Do psychedelics require Gi for their actions?

No, but perhaps Gz or GoA

A recent paper has generated a flurry of emails to me from many sources (VCs, Biotech/Pharma companies, academics):

So here’s my standard answer (for those interested):

Here is the published data which contradicts this finding:

1. GoA is the main Gi-like G protein in the brain and represents 1% of brain membrane protein. There is almost no Gi1, Gi2 or Gi3 in the brain. There is much Gz (PTX-insensitive Gi protein) in the brain and 5-HT2A can couple to Gz and to a lesser extent to GoA .

2. Studies by the McCorvy group show, in direct contradiction to these results, that blocking Gq blocks the head-twitch-response (HTR); the YM compound is extremely selective for Gq/11

3. Prior studies have shown that PTX enhances the HTR, directly contradicting the findings in the Nature paper.

5. Genetic deletion of Gq attenuates HTR

6. Activating Go/z signaling on 5-HT2A-expressing neurons by 5-HT1A receptors inhibits HTR

7. Our recent proximity proteomics studies show engagement of Gq/11 and arrestin pathways but no evidence for Gi/o/z

An interested reader can find many, many other studies contradicting the findings of the recent Nature paper