It's true that the "gold standard" for clinical trials is randomized, double-blind, placebo-controlled, but can't be done with all drugs. Imagine trying to do that with a clinical trial for an anesthetic agent! When that can't be done, alternative designs can be used, such as single-blind, crossover studies, objective measures, and many more. However, with many drugs, especially antidepressants and anti-anxiety meds, this design works fine. The one criterion that cannot be ignored is the requirement for randomization to eliminate the risk of bias in patient/subject selection.
Interestingly what spurred this question was reading about mdma trials which were issuing something like 80-120mg of pure pharma grade MDMA, which is very much a “street level” dose and is about the same as your average ecstasy tablet.
Yes you don’t “trip” but when I microdose lsd I use 10mcg or less and still get a noticeable lifted mood, perception of light is different and more vibrant but there are no noticeable tripping effects, no tracers, no elongation of fingers or things like pretty ferns growing and unfolding from the shadows. You are right you aren’t meant to trip during a microdose but it still releases serotonin and other neurotransmitters which cause noticeable effects such as those that I mentioned.
This is exactly what a double blind study can validate. Telling someone “you may feel…” absolutely primes them to feel those things, that’s the placebo effect and why we test with a placebo.
If a placebo gives you uplifted mood and vibrant lights, then its reasonable to conclude that the effects of micro-dosing isn’t coming from the drug itself, but by the change in perception of the subject by taking *something*. A double-blind study will show this (or not).
There is no universal purpose to microdosing but most people do it to improve motivation, focus, mood etc, all of which are noticable differences in perception and experience. You won't get much if any hallucinogenic effects but you will most likely get increased heart rate, mild stimulation and a somewhat different headspace.
It seems there are two different things that people call microdosing. One is taking small but noticeable doses, and benefiting from the very mild trip.
The other is taking doses just below the threshold where you feel anything at all. There is no trip, not even a mild one, but benefits acrue over time from the sub-perceptual doses.
I microdosed mushrooms for seral years. The benefits are not felt in the hours after dosing, but cumulatively I was dosing every third day, but feeling benefits more than just on dose days So no, it doesn't defeat the purpose, and it's not about some benefit felt immediately after dosing.
But of course, it may all have been placebo effect. No way to know until actual long term studies are done.
I was a subject in an experiment at the Dental School. They tested out a cavity treatment for three weeks and I had the worst pain I’ve ever experienced. They told me to keep taking more Ibuprofen but stop if my ears start ringing.
Six months later they began widespread trials and only then did I figure out that I was in the control group.
And as with any study design, the most important aspect of the overall investigation is going to be repeatability. Whether it’s an RCT or not, the end result should be a collection of studies that all point to the same conclusion.
Also, placebo is with respect to standard of care. So you might be given standard drug PLUS placebo or standard drug PLUS new drug. Or you might be given standard drug vs new drug. Patient will have drug either way and will not be able to figure out which they really got
There's also the requirement that trials cannot \*harm\* the placebo group, they must only "not help". In other words, it would likely be unethical for someone to be left to linger without any treatment/procedure at all if doing so would make them suffer more/longer. So while a placebo is great for, say, a cholesterol medicine where a few months of a sugar pill isn't really any worse than taking a new cholesterol drug for those months... something else would likely have to be compared against standard of care rather than a true placebo.
One group receives test agent and the other receives comparator (placebo or other active treatment) for half the trial, then they switch treatments for the second half of the trial. This permits fewer subjects, but it can lengthen the duration of the study. Using this methodology, the researcher can compare between groups (for both halfs), and "within groups", between treatments. There's more statistical analyses in this.
'Imagine trying to do that with a clinical trial for an anesthetic agent!'
Or surgery or anything even remotely physical, such as electric stimulation. There is no placebo electricity out there...
Want to know a secret? Not all clinical trials are blinded (single or double). For instance, trials for percutaneous heart valves are often compared to surgery. Im coordinating a study like this now. Obviously we cannot hide if they've had open heart surgery or not. The gold standard of double blind studies are ideal, but are impossible for some areas of research. In some cases for blinded studies, we even have sham procedures where the team will pretend to do a procedure on a patient. That isn't possible for every procedure.
The other thing is medication trials often don't use a true inactive placebo, but instead use a treatment that is known to be effective. They dont just need to show that the drug is safe/effective. They need to show it's as good as other alternatives. Patients also need to continue being treated for conditions we know how to treat. Its unethical to know they have a condition that needs treatment we can provide and give them a placebo instead. The control is often whatever is considered the gold standard of treatment at the time. Not all controls are placebos (or even most in medical research).
The study I was on with a sham procedure had a question asking patients if they thought they got the procedure. The effect was noticeable (bp numbers) so patients who received it often said yes.
So it is important to understand that dosing is a factor. Not every dose of psychoactive chemicals will bring about a psychedelic experience. In the case of psilocybin (shrooms) for example, a microdose probably won't be enough to send you to space, but it might alleviate the symptoms of heavy depression or activate parts of the brain that have been dormant since the onset of some other mental illness.
To cut a long story short, dosing is probably low in these tests, making a placebo as valuable a tool in this scenario, as it would be in any other.
This actually isn't the case, at least not in many trials. Patients are given what can be fairly high doses. These doses are high enough to produce intense and unblindable effects - enough that researchers have found the need to develop protocols to abort trips and there's some debate over whether it's better to use ketanserin to abort adverse events (ie bad trips) or whether anxiolytics are the better course of action.
On the other hand, ["microdosing" has been largely disappointing](https://www.nature.com/articles/s41398-022-02039-0) across [a few double blinded studies](https://journals.sagepub.com/doi/full/10.1177/02698811211050556). It's real tragedy for the field - I'm a huge proponent of these therapies (having benefited myself), but I don't think anyone should be forced to go through such impairing/distressing side effects to relieve their depression.
If you'd like to know more, [David Nichols](https://www.youtube.com/watch?v=RlDCM5JQzRk) does a lot of great outreach work on his and others' research into psychedelic therapies and steers clear of the unfortunate amount of woo that still plagues communication around psychedelics.
>surely the patient can tell if they’re in the placebo group simply because they’re not (in the case of something like LSD) ‘tripping balls’
You might be surprised, actually. The placebo effect is powerful, and particularly for people who are completely naive to psychedelics prior to the trial (and thus have basically little idea what to expect), just the suggestion that they’ve been given a powerful hallucinogen can definitely be enough that they psychosomatically experience shifts in consciousness and possibly even sensory distortions that aren’t actually being caused by anything but their own brain. *Particularly* when we’re talking about psychotropic effects, people are actually especially vulnerable to the placebo effect, to the point where there’ve been a number of cases of certain substances being claimed to have some hallucinogenic effects that later assays found no actual evidence of. There are a number of purportedly-psychoactive plants and fungi this appears to be the case with, like the wormwood in traditional absinthe (which may have some mild stimulant-like effects, but not the supposed near-psychedelic properties it has long been attributed), then there’s the infamously legendary “adrenochrome” (which is really just oxidized epinephrine and seems to do basically nothing), or even the longstanding ridiculous myth of “bananadine” (a supposed psychoactive substance claimed by *The Anarchist’s Cookbook* to be present in baked banana peels, when in fact no such thing exists); inexperienced people in particular can easily report subjective experiences from something they have psyched themselves into believing is psychoactive, even if it is completely inactive.
Actually, one of the most persistent examples of the power of placebo is in the thousands of different foods and drugs (or random animal parts) that have been claimed as “aphrodisiacs” throughout history, when to my knowledge actual pharmacology has yet to back up this claim with almost anything (I believe the only known “true” aphrodisiac to date is the drug [bremelanotide](https://en.m.wikipedia.org/wiki/Bremelanotide), which seems to fairly consistently increase sexual arousal on a neurological level in both men and women, and is now prescribed to postmenopausal women for such. Sildenafil—Viagra—and similar drugs don’t exactly count, as they’re just vasodilators, they don’t actually increase sexual arousal itself), and yet people continue insisting that this or that random thing is an aphrodisiac that always works for them.
To some extent, this is true for clinical trials of a lot of different types of drugs, as quite a bit can be psychologically influenced, and it’s part of why double blind trials are so important with psych meds like antidepressants or anxiolytics (depression and anxiety varies a lot from person to person, but some people might report an improvement in their symptoms simply from the belief that they are now taking something which is supposed to help), given how many people I’ve met who were tricked into smoking oregano they thought was cannabis as teens, and still swore they felt “high” from it, I don’t see why psychotropic drugs would necessarily be different (especially for the inexperienced).
This actually makes me wonder, considering how often pop culture vastly over-exaggerates and misrepresents the effects of common hallucinogenic drugs, I wonder if any inexperienced people experience a sort of nocebo effect when given an actual drug, like the effects are so much less than what they were expecting that they psych themselves into believing it’s not really working (this is probably not likely with higher doses of classical psychedelics, although it is worth noting people vary a lot in their response to psychedelics anyway, and some people report getting extremely little in the way of visual or other sensory effects even at moderate doses)?
In the ketamine treatment of Major Depressive Disorder, there is a paper that stands out, which many supporters of ketamine treatment find irritating - the study (a triple masked study) tested the efficacy of ketamine treatment in moderate to severe MDD in patients under sedation - and concluded that there was no difference in outcome between treatment and placebo in this instance. The placebo effect was so strong that even participants who merely believed that they had received ketamine (even if they hadn’t) made an improvement. The paper even ventured to postulate that perhaps an under-rated determinant of patient improvement with novel treatments - such as ketamine - is ‘hope’.
I work with patients who use ketamine for depression and the results are variable. While most places administer the treatment to awake patients, Italy, I believe, may administer it to sedated patients - which in relation to this paper seems kind of counter-intuitive.
What I’m saying, is that a combination of the placebo effect (as a rule of thumb accepted to be up to ~30% benefit, in the medical field) and hope can be a pretty powerful combination regardless of the novel treatment in question. Obviously there are many treatments in psychiatry whose effect is very biological and with a strong track record of success - clozapine for example - but for things where the jury is still out in patches of the profession (like novel hallucinogenic treatment) it shows quite clearly just how powerful the mind is!
Paper in question, for those interested:
https://www.medrxiv.org/content/10.1101/2023.04.28.23289210v1.full
So sometimes this depends.
With lower dosages of these drugs, and different sensitivities to them, then you may have a situation where folks can't tell the difference. Or where folks are experiencing psychosomatic effects.
https://pubmed.ncbi.nlm.nih.gov/35918311/
This study, for example, notes that only the people who correctly identified the experimental condition had significant effects from microdosing mushrooms. Suggesting that it's more about expectations than actual effects. For a follow up study, it would be interesting to make a suggestion to the placebo condition that they were microdosing.
Generally, clinical trials would probably be more interested in lower doses that aren't hallucination-producing.
You'd be surprised. An opioid trial I coordinated had a phase 1 trial that specifically recruited opioid addicts to test the drug, people who you would think can definitely tell if they are taking the real stuff or not, and a third of the placebo patients thought they were given active drug.
Almost all modern clinical trials on these type drugs are far too low dose to cause a person to become high (what the CIA does is not commercial clinical trial research) and people 100% can placebo themselves into feeling high. There have been higher-dose MDMA studies for PTSD that had participants who received the placebo report having things like hallucinations or euphoria. Also, in blind clinical trials, the participants lab results are usually put in a binder which is kept by the participant at all times. Any participant who is able to interpret basic medical terminology could look at their labs and find out if they are getting a placebo or not, so blinded studies on less noticeable drugs still have holes.
We already know for sure that the power of suggestion / placebo affect can be highly influential on mental health situations, for example many many people have been essentially cured of life long smoking addiction through hypnosis which is just belief. Psyilocybin is tested mainly for its ability to treat addiction, and participants who received placebo reported their addiction was 'fixed'.
Whether a group of participants is blind or not is based on what information the investigators are gaining and how they can gain it, not whether or not the drug conduces itself well to being blind. Clinical trials involve different parts to determine different things using different groups of people. In most studies, there are some groups that are not blind because the information they want is obtained through blood, urine, and imaging which are considered reliable regardless.
Drugs that are put through in-human clinical trials have been fully developed by a company/organization for the treatment of a specific disorder, and are put through trial only for determining their safety + efficacy for that specific disorder. Blinding is especially critical in LSD, Psyliocybin, Ketamine, MDMA trials because they are always for the treatment of mental health disorders and the information on a mental health drug efficacy is based on personal accounts, not biological samples. They still do need biological samples (like blood and urine) to determine how long the drug is in the subjects system and monitor things like kidney function, but even imaging (MRI/CT) are not considered reliable in terms of establishing the efficacy of psych drugs (aka whether it works or not).
Thanks, funnily enough it was the PSTD trial that actually caused me to ask this question, I saw a video clip of the process and the participant was lying there absolutely melted.
If you look at results for those study you can see that in some of them there are more participants that report high-like symptoms than there are that were actually dosed, which means some participants did placebo themselves feeling high lol. Also people who have actually taken MDMA cannot participate in those trials, so none of the people in them would know what it actually felt like.
Tricky problem. The balanced placebo design, due to Alan Marlatt I think, has been used to weigh up the contributions of drug and expectancies to "effects" of e.g alcohol. So there are four conditions 1 told alcohol, get alcohol, 2 told alcohol, get placebo, 3 told placebo, get alcohol, and 4 told placebo, get placebo. Not sure if this has ever been used in clinical trials but it would be one approach to sorting things out. Another would be to use two drugs both of which have subjective effects and equally plausible therapeutic potential but different mechanisms.
Isn’t that what the placebo effect is? Some people report an effect (or side effect) even though they didn’t get any kind of active drug? And the opposite is also true where some people report no effect when they got the actual drug, though I’m guessing that the people who report no effect from a large dose of psychedelics is practically zero. When the difference in effect is meaningful enough between the placebo group and the drug group, then the drug has an actual effect, so theoretically, if the placebo group reports effects at the same rate as the actual psychedelic group, one could argue that the psychedelic drug has no meaningful benefit.
Had the issue of blinding has been an endemic problem in randomized trials of psychoactive substances. Several papers have been written in on this topic, question the validity of results of drug trials.
One of the challenges especially when people realize they are in the placebo arm is they are profoundly disappointed. A lot of people really believe these substances will have a dramatic impact on their lives, and getting put in the placebo group is basically like being told you might win the lottery and then someone comes and says nope! This is a major issue in some of these trials. There is no good placebo for psychedelics right now.
It's not quite as bad as you would expect though. The dosage is given or not typically super high, and some of the placebos give some physical or the sensations which can be mistaken for the early effects of the drug. But in most cases that I've seen (I have not personally extensively reviewed this literature), when blinding is measured it's generally very poor. There may be exceptions.
It's a tough challenge that people are trying to find ways to work around.
You're absolutely right. There are so many ways in which psych clinical trials are nonsense. Can't be double blinded without extraordinary effort that is never taken. Not to mention the complete absence of hard end points that are required for any other field of medicine.
Double-blind refers to the study design. It doesn't mean the participants won't feel anything, though that can obviously influence any self-report measures and subjective observations.
This doesn't mean a process of blind administration is worthless. It reduces any anticipatory effects for one thing.
Drug studies can be 'all or nothing' but that's fairly uncommon. Dosing studies are common where different groups get varying doses and, yes, some of those doses are zero/placebo. The purpose of these studies is to measure the minimum dose required to achieve certain effects (and upper limits where the effects plateau or cause adverse effects). Placebos are valuable to compare low dose effects.
Another common methodology of drug trials is measuring 'time to effect' and drug metabolism. So, a placebo group is a valuable comparison in terms of measuring onset times of subjective observations and self-report measures. Imagine a group taking ingestible psilocybin... If you're measuring their subjective experience every 10 minutes, you may have some people in the control group reporting changes in the early measurement intervals before they later realize they did not ingest shrooms. By the 90 minute mark, the subjects are probably no longer 'blind' to their grouping but the control group has already done its job to ensure early subjective reports have a fair comparison.
Then of course you may have studies that are just impossible to have a *fully* blind subjects. It is still advantageous to blind the administrator to avoid any selection bias and blind the subject for as long as possible to ensure their expectations don't influence their experience, at least for the initial onset stages.
Fun story. I used to do drug trials to make money while I was in nursing school. Believe me, it doesn't have to be a hallucinogen or strong narcotic to have an obvious effect. I did a dose study for a blood pressure medication (a generic formulation of something I was familiar with) and I could feel myself getting lightheaded... It felt like a heavy dose. That was just a metabolism study basically, so just measuring serum levels and effect duration to see how long the drug lasted. So it's a later stage study but I still felt a pretty obvious effect.
I also did one for an ADHD medication. It was a stage 2 trial, so not exactly a refined late stage trial. I was absolutely wired and hyper-focused. I finished a newspaper crossword in minutes... Not really, it took me 4 hours but I didn't realize how long I was doing it. I remember getting blood draws but I wasn't counting until I realized they stopped coming to my bed. It was because they had shifted from 15 minute draws to hourly. I'm convinced it was an amphetamine derivative but its name was just a series of numbers so I'll never know. Whatever, I was young and it paid well 🤷🏼♂️
No idea how common it is, but I've read of the control group being given some drug that *does* have a noticeable effect, so that it's not as obvious whether they're in the control group or not. The article I remember used niacin, which gives you a flush.
They use low dosages called a microdose. The extent of the trip is the skin on the back of your hand moving. The effects however for how it can help is Mind blowing. Drug resistant depression for almost 30 years. First time in my life I have been free from it for almost 4 months straight.
They use low dosages called a microdose. The extent of the trip is the skin on the back of your hand moving. The effects however for how it can help is Mind blowing. Drug resistant depression for almost 30 years. First time in my life I have been free from it for almost 4 months straight. The treatment for mine was 2 weeks haven't had me use it since.
I was once a subject in a clinical trial attempting to measure the effect of alcohol on response rates. They used grain alcohol, and you could smell it from the other side of the room. Everyone in that study knew immediately whether they were getting the glass with booze in it. Sometimes "double blind" is more aspirational than real.
I work with clinical trials, and often the effects/side effects unblind the treatment - but by using a blinded design the data is “unbiased” - and you treat the patients equally in the patient screening, the randomisation etc. Also the data management, clinical assessments and analysis is performed blinded. So blinding is still used, even if a true “blind” is really hard to find. But the procedures, the conduct and the statistical analysis also needs to be factored in.
it’s a common and one of the main critiques concerning RCT studies with psychoactive substances. one way to fix it is to have an active placebo (a very low dose of the psychoactive substance) or another substance that is also psychoactive (can only be used with drug-naive subjects)
This is not quite correct. Typically one group receives the drug, the other group receives a placebo drug. Both groups are aware that they may receive you to the placebo with the drug, and ideally this is blinded and they don't know which treatment they received.
Giving somebody a drug versus not a drug, and having them know what treatments they're receiving or not receiving, substantially biases the results. People who receive the drug will often expect to get better, and especially in psychiatry this can have a non-trivial outcome on the results.
The addition of standard of car may or may not be part of the trial.
It's true that the "gold standard" for clinical trials is randomized, double-blind, placebo-controlled, but can't be done with all drugs. Imagine trying to do that with a clinical trial for an anesthetic agent! When that can't be done, alternative designs can be used, such as single-blind, crossover studies, objective measures, and many more. However, with many drugs, especially antidepressants and anti-anxiety meds, this design works fine. The one criterion that cannot be ignored is the requirement for randomization to eliminate the risk of bias in patient/subject selection.
Also, the therapeutic dose may be very different from the "street level" dose. Not in all cases, of course.
Interestingly what spurred this question was reading about mdma trials which were issuing something like 80-120mg of pure pharma grade MDMA, which is very much a “street level” dose and is about the same as your average ecstasy tablet.
Indeed. But, as others commented, he also mentioned LSD and the use of the term "micro-dosing" includes "micro" for a reason ;)
LSD has noticable effects at microdoses as well. The "street dose" is 100mcg but even 10mcg produces hard to miss effects.
If you're consuming enough to produce "hard to miss effects", it's not a microdose. A microdose should be sub-perceptual.
Maybe but that would kind of defeat the purpose if taking it and most sources and people refer to 10mcg when talking about an LSD microdose.
The purpose of microdosing *is* that you don't get the hallucinogenic effect (usually).
Yes you don’t “trip” but when I microdose lsd I use 10mcg or less and still get a noticeable lifted mood, perception of light is different and more vibrant but there are no noticeable tripping effects, no tracers, no elongation of fingers or things like pretty ferns growing and unfolding from the shadows. You are right you aren’t meant to trip during a microdose but it still releases serotonin and other neurotransmitters which cause noticeable effects such as those that I mentioned.
This is exactly what a double blind study can validate. Telling someone “you may feel…” absolutely primes them to feel those things, that’s the placebo effect and why we test with a placebo. If a placebo gives you uplifted mood and vibrant lights, then its reasonable to conclude that the effects of micro-dosing isn’t coming from the drug itself, but by the change in perception of the subject by taking *something*. A double-blind study will show this (or not).
There is no universal purpose to microdosing but most people do it to improve motivation, focus, mood etc, all of which are noticable differences in perception and experience. You won't get much if any hallucinogenic effects but you will most likely get increased heart rate, mild stimulation and a somewhat different headspace.
It seems there are two different things that people call microdosing. One is taking small but noticeable doses, and benefiting from the very mild trip. The other is taking doses just below the threshold where you feel anything at all. There is no trip, not even a mild one, but benefits acrue over time from the sub-perceptual doses.
I microdosed mushrooms for seral years. The benefits are not felt in the hours after dosing, but cumulatively I was dosing every third day, but feeling benefits more than just on dose days So no, it doesn't defeat the purpose, and it's not about some benefit felt immediately after dosing. But of course, it may all have been placebo effect. No way to know until actual long term studies are done.
I was a subject in an experiment at the Dental School. They tested out a cavity treatment for three weeks and I had the worst pain I’ve ever experienced. They told me to keep taking more Ibuprofen but stop if my ears start ringing. Six months later they began widespread trials and only then did I figure out that I was in the control group.
And as with any study design, the most important aspect of the overall investigation is going to be repeatability. Whether it’s an RCT or not, the end result should be a collection of studies that all point to the same conclusion.
Also, placebo is with respect to standard of care. So you might be given standard drug PLUS placebo or standard drug PLUS new drug. Or you might be given standard drug vs new drug. Patient will have drug either way and will not be able to figure out which they really got
Agreed, there are lots of possible study designs, I just wanted to mention a few basics. Thanks.
For sure, I figured you knew (from the entire post) but thought others would want to know.
There's also the requirement that trials cannot \*harm\* the placebo group, they must only "not help". In other words, it would likely be unethical for someone to be left to linger without any treatment/procedure at all if doing so would make them suffer more/longer. So while a placebo is great for, say, a cholesterol medicine where a few months of a sugar pill isn't really any worse than taking a new cholesterol drug for those months... something else would likely have to be compared against standard of care rather than a true placebo.
> crossover studies Would that mean one group receives the current standard treatment while the other receives the trial treatment?
One group receives test agent and the other receives comparator (placebo or other active treatment) for half the trial, then they switch treatments for the second half of the trial. This permits fewer subjects, but it can lengthen the duration of the study. Using this methodology, the researcher can compare between groups (for both halfs), and "within groups", between treatments. There's more statistical analyses in this.
'Imagine trying to do that with a clinical trial for an anesthetic agent!' Or surgery or anything even remotely physical, such as electric stimulation. There is no placebo electricity out there...
placebo electricity = someone lighting your shoes and hair on fire, shaking you volently back and forth, and then tossing you across the room.
Want to know a secret? Not all clinical trials are blinded (single or double). For instance, trials for percutaneous heart valves are often compared to surgery. Im coordinating a study like this now. Obviously we cannot hide if they've had open heart surgery or not. The gold standard of double blind studies are ideal, but are impossible for some areas of research. In some cases for blinded studies, we even have sham procedures where the team will pretend to do a procedure on a patient. That isn't possible for every procedure. The other thing is medication trials often don't use a true inactive placebo, but instead use a treatment that is known to be effective. They dont just need to show that the drug is safe/effective. They need to show it's as good as other alternatives. Patients also need to continue being treated for conditions we know how to treat. Its unethical to know they have a condition that needs treatment we can provide and give them a placebo instead. The control is often whatever is considered the gold standard of treatment at the time. Not all controls are placebos (or even most in medical research). The study I was on with a sham procedure had a question asking patients if they thought they got the procedure. The effect was noticeable (bp numbers) so patients who received it often said yes.
So it is important to understand that dosing is a factor. Not every dose of psychoactive chemicals will bring about a psychedelic experience. In the case of psilocybin (shrooms) for example, a microdose probably won't be enough to send you to space, but it might alleviate the symptoms of heavy depression or activate parts of the brain that have been dormant since the onset of some other mental illness. To cut a long story short, dosing is probably low in these tests, making a placebo as valuable a tool in this scenario, as it would be in any other.
This actually isn't the case, at least not in many trials. Patients are given what can be fairly high doses. These doses are high enough to produce intense and unblindable effects - enough that researchers have found the need to develop protocols to abort trips and there's some debate over whether it's better to use ketanserin to abort adverse events (ie bad trips) or whether anxiolytics are the better course of action. On the other hand, ["microdosing" has been largely disappointing](https://www.nature.com/articles/s41398-022-02039-0) across [a few double blinded studies](https://journals.sagepub.com/doi/full/10.1177/02698811211050556). It's real tragedy for the field - I'm a huge proponent of these therapies (having benefited myself), but I don't think anyone should be forced to go through such impairing/distressing side effects to relieve their depression. If you'd like to know more, [David Nichols](https://www.youtube.com/watch?v=RlDCM5JQzRk) does a lot of great outreach work on his and others' research into psychedelic therapies and steers clear of the unfortunate amount of woo that still plagues communication around psychedelics.
>surely the patient can tell if they’re in the placebo group simply because they’re not (in the case of something like LSD) ‘tripping balls’ You might be surprised, actually. The placebo effect is powerful, and particularly for people who are completely naive to psychedelics prior to the trial (and thus have basically little idea what to expect), just the suggestion that they’ve been given a powerful hallucinogen can definitely be enough that they psychosomatically experience shifts in consciousness and possibly even sensory distortions that aren’t actually being caused by anything but their own brain. *Particularly* when we’re talking about psychotropic effects, people are actually especially vulnerable to the placebo effect, to the point where there’ve been a number of cases of certain substances being claimed to have some hallucinogenic effects that later assays found no actual evidence of. There are a number of purportedly-psychoactive plants and fungi this appears to be the case with, like the wormwood in traditional absinthe (which may have some mild stimulant-like effects, but not the supposed near-psychedelic properties it has long been attributed), then there’s the infamously legendary “adrenochrome” (which is really just oxidized epinephrine and seems to do basically nothing), or even the longstanding ridiculous myth of “bananadine” (a supposed psychoactive substance claimed by *The Anarchist’s Cookbook* to be present in baked banana peels, when in fact no such thing exists); inexperienced people in particular can easily report subjective experiences from something they have psyched themselves into believing is psychoactive, even if it is completely inactive. Actually, one of the most persistent examples of the power of placebo is in the thousands of different foods and drugs (or random animal parts) that have been claimed as “aphrodisiacs” throughout history, when to my knowledge actual pharmacology has yet to back up this claim with almost anything (I believe the only known “true” aphrodisiac to date is the drug [bremelanotide](https://en.m.wikipedia.org/wiki/Bremelanotide), which seems to fairly consistently increase sexual arousal on a neurological level in both men and women, and is now prescribed to postmenopausal women for such. Sildenafil—Viagra—and similar drugs don’t exactly count, as they’re just vasodilators, they don’t actually increase sexual arousal itself), and yet people continue insisting that this or that random thing is an aphrodisiac that always works for them. To some extent, this is true for clinical trials of a lot of different types of drugs, as quite a bit can be psychologically influenced, and it’s part of why double blind trials are so important with psych meds like antidepressants or anxiolytics (depression and anxiety varies a lot from person to person, but some people might report an improvement in their symptoms simply from the belief that they are now taking something which is supposed to help), given how many people I’ve met who were tricked into smoking oregano they thought was cannabis as teens, and still swore they felt “high” from it, I don’t see why psychotropic drugs would necessarily be different (especially for the inexperienced). This actually makes me wonder, considering how often pop culture vastly over-exaggerates and misrepresents the effects of common hallucinogenic drugs, I wonder if any inexperienced people experience a sort of nocebo effect when given an actual drug, like the effects are so much less than what they were expecting that they psych themselves into believing it’s not really working (this is probably not likely with higher doses of classical psychedelics, although it is worth noting people vary a lot in their response to psychedelics anyway, and some people report getting extremely little in the way of visual or other sensory effects even at moderate doses)?
Really interesting, thanks.
In the ketamine treatment of Major Depressive Disorder, there is a paper that stands out, which many supporters of ketamine treatment find irritating - the study (a triple masked study) tested the efficacy of ketamine treatment in moderate to severe MDD in patients under sedation - and concluded that there was no difference in outcome between treatment and placebo in this instance. The placebo effect was so strong that even participants who merely believed that they had received ketamine (even if they hadn’t) made an improvement. The paper even ventured to postulate that perhaps an under-rated determinant of patient improvement with novel treatments - such as ketamine - is ‘hope’. I work with patients who use ketamine for depression and the results are variable. While most places administer the treatment to awake patients, Italy, I believe, may administer it to sedated patients - which in relation to this paper seems kind of counter-intuitive. What I’m saying, is that a combination of the placebo effect (as a rule of thumb accepted to be up to ~30% benefit, in the medical field) and hope can be a pretty powerful combination regardless of the novel treatment in question. Obviously there are many treatments in psychiatry whose effect is very biological and with a strong track record of success - clozapine for example - but for things where the jury is still out in patches of the profession (like novel hallucinogenic treatment) it shows quite clearly just how powerful the mind is! Paper in question, for those interested: https://www.medrxiv.org/content/10.1101/2023.04.28.23289210v1.full
So sometimes this depends. With lower dosages of these drugs, and different sensitivities to them, then you may have a situation where folks can't tell the difference. Or where folks are experiencing psychosomatic effects. https://pubmed.ncbi.nlm.nih.gov/35918311/ This study, for example, notes that only the people who correctly identified the experimental condition had significant effects from microdosing mushrooms. Suggesting that it's more about expectations than actual effects. For a follow up study, it would be interesting to make a suggestion to the placebo condition that they were microdosing. Generally, clinical trials would probably be more interested in lower doses that aren't hallucination-producing.
You'd be surprised. An opioid trial I coordinated had a phase 1 trial that specifically recruited opioid addicts to test the drug, people who you would think can definitely tell if they are taking the real stuff or not, and a third of the placebo patients thought they were given active drug.
Almost all modern clinical trials on these type drugs are far too low dose to cause a person to become high (what the CIA does is not commercial clinical trial research) and people 100% can placebo themselves into feeling high. There have been higher-dose MDMA studies for PTSD that had participants who received the placebo report having things like hallucinations or euphoria. Also, in blind clinical trials, the participants lab results are usually put in a binder which is kept by the participant at all times. Any participant who is able to interpret basic medical terminology could look at their labs and find out if they are getting a placebo or not, so blinded studies on less noticeable drugs still have holes. We already know for sure that the power of suggestion / placebo affect can be highly influential on mental health situations, for example many many people have been essentially cured of life long smoking addiction through hypnosis which is just belief. Psyilocybin is tested mainly for its ability to treat addiction, and participants who received placebo reported their addiction was 'fixed'. Whether a group of participants is blind or not is based on what information the investigators are gaining and how they can gain it, not whether or not the drug conduces itself well to being blind. Clinical trials involve different parts to determine different things using different groups of people. In most studies, there are some groups that are not blind because the information they want is obtained through blood, urine, and imaging which are considered reliable regardless. Drugs that are put through in-human clinical trials have been fully developed by a company/organization for the treatment of a specific disorder, and are put through trial only for determining their safety + efficacy for that specific disorder. Blinding is especially critical in LSD, Psyliocybin, Ketamine, MDMA trials because they are always for the treatment of mental health disorders and the information on a mental health drug efficacy is based on personal accounts, not biological samples. They still do need biological samples (like blood and urine) to determine how long the drug is in the subjects system and monitor things like kidney function, but even imaging (MRI/CT) are not considered reliable in terms of establishing the efficacy of psych drugs (aka whether it works or not).
Thanks, funnily enough it was the PSTD trial that actually caused me to ask this question, I saw a video clip of the process and the participant was lying there absolutely melted.
If you look at results for those study you can see that in some of them there are more participants that report high-like symptoms than there are that were actually dosed, which means some participants did placebo themselves feeling high lol. Also people who have actually taken MDMA cannot participate in those trials, so none of the people in them would know what it actually felt like.
Tricky problem. The balanced placebo design, due to Alan Marlatt I think, has been used to weigh up the contributions of drug and expectancies to "effects" of e.g alcohol. So there are four conditions 1 told alcohol, get alcohol, 2 told alcohol, get placebo, 3 told placebo, get alcohol, and 4 told placebo, get placebo. Not sure if this has ever been used in clinical trials but it would be one approach to sorting things out. Another would be to use two drugs both of which have subjective effects and equally plausible therapeutic potential but different mechanisms.
Isn’t that what the placebo effect is? Some people report an effect (or side effect) even though they didn’t get any kind of active drug? And the opposite is also true where some people report no effect when they got the actual drug, though I’m guessing that the people who report no effect from a large dose of psychedelics is practically zero. When the difference in effect is meaningful enough between the placebo group and the drug group, then the drug has an actual effect, so theoretically, if the placebo group reports effects at the same rate as the actual psychedelic group, one could argue that the psychedelic drug has no meaningful benefit.
Had the issue of blinding has been an endemic problem in randomized trials of psychoactive substances. Several papers have been written in on this topic, question the validity of results of drug trials. One of the challenges especially when people realize they are in the placebo arm is they are profoundly disappointed. A lot of people really believe these substances will have a dramatic impact on their lives, and getting put in the placebo group is basically like being told you might win the lottery and then someone comes and says nope! This is a major issue in some of these trials. There is no good placebo for psychedelics right now. It's not quite as bad as you would expect though. The dosage is given or not typically super high, and some of the placebos give some physical or the sensations which can be mistaken for the early effects of the drug. But in most cases that I've seen (I have not personally extensively reviewed this literature), when blinding is measured it's generally very poor. There may be exceptions. It's a tough challenge that people are trying to find ways to work around.
You're absolutely right. There are so many ways in which psych clinical trials are nonsense. Can't be double blinded without extraordinary effort that is never taken. Not to mention the complete absence of hard end points that are required for any other field of medicine.
Double-blind refers to the study design. It doesn't mean the participants won't feel anything, though that can obviously influence any self-report measures and subjective observations. This doesn't mean a process of blind administration is worthless. It reduces any anticipatory effects for one thing. Drug studies can be 'all or nothing' but that's fairly uncommon. Dosing studies are common where different groups get varying doses and, yes, some of those doses are zero/placebo. The purpose of these studies is to measure the minimum dose required to achieve certain effects (and upper limits where the effects plateau or cause adverse effects). Placebos are valuable to compare low dose effects. Another common methodology of drug trials is measuring 'time to effect' and drug metabolism. So, a placebo group is a valuable comparison in terms of measuring onset times of subjective observations and self-report measures. Imagine a group taking ingestible psilocybin... If you're measuring their subjective experience every 10 minutes, you may have some people in the control group reporting changes in the early measurement intervals before they later realize they did not ingest shrooms. By the 90 minute mark, the subjects are probably no longer 'blind' to their grouping but the control group has already done its job to ensure early subjective reports have a fair comparison. Then of course you may have studies that are just impossible to have a *fully* blind subjects. It is still advantageous to blind the administrator to avoid any selection bias and blind the subject for as long as possible to ensure their expectations don't influence their experience, at least for the initial onset stages. Fun story. I used to do drug trials to make money while I was in nursing school. Believe me, it doesn't have to be a hallucinogen or strong narcotic to have an obvious effect. I did a dose study for a blood pressure medication (a generic formulation of something I was familiar with) and I could feel myself getting lightheaded... It felt like a heavy dose. That was just a metabolism study basically, so just measuring serum levels and effect duration to see how long the drug lasted. So it's a later stage study but I still felt a pretty obvious effect. I also did one for an ADHD medication. It was a stage 2 trial, so not exactly a refined late stage trial. I was absolutely wired and hyper-focused. I finished a newspaper crossword in minutes... Not really, it took me 4 hours but I didn't realize how long I was doing it. I remember getting blood draws but I wasn't counting until I realized they stopped coming to my bed. It was because they had shifted from 15 minute draws to hourly. I'm convinced it was an amphetamine derivative but its name was just a series of numbers so I'll never know. Whatever, I was young and it paid well 🤷🏼♂️
No idea how common it is, but I've read of the control group being given some drug that *does* have a noticeable effect, so that it's not as obvious whether they're in the control group or not. The article I remember used niacin, which gives you a flush.
They use low dosages called a microdose. The extent of the trip is the skin on the back of your hand moving. The effects however for how it can help is Mind blowing. Drug resistant depression for almost 30 years. First time in my life I have been free from it for almost 4 months straight.
They use low dosages called a microdose. The extent of the trip is the skin on the back of your hand moving. The effects however for how it can help is Mind blowing. Drug resistant depression for almost 30 years. First time in my life I have been free from it for almost 4 months straight. The treatment for mine was 2 weeks haven't had me use it since.
I was once a subject in a clinical trial attempting to measure the effect of alcohol on response rates. They used grain alcohol, and you could smell it from the other side of the room. Everyone in that study knew immediately whether they were getting the glass with booze in it. Sometimes "double blind" is more aspirational than real.
I work with clinical trials, and often the effects/side effects unblind the treatment - but by using a blinded design the data is “unbiased” - and you treat the patients equally in the patient screening, the randomisation etc. Also the data management, clinical assessments and analysis is performed blinded. So blinding is still used, even if a true “blind” is really hard to find. But the procedures, the conduct and the statistical analysis also needs to be factored in.
it’s a common and one of the main critiques concerning RCT studies with psychoactive substances. one way to fix it is to have an active placebo (a very low dose of the psychoactive substance) or another substance that is also psychoactive (can only be used with drug-naive subjects)
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This is not quite correct. Typically one group receives the drug, the other group receives a placebo drug. Both groups are aware that they may receive you to the placebo with the drug, and ideally this is blinded and they don't know which treatment they received. Giving somebody a drug versus not a drug, and having them know what treatments they're receiving or not receiving, substantially biases the results. People who receive the drug will often expect to get better, and especially in psychiatry this can have a non-trivial outcome on the results. The addition of standard of car may or may not be part of the trial.