[Nursie]

The issue here has to be that it's hard to mask MDMA - people are going to know they're on something even at therapeutic (rather than recreational) doses, are they not? Is that really poor blinding?

Antidepressants tend to be long lasting and slow acting (AFAICT) which MDMA is not.

[pchivers]

True, antidepressants are much slower acting than MDMA, but you're still looking at 80-90% of people in antidepressant trials who can correctly guess which group they're in (due to side effects such as dry mouth, sleep problems, sexual dysfunction, etc.).

Regarding the issue of whether or not it is poor blinding, I guess it is a bit like the tree falling in the forest but nobody is around to hear it: if you conduct a placebo-controlled study, but all the participants can correctly guess which group they're in, is it really a placebo-controlled study?

[Nursie]

Likely a rhetorical question on your part there, but it is an interesting conundrum. Because the drug works directly on the brain and folks emotions, and because those effects are directly bound up with the therapeutic area under study, I can't help thinking a placebo would be really hard to do well here. Any other phenethylamine that subjectively mimics MDMA is going to be messing with the same systems.

I guess (as may have been suggested elsewhere) you could use a non-seratonergic stimulant of some sort to give people the feeling that they are on something, and rely on them not being able to tell what it is. You'd need to screen for anyone that had any recreational experience though.

[disgruntledphd2]

Yeah, placebo controlled studies of mind-altering chemicals are hard. I've done quite a lot of research on placebo, and would never expect to be able to blind effectively without using an active drug (low dose). Something like methylphenidrate might work, as noted by the top comment, but even then you don't really have a control, as you really are just estimating the effects of one chemical against another (which tends to require far larger studies to demonstrate an affect).

Speed would probably work. One thing that interests me though is whether or not the patients were treated seperately. Having been surrounded by people on MDMA while not partaking myself, at least in my anecdotal experience it can affect your state of mind, which could be one reason for the rather large placebo effects (given that the treatment is so obvious, one would expect placebo effects to be artificially lowered.

[gruseom]

If you conduct a placebo-controlled study, but all the participants can correctly guess which group they're in, is it really a placebo-controlled study?

No, it's not, and the question of how many allegedly double-blind studies are compromised by this leakage deserves a lot more attention.