LSD flattens the brain′s energy landscape: evidence from receptor-informed network control theory

This preprint (2021) combines data of the brain’s resting state under the influence of LSD and cortical mapping of 5-HT2A receptors within the framework of network control theory to validate the central tenets of the REBUS model of psychedelics. In accordance with this model, LSD-induced flattening of the brain’s energy landscape, corresponding to greater flexibility for state transitions and more dwell time in brain states than encode bottom-up activity (e.g. salience network) and decreased persistence of states dominated by top-down (frontoparietal) activity.


Psychedelics like lysergic acid diethylamide (LSD) offer a powerful window into the function of the human brain and mind, by temporarily altering subjective experience through their neurochemical effects. The RElaxed Beliefs Under Psychedelics (REBUS) model postulates that 5-HT2a receptor agonism allows the brain to explore its dynamic landscape more readily, as suggested by more diverse (entropic) brain activity. Formally, this effect is theorized to correspond to a reduction in the energy required to transition between different brain-states, i.e. a ″flattening of the energy landscape.″ However, this hypothesis remains thus far untested. Here, we leverage network control theory to map the brain′s energy landscape, by quantifying the energy required to transition between recurrent brain states. In accordance with the REBUS model, we show that LSD reduces the energy required for brain-state transitions, and, furthermore, that this reduction in energy correlates with more frequent state transitions and increased entropy of brain-state dynamics. Through network control analysis that incorporates the spatial distribution of 5-HT2a receptors, we demonstrate the specific role of this receptor in flattening the brain′s energy landscape. Also, in accordance with REBUS, we show that the occupancy of bottom-up states is increased by LSD. In addition to validating fundamental predictions of the REBUS model of psychedelic action, this work highlights the potential of receptor-informed network control theory to provide mechanistic insights into pharmacological modulation of brain dynamics.

Authors: S. Parker Singleton, Andrea I Luppi, Robin L. Carhart-Harris, Josephine Cruzat, Leor Roseman, Gustavo Deco, Morten L. Kringelbach, Emmanuel A. Stamatakis & Amy Kuceyeski


A great explanation of this paper was given by Parker Singleton on Twitter. Interesting Engineering also covered the paper.

This paper may also pair well with Girna et al (2021).

The data from the 15 participants on 75ug of LSD (but not the new computer/brain-simulation models) come from Carhart-Harris et al (2017).

There are many different ways of peering inside our brains. We can do this with (repeated) fMRI studies that can take multiple snapshots of a brain. Another technique is called PET which can show changes in a system over time. Combining these techniques, and a few others, this paper provides more evidence for the leading theory of our brain on psychedelics.

This paper builds on earlier work that argues psychedelics relax our prior beliefs (REBUS). This framework argues that old beliefs are let go more easily and be replaced by new ideas, connections, or observations. This can explain how psychedelics allow a person to process emotions. Or how creative ideas are given space to flourish.

What makes this paper so special?

  • It calculated the influence of the serotonin 2a receptor and found it to be very well positioned to the flattening of the hierarchy
  • The paper combined fMRI, dMRI, PET, and NCT to show the flattening of the hierarchy from multiple angles
  • The easier information flow (in a flatter hierarchy) can both explain the synaesthesia experiences as well as the letting go of old beliefs. In other words, it has great explanatory power

Our brains not only become ‘flatter’ but also show a higher level of disorder (entropy). One way to interpret this is to say that there are more options available whilst under the influence of psychedelics.

Although the paper is quite technical, the graphs do help make sense of this exciting new research. The next steps could include the same analyses with different psychedelics, at different dosages (now 75μg LSD), and to find a relationship with the subjective experience (now no significant relationship was found).

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