This was my PhD thesis! Here is the link to the full manuscript.

Abstract:

Psychedelics, such as lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and psilocybin, are hallucinogenic drugs that act on the 5-HT2A receptor. Their effects can be analysed on three different levels: (1) phenomenology, or subjective experience, as psychedelics strongly alter a person’s state of consciousness; (2) neuroimaging, using tools such as functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG); and (3) pharmacology, or their biochemical interactions with various receptors in the brain. In the last ten years, there has been a considerable rise in psychedelic research due to emerging evidence that they can be effective for treating a wide range of conditions, including depression, substance use disorder, end-of-life anxiety, and post-traumatic stress disorder (PTSD). A popular theory known as RElaxed Beliefs Under pSychedelics (REBUS) posits that psychedelics “flatten” the functional hierarchy of the brain; that is, they diminish the inhibitory effect of higher-order, associative cortical networks on lower-order, sensory networks. However, it is challenging to test REBUS because it proposes that psychedelics modify the weights of the prior beliefs, or “priors,” encoded in higher-order networks, yet there are no robust models that systematically link priors to the activity of these networks, as recorded by MEG or fMRI. Instead, it is more straightforward to measure hierarchy directly on the connectivity of these networks, without assuming that the connectivity instantiates priors.

My aims in this thesis are twofold. The first is to provide a comprehensive overview of the current landscape of scientific literature about the effects of psychedelics on healthy humans. In particular, I conduct systematic reviews and meta-analyses of the three levels of analysis mentioned earlier – phenomenology, neuroimaging, and pharmacology – across three different psychedelics (DMT, LSD, and psilocybin). I discover that there are highly nonlinear relationships both between drugs and also between levels of analysis. The second aim is to measure brain hierarchy under psychedelics with simple, empirically tractable methods. In particular, I discuss two different measures: irreversibility, or the asymmetry between sending and receiving neural signals; and trophic coherence, which decomposes networks into hierarchical levels. I apply these two measures to an existing MEG dataset of healthy human participants who were administered LSD. My analyses reveal that LSD decreases both irreversibility and trophic coherence, suggesting that LSD does indeed flatten the functional hierarchy of the brain. Furthermore, the spatial distribution of changes in irreversibility and hierarchical levels on LSD is consistent with the findings of the meta-analysis. In particular, the meta-analysis demonstrates that LSD, more than other psychedelics, alters the quality and intensity of visual hallucinations, while also elevating connectivity between the visual network and other brain networks. LSD reduces irreversibility and top-down hierarchical levels most in the regions of the brain that are involved in visual processing. Taken together, these results indicate that LSD diminishes the influence of visual network activity on hierarchically directed connectivity in the brain, which may explain the profound effects of LSD-induced visual hallucinations on higher-order cognitive processes such as a person’s sense of self. Furthermore, this thesis constitutes the first attempt to measure the hierarchy of directed information flow in the brain under psychedelics. Future work could deploy the same methods to determine whether the flattening of hierarchy predicts the therapeutic response to psychedelics.