Psychedelic Journal Club: How Do Psychedelics Work? Part 2

A commentary on the article “Models of psychedelic drug action: modulation of cortical- subcortical circuits” by Manoj Doss et al., published in Brain.

Even though the “psychedelic renaissance” is underway, U.S. federal funding for research is still scarce.

Last year, the NIH awarded a grant to Johns Hopkins researchers to study whether psychedelics could be effective as a treatment for tobacco addiction. But before that, there was a 50-year funding drought during which no government money was given to psychedelic research involving the treatment of human subjects.

I’ve learned from conversations with psychedelic neuroscientists that a common criticism mounted against the field of psychedelic science from grant reviewers and other skeptical scientists centers on the question of how psychedelics work. Not enough is currently known about exactly how psychedelics produce their profound consciousness-altering acute effects and longer-term changes to personality and worldview. There are prominent theories that have been proposed, such as the REBUS model laid out by Robin Carhart-Harris and Karl Friston. But there is no broad consensus about psychedelics’ mechanisms of action.

The reason that this mystery at the heart of psychedelic science causes funding agencies and skeptics to balk at the optimism surrounding psychedelic medicine and the steadily growing interest in basic psychedelic science is that they see a possibility that the mechanism of action of psychedelics is just a nonspecific dysregulation of brain activity.  In other words, psychedelics might just be increasing noise in the brain, with fundamentally unpredictable consequences. If this were so, it would severely limit the therapeutic usefulness of psychedelics; if their effects could not be precisely predicted, their safety and efficacy could not be guaranteed.

“If this were so, it would severely limit the therapeutic usefulness of psychedelics; if their effects could not be precisely predicted, their safety and efficacy could not be guaranteed.”   

Hypothetically, hallucinations and sensory distortions may be caused by any changes in sensory cortical neural activity that disconnect cortical representations from their source external stimuli. Under normal conditions, our visual systems do a commendable job of accurately estimating the contents and layout of our environment based on the light that falls onto our retinas. Veridical representations of our environment and the objects within it, generated and maintained in visual cortex, correspond to our actual physical environment. When the processes that generate these representations malfunction, we might perceive something that isn’t really out there: a hallucination.

Patterns of brain activity are thought to be subject to nonlinear effects characteristic of chaotic and complex systems1. It is thus plausible that the amount of disruption of normal cortical processes sufficient to engender large-scale changes across neural populations networks of cortical areas is small enough to be accomplishable by nonspecific actions of psychedelics. Just like a flap of a butterfly’s wings in Brazil might cause a tornado in Texas, an arbitrary psychedelic disturbance in small group of neurons might cause large-scale brain activity changes with unpredictable effects on mood, perception, and cognition.

Solving mysteries at the heart of a natural phenomenon is an essential part of any scientific endeavor. And, normally, funding agencies are motivated to support efforts to solve theoretical mysteries, rather than hesitant to approach the questions altogether. Be that as it may, solving this particular mystery—developing a convincing explanation of how psychedelics work—is critical if psychedelic researchers hope for their field to progress at all. To break through the suppressing influences of pessimistic, skeptical, and hesitant scientific gatekeepers, psychedelic scientists need a solid theory. Luckily, understanding psychedelics’ neural mechanisms is an active research area with multiple leads

In a new paper, published in the journal Brain, Doss and colleagues review two of the most promising general theories of psychedelics’ mechanisms of action, and propose a new theory of their own2. The two leading theories discussed in the article are Relaxed Beliefs Under Psychedelics (REBUS), and the cortico-striatal thalamo-cortical loop model (CSTC). The REBUS model was summarized and discussed in a previous Psychedelic Journal Club column.

The CSTC model proposes that the fundamental mechanism of action of psychedelic administration is disrupting the thalamic coordination of sensory inputs and feedback signals to cortex3. The thalamus is a subcortical brain structure that is often thought of as a kind of relay hub in the brain, taking inputs from both sensory organs and higher-level cortical areas that issue feedback and lateral signals, and coordinating how these signals are projected, like a switchboard, to different brain areas. Occupying this central position in brain networks, the thalamus regulates flows of information between different brain areas in order to coordinate computational processes and maintain stable representations of the sensory environment.

5-HT2A receptors, the serotonin receptors that are bound with high affinity by serotonergic psychedelics such as LSD, psilocin, and mescaline, are richly expressed on presynaptic terminals of thalamocortical afferents. In other words, psychedelics seem to have some particular activity on the neurons of the thalamus that send signals to cortex. Psychedelic activation at these sites may dysregulate the transmission of inputs to cortical processing areas, allowing levels of information to flow at higher levels than are normally allowed. Theoretically, the excitation of these thalamocortical afferents by psychedelics may account for the acute psychoactive effects of psychedelics. With thalamic gating lifted by 5-HT2A receptor activation on presynaptic thalamocortical afferents, the information flowing into cortex might exceed the capacity of these processing areas and disrupt the cortico-cortical integration processes that normally bind distributed cortical areas into functionally connected networks.

“Diminishment of normally dominant brain networks in favor of more widespread connectivity is a hallmark feature of neuroimaging studies with psychedelics”

In their new paper, Doss and colleagues point out that the CSTC model leaves some pieces of the puzzle still missing. For instance, disinhibited thalamic gating should lead to increased thalamic activity and downstream prefrontal cortical activity. But neither of these predictions have borne out consistent empirical evidence.

In light of lingering questions not fully addressed by REBUS or CSTC, Doss and colleagues propose their own model of psychedelics’ action. Their model emphasizes the role of the claustrum, a subcortical population of neurons that also densely expresses 5-HT2A receptors. According to the cortico-claustro-cortical model (CCC) put forth by Doss and co-authors, the normal role of the claustrum is to activate and entrain canonical network states according to shifting task demands, and therefore, dysregulation of the claustrum by psychedelics leads to the disintegration of canonical networks. Presumably, the consequence of disintegrating normally active brain networks is that new brain networks can be established, altering perception and cognition. Diminishment of normally dominant brain networks in favor of more widespread connectivity is a hallmark feature of neuroimaging studies with psychedelics4. So to the extent that the role of the claustrum is to instantiate and maintain these canonical networks according to task demands, it makes sense to posit a critical role of the claustrum in psychedelics’ neural mechanisms.

The three models of psychedelics’ mechanisms of action in the brain described in this new paper by Doss and colleagues are all promising leads in the effort to better understand these enigmatic drugs. Refining these models, generating predictions, and testing their limits with rigorous experiments are the critical next steps towards increasing acceptance of psychedelic research within the broader scientific community.

Link to Article

How do you think psychedelics work? Tell us in the comments below!


Written by Sean Noah
Illustrated by Sean Noah
Edited by Carolyn Amir and Arielle Hogan


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1. Cocchi, L., Gollo, L. L., Zalesky, A. & Breakspear, M. Criticality in the brain: A synthesis of neurobiology, models and cognition. Prog Neurobiol 158, 132-152, doi:10.1016/j.pneurobio.2017.07.002 (2017).
2. Doss, M. K. et al. Models of psychedelic drug action: modulation of cortical-subcortical circuits. Brain, doi:10.1093/brain/awab406 (2021).
3. Vollenweider, F. X. & Preller, K. H. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nature Reviews Neuroscience 21, 611-624, doi:10.1038/s41583-020-0367-2 (2020).
4. Carhart-Harris, R. L. et al. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc Natl Acad Sci U S A 113, 4853-4858, doi:10.1073/pnas.1518377113 (2016).

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Sean Noah

Sean is a postdoctoral researcher at the UC Berkeley Center for the Science of Psychedelics. He studies the link between how psychedelics change neural activity in visual cortex and their effects on visual perception. He received his PhD from UC Davis, where he studied the neural mechanisms of visual attention.