness the power of the placebo effect to enhance healing, rather than trying to do away with it I mean, is the goal healing people? Or is it to only heal them if they get better by the direct effect of a (patentable/sellable) chemical? Whose interests is the healthcare industry serving or protecting?

tsimionescu 2y ago
You are conflating two things: medical research and the practice of medicine. During the normal practice of medicine, most doctors do everything they can to harness the power of the placebo effect: they reassure the patient, they speak calmly and warmly, they encourage religious people to pray, etc. Doctors care about a positive outcome, and will take any help they can get to achieve it. In medical research, we are interested in figuring out if a particular drug helps for a particular condition. We already know that for some conditions, even giving patients a drink of water helps a bit. We need to understand if the drug is better than that, or if it only appears to help. The placebo effect is a baseline of noise in this case, and we need some way to filter it out to understand if there is some signal from the drug itself. If not, then you might as well give the patients some water rather than waste their money on an expensive hard to reproduce potentially poisonous substance.
eviks 2y ago
There is nothing to harness, it's just noise. But also homeopathy exist, so the broader healthcare industry is happy to feed anyone gullible enough with sugar pills to harness this power
lukas099 2y ago
Pretty much every intervention that a doctor prescribes does "harness the power of the placebo effect". It just also is effective beyond that effect.
aredox 2y ago
Oh, it's already done, it's called homeopathy. And it's a striving business, don't worry, the patients'needs are ignored just as much.

mannyv 2y ago

It's amusing that the placebo effect is so strong that they needed to create a standard that eliminated it. Instead, they should figure out a way to induce it more consistently.

lukas099 2y ago
When you perform a medical intervention that is effective beyond placebo, you are also inducing placebo. Drug research is just trying to find the most effective treatments, not trying to get rid of the placebo effect. Also, I think most doctors are happy to let patients have their placebos of choice (crystals or herbs or what have you), as long as it doesn't interfere with the rest of their treatment.
aredox 2y ago
They figured it out, it is called homeopathy and it racks millions each year.
Dylan16807 2y ago
People do try to figure that out. But the benefit of removing placebo effect in a study is that you find things you can add on top of placebo effect.

spacetimeuser5 2y ago

>>By striving to cleave the drug’s effects from the context in which it’s given—to a patient by a therapist, both of whom are hoping for healing—blinded studies may fail to capture the full picture. The amount of monkey types amongst these researchers is spectacular. In the current AI boom, with various RAG and prompt engineering, everyone is striving to maximize context, and no-one would deny that modern AI emulates parts of human mind/brain. And context sensitivity of quantum systems is also pretty much obvious. Modern astronomy, for example, can pretty much as well challenge the standard of randomized controlled trials: no one uses experimental planets and galaxies to test their null hypotheses. No engineer would strive to falsify the objects they are developing by deliberately designing non-working engines etc. And this is pretty much considered science. While these "social scientists" are still full of medieval bullshit, so that it is more optimal to commit suicide than use their evidence-skewed medicine, which under the hood by default considers the subjects are either rocks or dead.

nathan_compton 2y ago
I don't really get what you are saying here. RTCs are designed precisely to allow one to draw statistical conclusions which would be untenable due to confounding effects that would be impossible to disentangle otherwise, particularly in regimes where effect sizes are small and results are sometimes difficult to quantify. I'm having trouble understanding what you are even getting at with comparisons to astronomy, where the absence of controlled experiments isn't some grand innovation astronomers cooked up but a basic constraint imposed by studying stuff that is light years away. Any decent epistemologist would tell you that the character of knowledge generated by astronomical observations is of a lower quality than that of a RCT. I'm sure some astronomers or cosmologists would give their left arm to do a randomized controlled trial!
- spacetimeuser5 2y ago
  With astronomy, where the data are mainly derived from observations and simulations, no one is spreading alarms that it is not science. While with RCTs - and specifically RCTs in the filed of human cognitive neuroscience and psychedelics - there is all this monkey circus regarding whether placebos or psychedelic experiences are real. In human neuroscience ~80% of data is derived as well from observations and is effectively non-reverse-engineerable, while the hype regarding pseudoscience is much higher. You buy aspirin in a pharmacy and the drug's instruction label lists tons of adverse effects - this is obviously a seemingly high quality of knowledge resulting from hard work in RCTs. Yet, there's absolutely no information predicting which exact adverse/beneficial effects will manifest in a specific person in a specific state of consciousness - and this is the actual empirical level where RCT derived information should actually matter and where it is ~50% useless (due to lack of context in RCTs themselves).

CogitoCogito 2y ago

> How do you study mind-altering drugs when every clinical-trial participant knows they’re tripping? Are there really no protocols for research in which participants can tell whether they have received a certain drug or not? I mean sure I think that double-blind is best for research, but are there really not other cases in which they deal with the patients knowing? Edit: > By striving to cleave the drug’s effects from the context in which it’s given—to a patient by a therapist, both of whom are hoping for healing—blinded studies may fail to capture the full picture. Okay I see the issue is that patients not being blind to the treatment is (thought to be) necessary for the treatment to work. Okay yeah so that means it's hard to make the participants blind in anyway. Still I'm surprised there aren't approaches to deal with this. Of course it might mean by definition double-blind trials aren't possible, but then again maybe that's not always appropriate. I can see the pandora's box being opened by allowing drug studies to bypass these restrictions though so I guess I see why people don't like it. Later in the article: > In an email, an FDA spokesperson told me that blinded RCTs provide the most rigorous level of evidence, but “unblinded studies can still be considered adequate and well-controlled as long as there is a valid comparison with a control.” In such cases, the spokesperson said, regulators can take into account things like the size of the treatment effect in deciding whether the treatment performed significantly better than the placebo.

jerf 2y ago
Yes, there are, which honestly makes this entire article premise a bit bizarre. Double blind and all that is an ideal, not a requirement. It can't be a requirement, because whether we can run double-blind or any other kind of study is not always a matter of how good we are or how much effort we are willing to put in, but a characteristic of the thing we want to study, as it is here. It's hardly the only drug where the participants can have a pretty good guess whether they're on a placebo or not. As just an example off the top of my head, I doubt there were a whole lot of chemotherapy testers who thought they were vomiting for days and losing their hair due to a placebo. Contrary to frequently-expressed opinion online, we are not in fact constrained to running only super-massive-sample-size triple-blind preregistered peer-reviewed gold-plated scientific studies and only permitted to say we might have an opinion if a metanalysis of multiple of those concurs. It's nice when we can do that, but the universe is not always so accommodating.

hereme888 2y ago

The title itself is hilarious if you think about it. But in an important note, I don't like that I never read of the warnings for psychedelics, like triggering schizophrenia.

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freeqaz 2y ago
I actually spoke to a doctor about this once during a psych eval. You can get screened if you're worried about schizophrenia and there are strong indicators that you're likely to develop it. (Which would mean to probably avoid psychedelics) In general though it doesn't seem like they will cause it. Just accelerate the onset.
- hereme888 2y ago
  Good to know, thanks!
observationist 2y ago
Numerous studies have shown that the overall rate of occurrence in drug users is the same as the rate of occurrence in non drug users. Drug use causes schizophrenic breaks to happen earlier in susceptible individuals. The nature of schizophrenia makes the situation a "when" and not "if" question; around 1% of the population will have a schizophrenic episode and break from reality, regardless of whether they abstain from drugs or not. Almost any psychoactive drug can trigger early schizophrenic breaks; even caffeine or extreme stress and social trauma can be the trigger. Drug use can result in other forms of psychosis. Psychedelics can result in pathological derealization, when the individual begins to question everything about their life up to that point, becoming vulnerable to any potential model of the world that offers plausible answers. Persistent use can detach someone from reality, making it hard for them to integrate with normal society and maintain a normal, responsible life. Any drug use should be done responsibly. Harm reduction sites and drug safety activists and influencers have provided a huge wealth of information. Things that should be taught in school can nonetheless be found online, giving you the necessary health, use, preparation, and other harm reduction information necessary to be a responsible user. It's awesome that mainstream academia and the medical establishment are allowing this research. A better informed society will be a safer, healthier society, without the misinformation and stigmatized gossip that passed for "drug safety" in recent history.

taeric 2y ago

This is the second narrative I've seen recently where folks seem to think they have a strong argument against RTCs. Just, what? Yes, there have been advancements in statistical tools. And we actively know some causal pathways. More, sometimes the expensive randomized trials are just not worth the standard ROI calculations... But, to think that you have found some magic bullet against RTCs shows you don't really appreciate why they are so vital. And is usually a sign that you are reading the narrative of someone invested in an outcome.

sowut 2y ago

when i was 17 i found out about mushrooms and would take 1/8th ounce once a month for about 6 months which culminated in me absolutely convinced i was jesus for about 6 years. good stuff

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mythrwy 2y ago
If you are Jesus, maybe skip the crucifixion part this time?
- sowut 2y ago
  turns out everyone is their own personal jesus

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fl0ki 2y ago

It looks like I get to be the one to comment a classic criticism of RCT absolutism. There have been no RCTs on parachutes or bulletproof vests. Volunteers welcome.

pmyteh 2y ago
They found some volunteers and did the study! This is one of the classics from the Christmas BMJ: https://www.bmj.com/content/363/bmj.k5094 https://www.bmj.com/content/363/bmj.k5094 The study has... let's just say "other methodological problems". But they did do an RCT of parachute use! (The open peer review correspondence is quite fun, too).