September 28th

The paper is in its 2nd round of review so keep an eye out! Original version is on BioRxiv. I’ll post when it clears review!

The effect seems to rely on slower metabolism leading to sustained activation of the 5-HT2B receptor. Low dose LSD/psilocybin are off the receptor within 10 hours while a typical fenfluramine dose causes the receptor to remain bound for 24 hours. FYI MDMA has a similarly dangerous kinetic profile.

We also calculated time course kinetics based on human data and demonstrate clear differences in kinetics between known valvulopathic drugs and low dose psychedelics that suggest the risk profile is very low with microdosing LSD or psilocybin.

A caveat: while mouse and human 5-HT2B receptor show no differences in affinity or efficacy, there are differences in metabolism. This slightly limits interpretability, but this is somewhat amended given that we used a known valvulopathic drug and showed pathological effects in mice.

Well, the speculation has good rationale. Based on their receptor pharmacology, they should have cardiovascular risk. However, my findings failed to demonstrate that effect and this is likely due to pharmacokinetics. Mouse and human 5-HT2B receptor show no differences in affinity or efficacy. [1/x]

Thank you so much! It was so good (as always) to see you!

@connorhaggarty.bsky.social I am bummed we didn’t get a chance to actually chat! Winter brain?