In this report we look at the recent reveal of the first-ever Phase 3 trial data testing LSD. A press release touted extraordinary results but how impressive were the findings really? And how does this data compare to recent Phase 3 findings for psilocybin? Yep, I’m stoking the age-old acid versus mushroom debate. I’m also going to look at how magic mushrooms were depicted in a recent TV show.
Anyone with an eye on psychedelic news surely saw a headline or two recently proclaiming wildly effective top-line results from the first ever Phase 3 human trial testing LSD as a treatment for depression. Words like ‘profound’ were used to describe these ‘best ever’ results for a late-state psychedelic clinical trial, and the very next day Definium Therapeutics, the company developing the treatment, reported raising $700 million dollars in new funding.
This was undoubtedly a blockbuster moment for psychedelic medicine. And the way Definium presented its data certainly foreshadowed the coming of a promising new treatment for depression.
The big showcase slide revealed a single 100 microgram dose of LSD led to a big drop on a scale of depression frequently used in mental health studies, known as the Montgomery–Åsberg Depression Rating Scale. And that drop seemed to hold relatively strong for up to three months.
Compared to the placebo response these results are undeniably ‘profound’, and that slide looks pretty impressive. But as with all clinical data, you can draft it up in a million different ways. Perhaps another way to view this top-line data is to compare it to some other trials testing current ‘best-in-class’ antidepressant drugs.
Here’s another slide. This one pulls data from a big Phase 3 antidepressant trial conducted around a decade ago, encompassing over 600 participants.
The trial was testing the efficacy of a new-ish antidepressant drug called vortioxetine (or Trintellix). Setting aside the more pronounced placebo effect, changes to MADRS scores in those taking the active drug after six weeks were pretty similar to what Definium is reporting with LSD. At the eight week point they were even slightly better.
And these results are generally considered relatively modest in the world of antidepressant clinical studies. When put to clinical trial, more traditional SSRI and SNRI antidepressants tend to deliver anywhere from a 10 to 20 point drop on MADRS ratings after a couple of months of use.
Of course I don’t want to compare apples to oranges here. Caveats abound.
For example, LSD is just one dose whereas these antidepressants are daily medicines. And the broader side effects from most antidepressants are well chronicled, from blunted emotions to sexual dysfunction. So you could easily look at the LSD data and say, hey, this is a drug that works faster than traditional antidepressants and doesn’t have the same side effects.
Another slide worth briefly looking at from the Definium release is the percentage of participants that hit remission at the six week point after their LSD dose.
Here we see 24% of people scoring low enough on the MADRS to be considered in remission. That’s about one in four participants. As neuroscientist Martin Arjns told Josh Hardman at Psychedelic Alpha, this “seems on the lower side of what you would expect in the landscape of depression treatments, where 30-40% remission rates are more customary.”
There’s plenty more data points in the Definium press release but I think this is a good moment to temper expectations into how powerful psychedelics seem to be looking as antidepressant medicines.
As we are slowly getting more Phase 3 data there are plenty of ways to frame the results but one controversial take is it may look like psychedelics are just about as effective as antidepressants; at least when we track things by brute force quantitative scales like MADRS.
One musing I’d like to leave you with is the question I floated up top.
What if LSD is a better antidepressant than psilocybin?
