It presents a plausible unified theory of how psychedelics work.
It’s a wonderful jumping-off point into the literature. Every paragraph is full of pointers to research that’s come out in the last 5 years, and boy are there a lot of rabbit holes to go down – it’s filled out my reading list for the next several months.
REBUS is a (somewhat dubious) acronym for RElaxed Beliefs Under pSychedelics. The basic idea: psychedelics reduce the weight of held beliefs and increase the weight of incoming sensory input, allowing the beliefs to be more readily changed by the new sensory information.
The brain generates mental models that predict upcoming sensory inputs. (The predictions are called “priors,” as in “prior beliefs.”)
These predictive models are layered on top of each other in a hierarchy – the higher levels send predictions down the hierarchy; the lower levels report sense data upwards.
In cases where the model’s top-down predictions do not match the bottom-up sensory input, the model either (a) updates its priors based on the new sense data, or (b) ignores the sense data and maintains its priors.
Carhart-Harris & Friston theorize that the main thing psychedelics are doing is relaxing the weight of the brain’s top-down prediction-making (“REBUS”) and increasing the weight of the bottom-up sense information (“the Anarchic Brain”). This allows bottom-up information to have more influence on our conscious experience, and also on the configuration of the hierarchy overall.
Carhart-Harris & Friston analogize this process to annealing – heating up a metal dissolves its crystalline structure, then a new structure recrystallizes as the metal cools:
The hypothesized flattening of the brain’s (variational free) energy landscape under psychedelics can be seen as analogous to the phenomenon of simulated annealing in computer science – which itself is analogous to annealing in metallurgy, whereby a system is heated (i.e., instantiated by increased neural excitability), such that it attains a state of heightened plasticity, in which the discovery of new energy minima (relatively stable places/trajectories for the system to visit/reside in for a period of time) is accelerated (Wang and Smith, 1998).
Subsequently, as the drug is metabolized and the system cools, its dynamics begin to stabilize – and attractor basins begin to steepen again (Carhart-Harris et al., 2017). This process may result in the emergence of a new energy landscape with revised properties.
Psychedelics “heat up” the brain, increasing plasticity and weakening the influence of prior beliefs. As the psychedelic stops being active, the brain “cools” – the hierarchy re-forms, though perhaps in a different configuration than the pre-psychedelic configuration.
This explains how psychedelic trips can cause changes that last long after the substance has exited the body – in those cases, the psychedelic facilitated a change in the organization of the brain’s cognitive hierarchy.
Psychedelic therapy is showing promise for mental disorders associated with too-rigid thought patterns – depression, anxiety, addictions, maybe OCD, maybe eating disorders. In predictive-coding lingo, “disorders that may rest on particularly rigid high-level priors that dominate cognition.”
In these disorders, new information can’t revise the existing story of how things are, because strong priors suppress the new info before it can update anything.
The REBUS model straightforwardly explains how psychedelics help with disorder like this – by relaxing the strong top-down priors and boosting the bottom-up inputs, bottom-up inputs have more ability to effect the system. Here’s an illustration from the paper:
The top sketch is a brain where strong top-down priors dominate. New sensory inputs are suppressed and can’t update the hierarchy. The bottom sketch is the same brain while on a psychedelic – the top-down priors have been relaxed and bottom-up sensory information flows more freely through the system, causing a bigger impact.
Okay, nice theory, but can we observe this in the brain? Is there any evidence for it?
Carhart-Harris & Friston place the default mode network at top of the brain’s predictive hierarchy. The default mode network is the network of brain regions that’s most active when the brain isn’t engaged with any specific task. It also appears to be the seat of one’s sense of self. The default mode network is intensely relaxed by strong psychedelic experiences – this is subjectively felt as ego dissolution, and allows for the propagation of bottom-up sense data (which are also boosted by psychedelics).
Carhart-Harris & Friston identify two mechanisms by which psychedelics may relax the default mode network – activation of 5-HT2AR serotonin receptors (there are lots of these receptors in the default mode network), and disruption of α and βwave patterns, which seem to propagate top-down expectations through the brain (and are correlated with default mode network activity).
In addition to the brain-scan-style evidence they cite throughout the paper, Carhart-Harris & Friston dedicate a long section to behavioral evidence (“Behavioral Evidence of Relaxed Priors under Psychedelics”). Briefly, there are several studies showing that surprise & consistency-making responses to sensory stimuli are reduced while on psychedelics, which is what we’d expect if the influence of top-down priors was lessened.
To sum up, REBUS and the Anarchic Brain places psychedelics in a predictive coding framework to give a unified theory of what psychedelics do – they decrease the influence of top-down prediction-making and increase the influence of bottom-up sense data. The theory has the nice quality of tying many disparate psychedelic phenomena together with an underlying explanation of what’s going on. Plus, it gives a brain-based explanation for why psychedelic therapy is helpful for disorders like depression, anxiety, and addiction.
Our first mention of Neural Annealing in relation to psychedelics was in Algorithmic Reduction of Psychedelic States in 2016, and we are pleased to see that the concept is becoming a live idea in academic neuroscience in 2019.*
From our point of view, an extremely promising area of research that mainstream neuroscience has yet to explore is the Symmetry Theory of Valence. In particular, we claim that the very reason why Neural Annealing improves not only global control, belief, and behavioral consistency, but also mood and sense of wellbeing is because it smooths and symmetrifies your neural patterns of activation. Will this turn out to become part of mainstream neuroscience in the future? Well, since QRI was calling Neural Annealing years in advance, perhaps in retrospect you’ll also see that we were on the money when it came to the mathematics of valence. Only time (and funding) will tell.
How do psychedelic drugs produce their characteristic range of acute effects in perception, emotion, cognition, and sense of self? How do these effects relate to the clinical efficacy of psychedelic-assisted therapies? Efforts to understand psychedelic phenomena date back more than a century in Western science. In this article I review theories of psychedelic drug effects and highlight key concepts which have endured over the last 125 years of psychedelic science. First, I describe the subjective phenomenology of acute psychedelic effects using the best available data. Next, I review late 19th-century and early 20th-century theories—model psychoses theory, filtration theory, and psychoanalytic theory—and highlight their shared features. I then briefly review recent findings on the neuropharmacology and neurophysiology of psychedelic drugs in humans. Finally, I describe recent theories of psychedelic drug effects which leverage 21st-century cognitive neuroscience frameworks—entropic brain theory, integrated information theory, and predictive processing—and point out key shared features that link back to earlier theories. I identify an abstract principle which cuts across many theories past and present: psychedelic drugs perturb universal brain processes that normally serve to constrain neural systems central to perception, emotion, cognition, and sense of self. I conclude that making an explicit effort to investigate the principles and mechanisms of psychedelic drug effects is a uniquely powerful way to iteratively develop and test unifying theories of brain function.
Subjective rating scale items selected after psilocybin (blue) and placebo (red) (n = 15) (Muthukumaraswamy et al., 2013). “Items were completed using a visual analog scale format, with a bottom anchor of ‘no, not more than usually’ and a top anchor of ‘yes, much more than usually’ for every item, with the exception of ‘I felt entirely normal,’ which had bottom and top anchors of ‘No, I experienced a different state altogether’ and ‘Yes, I felt just as I normally do,’ respectively. Shown are the mean ratings for 15 participants plus the positive SEMs. All items marked with an asterisk were scored significantly higher after psilocybin than placebo infusion at a Bonferroni-corrected significance level of p < 0.0022 (0.5/23 items)” (Muthukumaraswamy et al., 2013, p. 15176).
Neuropharmacology and Neurophysiological Correlates of Psychedelic Drug Effects
Klee recognized that his above hypotheses, inspired by psychoanalytic theory and LSD effects, required neurophysiological evidence. “As far as I am aware, however, adequate neurophysiological evidence is lacking … The long awaited millennium in which biochemical, physiological, and psychological processes can be freely correlated still seems a great distance off” (Klee, 1963, p. 466, 473). What clues have recent investigations uncovered?
A psychedelic drug molecule impacts a neuron by binding to and altering the conformation of receptors on the surface of the neuron (Nichols, 2016). The receptor interaction most implicated in producing classic psychedelic drug effects is agonist or partial agonist activity at serotonin (5-HT) receptor type 2A (5-HT2A) (Nichols, 2016). A molecule’s propensity for 5-HT2A affinity and agonist activity predicts its potential for (and potency of) subjective psychedelic effects (Glennon et al., 1984; McKenna et al., 1990; Halberstadt, 2015; Nichols, 2016; Rickli et al., 2016). When a psychedelic drug’s 5-HT2A agonist activity is intentionally blocked using 5-HT2Aantagonist drugs (e.g., ketanserin), the subjective effects are blocked or attenuated in humans under psilocybin (Vollenweider et al., 1998; Kometer et al., 2013), LSD (Kraehenmann et al., 2017a,b; Preller et al., 2017), and ayahuasca (Valle et al., 2016). Importantly, while the above evidence makes it clear that 5-HT2A activation is a necessary (if not sufficient) mediator of the hallmark subjective effects of classic psychedelic drugs, this does not entail that 5-HT2A activation is the sole neurochemical cause of all subjective effects. For example, 5-HT2A activation might trigger neurochemical modulations ‘downstream’ (e.g., changes in glutamate transmission) which could also play causal roles in producing psychedelic effects (Nichols, 2016). Moreover, most psychedelic drug molecules activate other receptors in addition to 5-HT2A (e.g., 5-HT1A, 5-HT2C, dopamine, sigma, etc.) and these activations may importantly contribute to the overall profile of subjective effects even if 5-HT2A activation is required for their effects to occur (Ray, 2010, 2016).
How does psychedelic drug-induced 5-HT2A receptor agonism change the behavior of the host neuron? Generally, 5-HT2A activation has a depolarizing effect on the neuron, making it more excitable (more likely to fire) (Andrade, 2011; Nichols, 2016). Importantly, this does not necessarily entail that 5-HT2Aactivation will have an overall excitatory effect throughout the brain, particularly if the excitation occurs in inhibitory neurons (Andrade, 2011). This important consideration (captured by the adage ‘one neuron’s excitation is another neuron’s inhibition’) should be kept in mind when tracing causal links in the pharmaco-neurophysiology of psychedelic drug effects.
The concept of functional connectivity rests upon fMRI brain imaging observations that reveal temporal correlations of activity occurring in spatially remote regions of the brain which form highly structured patterns (brain networks) (Buckner et al., 2013). Imaging of brains during perceptual or cognitive task performance reveals patterns of functional connectivity known as functional networks; e.g., control network, dorsal attention network, ventral attention network, visual network, auditory network, and so on. Imaging brains in taskless resting conditions reveals resting-state functional connectivity (RSFC) and structured patterns of RSFC known as resting state networks (RSNs; Deco et al., 2011). One particular RSN, the default mode network (DMN; Buckner et al., 2008), increases activity in the absence of tasks and decreases activity during task performance (Fox and Raichle, 2007). DMN activity is strong during internally directed cognition and a variety of other ‘metacognitive’ functions (Buckner et al., 2008). DMN activation in normal waking states exhibits ‘inverse coupling’ or anticorrelation with the activation of task-positive functional networks, meaning that DMN and functional networks are often mutually exclusive; one deactivates as the other activates and vice versa (Fox and Raichle, 2007).
Taken together, the recently discovered neurophysiological correlates of subjective psychedelic effects present an important puzzle for 21st-century neuroscience. A key clue is that 5-HT2A receptor agonism leads to desynchronization of oscillatory activity, disintegration of intrinsic integrity in the DMN and related brain networks, and an overall brain dynamic characterized by increased between-network global functional connectivity, expanded signal diversity, and a larger repertoire of structured neurophysiological activation patterns. Crucially, these characteristic traits of psychedelic brain activity have been correlated with the phenomenological dynamics and intensity of subjective psychedelic effects.
21st-Century Theories of Psychedelic Drug Effects
Entropic Brain Theory
Entropic Brain Theory (EBT; Carhart-Harris et al., 2014) links the phenomenology and neurophysiology of psychedelic effects by characterizing both in terms of the quantitative notions of entropy and uncertainty. Entropy is a quantitative index of a system’s (physical) disorder or randomness which can simultaneously describe its (informational) uncertainty. EBT “proposes that the quality of any conscious state depends on the system’s entropy measured via key parameters of brain function” (Carhart-Harris et al., 2014, p. 1). Their hypothesis states that hallmark psychedelic effects (e.g., perceptual destabilization, cognitive flexibility, ego dissolution) can be mapped directly onto elevated levels of entropy/uncertainty measured in brain activity, e.g., widened repertoire of functional connectivity patterns, reduced anticorrelation of brain networks, and desynchronization of RSN activity. More specifically, EBT characterizes the difference between psychedelic states and normal waking states in terms of how the underlying brain dynamics are positioned on a scale between the two extremes of order and disorder—a concept known as ‘self-organized criticality’ (Beggs and Plenz, 2003). A system with high order (low entropy) exhibits dynamics that resemble ‘petrification’ and are relatively inflexible but more stable, while a system with low order (high entropy) exhibits dynamics that resemble ‘formlessness’ and are more flexible but less stable. The notion of ‘criticality’ describes the transition zone in which the brain remains poised between order and disorder. Physical systems at criticality exhibit increased transient ‘metastable’ states, increased sensitivity to perturbation, and increased propensity for cascading ‘avalanches’ of metastable activity. Importantly, EBT points out that these characteristics are consistent with psychedelic phenomenology, e.g., hypersensitivity to external stimuli, broadened range of experiences, or rapidly shifting perceptual and mental contents. Furthermore, EBT uses the notion of criticality to characterize the difference between psychedelic states and normal waking states as it “describes cognition in adult modern humans as ‘near critical’ but ‘sub-critical’—meaning that its dynamics are poised in a position between the two extremes of formlessness and petrification where there is an optimal balance between order and flexibility” (Carhart-Harris et al., 2014, p. 12). EBT hypothesizes that psychedelic drugs interfere with ‘entropy-suppression’ brain mechanisms which normally sustain sub-critical brain dynamics, thus bringing the brain “closer to criticality in the psychedelic state” (Carhart-Harris et al., 2014, p. 12).
Integrated Information Theory
Integrated Information Theory (IIT) is a general theoretical framework which describes the relationship between consciousness and its physical substrates (Oizumi et al., 2014; Tononi, 2004, 2008). While EBT is already loosely consistent with the core principles of IIT, Gallimore (2015) demonstrates how EBT’s hypotheses can be operationalized using the technical concepts of the IIT framework. Using EBT and recent neuroimaging data as a foundation, Gallimore develops an IIT-based model of psychedelic effects. Consistent with EBT, this IIT-based model describes the brain’s continual challenge of minimizing entropy while retaining flexibility. Gallimore formally restates this problem using IIT parameters: brains attempt to optimize the give-and-take dynamic between cause-effect information and cognitive flexibility. In IIT, a (neural) system generates cause-effect information when the mechanisms which make up its current state constrain the set of states which could casually precede or follow the current state. In other words, each mechanistic state of the brain: (1) limits the set of past states which could have causally given rise to it, and (2) limits the set of future states which can causally follow from it. Thus, each current state of the mechanisms within a neural system (or subsystem) has an associated cause-effect repertoire which specifies a certain amount of cause-effect information as a function of how stringently it constrains the unconstrained state repertoire of all possible system states. Increasing the entropy within a cause-effect repertoire will in effect constrain the system less stringently as the causal possibilities are expanded in both temporal directions as the system moves closer to its unconstrained repertoire of all possible states. Moreover, increasing the entropy within a cause-effect repertoire equivalently increases the uncertainty associated with its past (and future) causal interactions. Using this IIT-based framework, Gallimore (2015)argues that, compared with normal waking states, psychedelic brain states exhibit higher entropy, higher cognitive flexibility, but lower cause-effect information.
The first modern brain imaging measurements in humans under psilocybin yielded somewhat unexpected results: reductions in oscillatory power (MEG) and cerebral blood flow (fMRI) correlated with the intensity of subjective psychedelic effects (Carhart-Harris et al., 2012; Muthukumaraswamy et al., 2013). In their discussion, the authors suggest that their findings, although surprising through the lens of commonly held beliefs about how brain activity maps to subjective phenomenology, may actually be consistent with a theory of brain function known as the free energy principle (FEP; Friston, 2010).
In one model of global brain function based on the free-energy principle (Friston, 2010), activity in deep-layer projection neurons encodes top-down inferences about the world. Speculatively, if deep-layer pyramidal cells were to become hyperexcitable during the psychedelic state, information processing would be biased in the direction of inference—such that implicit models of the world become spontaneously manifest—intruding into consciousness without prior invitation from sensory data. This could explain many of the subjective effects of psychedelics (Muthukumaraswamy et al., 2013, p. 15181).
The four key features identified in filtration and psychoanalytic accounts from the late 19th and early 20th century continue to operate in 21st-century cognitive neuroscience: (1) psychedelic drugs produce their characteristic diversity of effects because they perturb adaptive mechanisms which normally constrain perception, emotion, cognition, and self-reference, (2) these adaptive mechanisms can develop pathologies rooted in either too much or too little constraint (3) psychedelic effects appear to share elements with psychotic symptoms because both involve weakened constraints (4) psychedelic drugs are therapeutically useful precisely because they offer a way to temporarily inhibit these adaptive constraints. It is on these four points that EBT, IIT, and PP seem consistent with each other and with earlier filtration and psychoanalytic accounts. EBT and IIT describe psychedelic brain dynamics and link them to phenomenological dynamics, while PP describes informational principles and plausible neural information exchanges which might underlie the larger-scale dynamics described by EBT and IIT. Certain descriptions of neural entropy-suppression mechanisms (EBT), cause-effect information constraints (IIT), or prediction-error minimization strategies (PP, FEP) are loosely consistent with Freud’s ego and Huxley’s cerebral reducing valve.
Qualia Computing comment: As you can see above, 21st century theories of psychedelic action have a lot of interesting commonalities. A one-line summary of what they all agree on could be: Psychedelics increase the available state-space of consciousness by removing constraints that are normally imposed by standard brain functioning. That said, they do not make specific predictions about valence. That is, they leave the question of “which alien states of consciousness will feel good and which ones will feel bad” completely unaddressed. In the following posts about the presentations of members of the Qualia Research Institute at The Science of Consciousness 2018 you will see how, unlike other modern accounts, our Qualia Formalist approach to consciousness can elucidate this matter.