Mid-century psychedelic neuroimaging studies in humans were dominated by the use of EEG, with LSD being the most common drug used. Today, fMRI studies of psilocybin, ketamine and LSD are the favourites (Scholkmann and Vollenweider, 2023). What neuroimaging technology are you most excited about? And, is there a particular drug that you think is most propitious to neuroimaging?

Parker Singleton: The above referenced outlook on using fNIRS in psychedelics is definitely something I’m looking forward to. More broadly, I’m seeing more and more groups collecting multi-modal data (simultaneous EEG-fMRI for example) which really diversifies the kinds of questions we can ask by combining advantages across techniques. As far as favorite drugs go for neuroimaging, I’m a big fan of DMT. The things we can do with DMT from a pharmacokinetic standpoint are really exciting to me, as someone who is interested in modeling the brain effects of psychedelic compounds.

Drummond McCulloch: There is a “enhanced neuroplasticity” hypothesis of psychedelic therapeutic action that is quite popular. The most powerful tool we have at the moment for testing this hypothesis is the PET radiotracer UCB-J which binds to the synaptic protein SV2A and provides an estimate of synaptic density, a proxy for neuroplasticity. I am excited to see whether this increases or decreases following psychedelic administration. However, the mood changes seen in these trials is so rapid that I believe it quite unlikely that the changes in synaptic density are responsible, as these can take days to weeks to fully emerge, though they may be involved in the persistent nature of effects. We know that functional brain activity is rapidly disrupted following psychedelic intake, so this represents a more obvious starting point for investigating the changes associated with changes in wellbeing. Thus, neuroimaging methods like fMRI, EEG and MEG show a lot of promise here. PET occupancy studies are also essential for informing dosing strategies.

There’s some research coming out of Basel and Maastricht that suggest that drugs psychonauts consider different, like LSD, Psilocybin, Mescaline and 2CB are really quite hard to tell apart in a blinded administration setting, except for the differences in duration. If I was being pessimistic I’d say that at the end of the day these drugs are so alike, that any attempt to distinguish them using as noisy a tool as functional neuroimaging is a lost cause. To be more optimistic, perhaps functional neuroimaging will prove to be superior to subjective experience reporting in distinguishing the differences between these. As such, I’d encourage researchers to evaluate several of theses drugs if possible in the same scanner and individual so that we can have a shot at working these differences out. Regarding molecular neuroimaging, I think it’s critically important that we perform dose-occupancy studies with all of these drugs so we know whether any apparent differences are dose or drug related, so far this has only been done for psilocybin. Additionally, it will be very interesting to see if any of the new 2A agonists without psychedelic subjective effects, or combinations with antagonists, have similar effects on functional brain activity and whether the so-called psychoplastogens produce persisting increases in synaptic density (using UCB-J PET), and if this relates to changes in wellbeing.