'Shrooms for depression. Did it work?

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Currently, the most read article the website of the Journal of the American Medical Association is not an article about Covid-19, cancer, heart disease, diabetes, or obesity. It’s about whether ‘shrooms treat depression. The article entitled “Single-Dose Psilocybin Treatment for Major Depressive Disorder” has been viewed 127,745 times since it was released less than a month ago. That’s more than double the views of the two most read Covid-19 articles this month combined.

Let’s be honest. Typical JAMA readers are not that interested in depression. Yes, depression is a monumentally important topic that drives interest in medical journals. But, frankly, this article is topping the charts because everyone’s kind of tickled that medical researchers gave a bunch of volunteers with moderate or severe symptoms of major depression a drug that, used recreationally, can cause people to have gripping conversations with their sneakers.

Did it work?

Volunteers who qualified were randomized to receive either one dose of psilocybin (pronounced sih-loh-SY-bin, but often referred to as “mushrooms” in non-medical settings) or the vitamin niacin as a placebo. Both groups also received psychological support/therapy.

Niacin was chosen as the placebo because it can cause flushing of the face. The hope was that the participants who received placebo might be fooled into thinking they actually got ‘shrooms, just because of that side effect.

Reader, I’ve never messed with mushrooms. But had I participated in this study as a patient, I’m pretty sure some facial flushing would not have thrown me off the scent as to whether I’d been randomly selected to join the drug or placebo arm. A warm sensation on the skin is probably resolvable from, say, temporarily mistaking your ficus for Copernicus.

Here’s why this matters. After 43 days, the researchers found statistically lower depression scores in individuals who had received psilocybin compared to those who had received placebo. At the start of the study, people in both groups had average depression scores corresponding to the lower end of the severe depression range. Seven weeks later, the average score among those who received psilocybin placed them in the mild depression category, while placebo recipients’ scores decreased a bit less, but still down to moderate (not bad, for placebo).

The problem is that the effects of psilocybin are often so intense (and mind-altering) that the participants probably easily figured out whether they got drug or placebo. That matters because it’s likely that people who chose to enter a trial testing the effect of mushrooms on major depression really wanted it to work. (They were also likely to have good feelings about the recreational side effects.) On top of that, the people who received placebo were likely, on some level, disappointed to have been excluded from getting the good stuff. Of the 53 volunteers who received placebo, nine of them (17%) ghosted on the researchers and did not follow up, compared to just one of the 51 (2%) who got the actual ‘shrooms.

Now, it’s reasonable to assume that the volunteers in the placebo group who ghosted probably did not have particularly favorable improvements in their depression scores. So, the 17% who were “lost to follow up” probably would not have changed the outcome of the study so as to have negated the apparent win for psilocybin, had they stuck around.

But it’s hard to ignore the fact that the follow up rate in the psilocybin group was 98%—that’s exceptionally good for a clinical trial. What I’m getting at is that people who were inclined to enter a study and possibly try mushrooms (and who really got to take them) may have greatly enjoyed the experience and wanted to do it again. And it’s easy to imagine why. Look, I personally have zero interest in trying psilocybin. But if I did, I wouldn’t mind the safety of a standardized dose, the knowledge that the drug I was ingesting was not tainted with anything more dangerous, not to mention a little medical supervision.

A win? Or a self-fulfilling prophecy?

I can’t help but wonder whether the participants who received psilocybin knew that they had gotten the “real drug” and were motivated to give responses on the depression scoring test that were favorable. This is called the “expectation effect”—which is almost the opposite of a placebo or nocebo effect. The idea is that when someone thinks they received “the real drug,” (and they’re right), they may report better outcomes.

If that’s what happened (even in part), that could indicate that the psilocybin recipients simply liked the experience—and they expressed this in their responses to the depression scoring questions. Then again, these folks probably weren’t intentionally lying in their answers. If enjoying psilocybin was—to the participant—indistinguishable from improved depressive symptoms 8-43 days later, who really cares? I’m happy if they are happy—even if they just think they are happy. The question is, how long would these findings be sustained? Do repeat doses work? We don’t know.

To be clear, I’m not accusing the participants of gaming the system in order to get more ‘shrooms just for recreational purposes. Rather, I believe that anyone with severe depression who chose to enter a study like this really wanted something new to work. The inability to truly blind the participants to whether they received the study drug or placebo, in my view, undermines our ability to interpret these findings.

Still, for a condition as difficult to treat as depression, any new ideas are welcome. This study shows that psilocybin was safe (if marked by a number of predictable short-lived side effects) and, very possibly, effective. Many clinical trials are akin to dead-ends for good ideas that didn’t work out. While it’s too soon to declare definitely that psilocybin reliably treats major depression, the notion that it might is no longer a mere hallucination.

Questions? Comments? Ideas? Please add them to the comments section…