Psychedelic microdoses and mood disorders

Can psychedelic drugs, like LSD, combat depression and anxiety? Some clinical trials testing high doses of the drugs have shown positive results. But there’s another phenomenon taking root amongst psychedelic advocates: microdosing, where very small amounts of the agent are used about 2 to 3 times per week. Users report improvements in mental health, wellbeing, and even cognitive ability. This is anecdotal though, and might be just a placebo effect; so Imperial College’s Balázs Szigeti put the claims to the test by using a self-blinding strategy, where users created their own placebo doses and didn’t know what they were taking when. Eva Higginbotham heard what they found...

Balázs - First, we asked participants to put their microdoses inside non-transparent gel capsules, and a microdose is just a small piece of blotter paper, so you can easily fit them inside the capsule. And as the next step, we also asked participants to prepare empty capsules, and those are going to function as placebos throughout this study. Now, after these two sets of capsules were prepared, they were put into envelopes and zipped bags together with QR codes and then those envelopes were shuffled and random numbers generated so on and so on and so on. But the net result of the self-blinding process was that participants ended up with capsules enough for four weeks without knowing which of those capsules contains a microdose inside, and which one of the capsules are a placebo. The second component is that when participants scan the aforementioned QR codes, that gave us a way to track who is doing what at what time. So they did not know at the end what they were taking, hence we called the method self-blinding because you are blinded to your own drug condition.

Eva - I see, so were they noting down how they felt after taking them?

Balázs - That's essentially the idea, but we have used all online surveys to measure the effects of placebos and microdosing. And on top of these self-reported survey questionnaires, we've also asked participants to log into a cognitive testing platform where they have played various games designed to measure cognitive performance - think of the little memory card games that everybody was playing as a kid - we measure things like that to quantify memory performance and measured reaction time on various mental orientation tasks. So those were the two outcome categories that we have measured. Broadly speaking, we measured how people are doing and also how well they are performing cognitively.

Eva - And what did you find?

Balázs - So first let's just focus on the psychological outcomes, and what's really interesting here is that if you just look at the microdose group alone, then we very clearly saw an improvement from baseline to after the four weeks dose period in well-being and in all of the psychological outcomes that we have measured. So in a way that really validates all of the positive anecdotes about microdosing, because we saw improvements, statistically significant improvements, in a broad range of mental health measures. However, the story gets a bit more blurry if we add in the placebo control group into the picture, because the placebo control group also improved. And once we looked at the difference between the placebo and the microdose group, that difference was not significant anymore. So I think what that means is that all of those benefits that microdosers are talking about, I think those benefits are real, but also taking placebo is sufficient to reproduce those benefits suggesting that likely the mechanism behind those benefits is not due to the pharmacological activity of the psychedelic microdose, but rather the placebo effect is sufficient to explain it.

Eva - What about in terms of the other things that you measured?

Balázs - Yeah, so the other outcome was cognitive performance and when it comes to the cognitive measures, neither the microdose nor the placebo group has changed significantly relative to their baseline. And there wasn't any difference in the changes observed between the microdose and the placebo group. And I think, by and large, that fits into the placebo narrative that we have found, and the reason for that is because these cognitive tests are much more objective than the self-reported psychological tests. How you feel and you think about your own wellbeing counts a lot for the self-reported psychological questionnaires, but when it comes to the cognitive measures, it is much more objective. We measure things like how many digits you can recall in reverse order and how you think about yourself is going to carry much less weight in those measures. In a way the self-reported psychological measures are much more susceptible to the placebo effect just by their nature, and in contrast, these cognitive performance measures are much more objective.

Eva - What's the take home message then? Do you think microdosing psychedelic drugs doesn't actually work in the way that the anecdotes online suggest?

Balázs - It's a complicated question because in many ways we have validated that anecdotal evidence about microdosing. Bear in mind that we very clearly observed improvements in a broad range of psychological measures in the microdose group. It is just that people who were taking placebos also improved equally. So in many ways, you know, microdosing does work. We just think that the mechanism behind it, it's not what people think, it's not related to the pharmacological effect of the drug. Another important aspect here is that like all other studies, this one comes with limitations as well. First and foremost, in this study, being not a clinical study but a citizen science study, people have used their own drug which likely they have sourced from the black market. And because of that, there is some uncertainty regarding the variability and the exact chemical composition of the microdoses that were used personally. I'm not too worried about this limitation, and the reason for that is because people who are microdosing out there in the real world, they're also sourcing their psychedelics from the black market. So the variability and the uncertainty present in our study is also present in all of the anecdotes that have led to the current popularity of microdosing. So when we want to summarise the scientific evidence about microdosing, it needs to be said that prior to our study, there have been three much smaller clinical studies by and large, they are also negative. However, even with our study, there are only four placebo control studies of psychedelics altogether, which is not a large body of evidence. So it's still very much could be the case that when we talk again in a few years time, and there are many more clinical studies available on microdosing, then we will have to conclude that microdosing is efficient.