2024 was a year of surprises and perhaps the biggest one in the world of mental health was the FDA’s decision regarding MDMA in August.
There were a lot of expectations that 2024 would be the year that the psychedelic medication, MDMA, would be approved by the FDA for the treatment of Post Traumatic Stress Disorder. However, in a startling turn of events the FDA rejected MDMA citing non-sufficient data collected. This is obviously a setback for the field and in this article I will explain what I believe went wrong and where this leaves us going forward with MDMA and other psychedelic research.
We’ve known for years in psychedelic research that it’s very hard to blind the psychedelic experience. People are very good at guessing what they got because when you receive the active medicine you have a huge, immediate experience as opposed to the placebo where you just sit there for 6 hours with nothing. The FDA has also known about this problem for years and gave the impression that they accepted this limitation. However, the FDA has seemingly moved the goal post and is very concerned about this issue that is known as functional unblinding. The reason this is a problem in research is that if a person swallows the pill and has this big experience with thoughts of “I got the active treatment” plus the additive biological effects of the medicine that will result in overestimating the effect of the treatment. On the other hand, if a person takes the pill and nothing happens with thoughts of “My last chance to get better just passed me by,” this will result in less of a placebo response and thus underestimate the placebo effect. One solution to this issue which has now become the new standard in the field is to design the study with a 3rd arm where a person receives a low dose psychedelic so that there still can be a psychedelic experience but without any antidepressant effect. Unfortunately, the MDMA studies done by MAPS (now called Lycos) did not include this 3rd arm so they will likely need to do another study which may take several years.
This setback does not really have an impact on other entities like psilocybin, and LSD as the field itself now understands that it needs to be more FDA-focused and FDA-compliant and that the study designs need to address functional unblinding so that they will get FDA approval. However, psilocybin for Major Depressive Disorder is still another 3-5 years away and LSD and other agents are greater than 5 years away. There has also been a fascinating development of non-psychedelic psychedelics that are manmade compounds with the same rapid and sustained benefits but without the psychedelic experience such as hallucinations that may have deleterious consequences; these agents are probably 10-15 years away from getting FDA approval.
Meanwhile, research continues with all these agents and one of the more intriguing studies published in 2024 was a study with LSD for Generalized Anxiety Disorder by Mindmed. What makes this study so interesting is that there was no therapy or support given--just follow up 4 weeks later. This is important because it addresses the question of how much of the benefit from the psychedelic is from the direct action of the drug, whether it be from the psychedelic experience or through a direct biological effect in contrast to the combination of the drug plus the psychotherapeutic surround which was minimized in this study. The same study also figured out the most effective dose was 100 ug and not the higher dose of 200 ug. The results showed a big improvement in anxiety and depression demonstrating that LSD has promising effects that is ready for Phase 3 trials.
As I mentioned in a previous article, psychedelics are probably going through a hype cycle where they are being overvalued and oversold in our imaginations. What often follows is compensatory disillusionment and it’s certainly disappointing to see that MDMA will be delayed a few years. Perhaps interest in psychedelics will dip a little but as we adjust our expectations there will be a plateau of progress; from there, the studies will be done in the way the FDA needs to see to get them approved which I believe will still happen.