How Do Classic Psychedelics Work in the Brain?
“We have a huge potential for doing novel, groundbreaking work by looking at synaptic density—a molecular target that has recently become available for in vivo imaging. This hasn’t really been exploited yet, but…seems to be a very interesting avenue”
Josh Hardman, Psychedelic Alpha: What do we know about mechanisms of psychedelic action, and what we can see through imaging work?
Dr. Gitte Knudsen: Through imaging work, we know for a fact that it’s the stimulation of the serotonin 2A (5-HT2A) receptor that leads to psychedelic experiences. We also know this from behavioural studies where people have administered 5-HT2A receptor antagonists and shown that they can completely, or almost completely, block the psychedelic experience.
So that is the primary pharmacology of the classic psychedelics: psilocybin, psilocin, LSD, DMT, etc. We also know that the 5-HT2A receptors are primarily located in the pyramidal neurons in the cortex and that when sufficiently stimulated by serotonergic psychedelics, the experiential effects occur.
What happens alongside the stimulation, and the resulting psychedelic experience, becomes a little bit more uncertain. We believe, based on animal work and to some extent imaging work, that the pharmaceutical agonist effect, and perhaps also the psychedelic experience itself, is associated with neuroplasticity. Here, we have huge potential for doing novel, groundbreaking work by investigating synaptic density via a molecular target, SV2A, that has recently become available for in vivo imaging. This hasn’t really been fully exploited yet, but looking at changes in synaptic density after stimulation of the 5-HT2A receptors seems to be a very interesting avenue to pursue. We’ve done some of it, but maybe I can get back to that later.
The neuroplasticity phenomenon has also been associated directly with serotonergic psychedelics. Animal studies, particularly from the Castrén group in Finland, that seem to suggest these serotonergic psychedelics can stabilise the receptor associated with brain-derived neurotrophic factor (BDNF). Their finding suggests is that if you can stabilise the receptor that BDNF is interacting with, you can also augment neuroplasticity. I think this is an interesting theory, but we don’t yet know for sure if it’s the case or not.
And of course, there’s all the animal work where people have looked at the synaptic density, and the dendrites, and how the axons begin sprouting after doses of serotonergic psychedelics. So this is where we are now, on the molecular level.
When it comes to other aspects of the brain—meso level or macro level—people have also studied the circuit levels, where they look at networks across the brain. Here, the excitation of the serotonergic psychedelics shows consistently, that there is increased global integration across the brain and, in parallel, a reduced integrity of high-level association networks such as the default mode network (DMN). So there seems to be a decrease in within-network connectivity and an increase in between-network connectivity. This has been shown mostly for psilocybin and, to a lesser extent, for LSD.