Human brain changes after first psilocybin use

https://www.nature.com/articles/s41467-026-71962-3

“Diffusion tensor imaging and fMRI were completed both an hour and a month after ingestion of 25mg psilocybin among healthy participants. A decrease in axial diffusivity was noted in bilaterally in prefrontal subcortical tracts, in correspondence to a reduction in brain network modularity.”

“Network modularity (numerical decrease) has a negative relationship with well-being (large increase)”

If decreased network modularity can predict greater well-being, what can we speculate? An overarching theme that is arising in the research is that greater entropy leads to greater well-being. If entropy can lead to decreased modularity, what can we speculate? What is the purpose of decreased modularity? Perhaps we are better off asking how we can utilize decreased modularity. Moreover, how can we modify our research so as to trigger a further decrease in this modularity, even under the same baseline psilocybin dose of 25mg? 

If entropy can be converted into well-being via subjective effort, what can help produce greater entropy? The question we are circling is how we can maximize our production and utilization of entropy. 

We observe the starting conditions:

“A single high-dose of psilocybin has been shown to strongly agonize the 5HT-2AR and lead to observable neuroplastic effects, such as synaptogenesis.”

“Model shows that increased well-being at one-month post-25 mg can be explained by increased brain entropy (LZc) across all sensors, but also that the strongest path entails brain entropy first predicting next-day insight, which then, in-turn, predicts improvements in well-being (1-month).”

A high-dose of psilocybin can initialize the neuroplastic window that allows entropy to be produced into insight. Perhaps that this initial window can and should be viewed as the first step at the base of a mountain. Therefore, I believe the point of the correlational and predictive modeling graph seems to lay in the fact that LCz may not necessarily turn into insight, and thus has a lower correlation to well-being than does insight. The article already seems to have suggested this. 

“Future work could examine additional, more specific dimensions of experience, such as emotional breakthrough.”

And it hints at future work. This would constitute an admission of the ‘mountain’ that can exist after the initial baseline dose. We can consider at length what might constitute an emotional breakthrough, and we can look further, at other more abstract-cognitive and perceptual shifts that can be facilitated by factors such as integration therapists or psychedelic guides, and/or other educational materials and/or recordings that are provided before, during, and after.

“If the effects are truly reflective of microstructural change, then decreases in AD and FA exclusively after the 25 mg dose might tentatively relate to two types of change: the pruning of weak or redundant connections and/or neurogenesis with under-myelinated axons.”

The difficulty in assessing the exact correlation lies in the number of potential confounds, such as cross-over synapses: axons and synapses overlap each other in abundance and create difficulty in assessing why decreases in axial diffusion are occurring. This parallels, structurally, a potential confound that may arise in attempting to understand why decreased modularity would occur. What leads to the greatest decreases of modularity? Emotional breakthroughs, or perceptual and cognitive shifts? And what may lead to these shifts, and how may these shifts further lead to decreases in both modularity and axial diffusion? 

Principally, this turns into a discussion, in one sense, about set and setting, or the starting conditions of the participant. But it also involves a discussion about the dynamism of these second-order effects which are created by mental activity during the trip itself. These questions, if addressed, may be able to help steer future research. We might want to ask, for example, what exact factors lead to greater decreases of AD and modularity? 

“Future research in larger samples could test whether acute EEG changes, induced by 5-HT2AR agonist psychedelics, can predict downstream anatomical neuroplasticity or therapeutically-relevant functional brain changes.”

The point is again addressed. The article questions how brain activity registered by an EEG can predict greater neuroplasticity. If we are referring to greater LCz—greater complexity in signalling patterns—we may as well turn back to the question as to which mental stimuli lead to this, and why. Answering the why may help steer research toward increasingly pragmatic research questions.

“Doss et al. found similar effects with psilocybin-therapy for depression that they labeled increased ‘’neural flexibility’”

We return to the idea that increased entropy in the brain produces a state whereby a more flexible, less modular state can be acquired. 

“It remains plausible—if not likely—that functional brain changes do occur, but that their detection is dependent on—or sensitive to— experimental modalities, metrics and parameter decisions.”

Toward the end, experimental modalities, metrics, and parameters are touched upon.

“Participants set an intention for the psilocybin sessions before dosing, which was written on a white board in the dosing room.”

It would have been interesting to examine the metrics and parameters of the sessions themselves. We can speculate that designing and implementing a certain variety of intentions before the trip could significantly alter findings regarding decreased brain modularity, changes in functional connectivity, and changes in axial diffusion.

The main reason for this speculation is based upon the theory of the learning brain—that the brain is already capable of inducing states of entropy. In other words, the brain is already ‘plastic’, and capable of rewiring itself through physical and mental activity. If the brain is already capable of inducing neurogenesis through non-chemical means, why can we not also explore the various experimental modalities within these studies? For example, if certain topics are visited by a therapist during a trip—particularly in the cognitive and/or dialectical vein—perhaps there would be structural or functional changes of greater significance. This would constitute a worthy expansion of this study, and could form potential new objectives for future studies. It is not only a matter of exploring how set and setting influence neuroplasticity, but also asking exactly the reasons for such influences,  exploring those reasons thoroughly, and then reworking future studies to narrow our explorations.

I believe that if the study were duplicated—albeit with particularized changes in regard to utilized experimental modalities—the findings would change substantially. Consider the findings on advanced practitioners of meditation and the corresponding changes in brain structure. We find reduced axial diffusion, decreases in axial and radial diffusivity, increases in fractional anisotropy, and axonal remodeling. Future research in larger samples could utilize experimental modalities—such as meditation after ingestion—to examine if there would be structural changes of greater significance. Although some studies have been completed on patients who were both experienced meditators and users of psilocybin, metrics did not account for any changes in anatomical changes.