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The problem with studying psychoactive substances is that they can't realistically rule out a placebo effect. Psilocybin has strong side effects, but niacin (th

The problem with studying psychoactive substances is that they can't realistically rule out a placebo effect. Psilocybin has strong side effects, but niacin (the placebo for the control group) has no side effects, so people know whether they are in the treatment group or control group. The apparent positive impact of psilocybin could just be a placebo effect. A better idea would perhaps be to test two different psychoactive drugs with similar effects, like LSD and psilocybin, so people don't know which they got.

zug_zug 3y ago
Great point, and the study even admits that point "Limitations: First, the success of allocation blinding was not assessed, and it is likely that the acute psychoactive effects of psilocybin produced some degree of functional unblinding that may have contributed to the observed effect in psilocybin-treated participants and the increased dropout rate in niacin-treated participants." Unblinding = participants figure out if they got the real thing I think a recent ketamine study found a lot of the clinical effect went away if participants weren't awake/aware of the treatment. Wonder if that could be used here.
- cubefox 3y ago
  Yeah, though perhaps it is the trip itself that causes the antidepressive effect, so if you prevent the trip via sleep, the effect goes away.
  - carlmr 3y ago
    Exactly my thought. It's often reported that the antidepressant effect came from the increased ability to look at your problems from a new perspective. If this new perspective isn't experienced, it seems highly unlikely this would work. Thinking about the mechanism of classic anti-depressants like SSRIs, you expect a boosted effect of the happy chemicals to make people more happy. With anything that is few or single-dose you expect changes in thought and behavior patterns to have the antidepressant effect. These lasting changes must come from something that is not happy chemicals, but a new perspective on life.
- amanaplanacanal 3y ago
  It’s also possible that the conscious experience of the effect is part of what makes it work. I’m not sure how you would test that out.
  - zmgsabst 3y ago
    I don’t think you can. But if a certain action routinely produces sustained change, that can also be fine. Eg, you can’t blind participants to whether they receive real therapy or a conversation about the weather, but we’ve concluded that therapy is useful. And you can’t for a similar reason, in that the experience is itself the treatment.
- NeuroCoder 3y ago
  I missed that study and that is a brilliant way of blinding participants for this sort of thing.
Notatheist 3y ago
>they can't realistically rule out a placebo effect. Kind of like every other treatment for depression? Not being funny here but I don't think we gave the control groups in clinical trials for MAOIs brutal kicks to their blood pressure every morning.
- NeuroCoder 3y ago
  Most common first line treatments for depression don't show any effect for weeks so this is a valid criticism. Things like Xanax for anxiety have an immediate effect though so it's not like we don't deal with this sort of thing.
robwwilliams 3y ago
They may have chosen niacin for its mild flushing effect, which can be quite noticeable, but usually at a higher dose than given here.
travisjungroth 3y ago
At some point a treatment is effective enough that it stretches the credibility of placebo effect. And even if you hold onto the placebo effect, that’s just the mechanism. It doesn’t make it any less effective. If you have a treatment that has an extremely strong impact on depression, it seems worth continuing to study and to also distribute it more broadly. Whether it’s because of psychedelics or the thought of them, people are getting helped. Your suggestion would only see the difference between the drugs. They both could be wildly more effective than antidepressants but similar to each other, and that study wouldn’t show it.
- cubefox 3y ago
  Yeah. If the psilocybin effect was merely a placebo effect, that effect would probably wear off after a while, and it would stop working. So this is detectable, though not in a short term trial. The proposal with using both psilocybin and LSD is based on this assumption: If both substances yield a similar outcome, it is more likely that they both don't work rather than that they both do work (to a similar degree). Presumably the prior probability that two hallucinogens treat depression is rather low. Because most substances don't treat any disorders, let alone depression in particular.

zug_zug 3y ago

Great point, and the study even admits that point "Limitations: First, the success of allocation blinding was not assessed, and it is likely that the acute psychoactive effects of psilocybin produced some degree of functional unblinding that may have contributed to the observed effect in psilocybin-treated participants and the increased dropout rate in niacin-treated participants." Unblinding = participants figure out if they got the real thing I think a recent ketamine study found a lot of the clinical effect went away if participants weren't awake/aware of the treatment. Wonder if that could be used here.

cubefox 3y ago
Yeah, though perhaps it is the trip itself that causes the antidepressive effect, so if you prevent the trip via sleep, the effect goes away.
- carlmr 3y ago
  Exactly my thought. It's often reported that the antidepressant effect came from the increased ability to look at your problems from a new perspective. If this new perspective isn't experienced, it seems highly unlikely this would work. Thinking about the mechanism of classic anti-depressants like SSRIs, you expect a boosted effect of the happy chemicals to make people more happy. With anything that is few or single-dose you expect changes in thought and behavior patterns to have the antidepressant effect. These lasting changes must come from something that is not happy chemicals, but a new perspective on life.
amanaplanacanal 3y ago
It’s also possible that the conscious experience of the effect is part of what makes it work. I’m not sure how you would test that out.
- zmgsabst 3y ago
  I don’t think you can. But if a certain action routinely produces sustained change, that can also be fine. Eg, you can’t blind participants to whether they receive real therapy or a conversation about the weather, but we’ve concluded that therapy is useful. And you can’t for a similar reason, in that the experience is itself the treatment.
NeuroCoder 3y ago
I missed that study and that is a brilliant way of blinding participants for this sort of thing.

Notatheist 3y ago

>they can't realistically rule out a placebo effect. Kind of like every other treatment for depression? Not being funny here but I don't think we gave the control groups in clinical trials for MAOIs brutal kicks to their blood pressure every morning.

NeuroCoder 3y ago
Most common first line treatments for depression don't show any effect for weeks so this is a valid criticism. Things like Xanax for anxiety have an immediate effect though so it's not like we don't deal with this sort of thing.

robwwilliams 3y ago

They may have chosen niacin for its mild flushing effect, which can be quite noticeable, but usually at a higher dose than given here.

travisjungroth 3y ago

At some point a treatment is effective enough that it stretches the credibility of placebo effect. And even if you hold onto the placebo effect, that’s just the mechanism. It doesn’t make it any less effective. If you have a treatment that has an extremely strong impact on depression, it seems worth continuing to study and to also distribute it more broadly. Whether it’s because of psychedelics or the thought of them, people are getting helped. Your suggestion would only see the difference between the drugs. They both could be wildly more effective than antidepressants but similar to each other, and that study wouldn’t show it.

cubefox 3y ago
Yeah. If the psilocybin effect was merely a placebo effect, that effect would probably wear off after a while, and it would stop working. So this is detectable, though not in a short term trial. The proposal with using both psilocybin and LSD is based on this assumption: If both substances yield a similar outcome, it is more likely that they both don't work rather than that they both do work (to a similar degree). Presumably the prior probability that two hallucinogens treat depression is rather low. Because most substances don't treat any disorders, let alone depression in particular.