Excerpts from Unifying Theories of Psychedelic Drug Effects (2018) by Link Swanson (these are just key quotes; the full paper is worth reading)

Abstract

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.

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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-HT_2A) (Nichols, 2016). A molecule’s propensity for 5-HT_2A 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-HT_2A agonist activity is intentionally blocked using 5-HT_2A antagonist 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-HT_2A activation is a necessary (if not sufficient) mediator of the hallmark subjective effects of classic psychedelic drugs, this does not entail that 5-HT_2A activation is the sole neurochemical cause of all subjective effects. For example, 5-HT_2A 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-HT_2A (e.g., 5-HT_1A, 5-HT_2C, dopamine, sigma, etc.) and these activations may importantly contribute to the overall profile of subjective effects even if 5-HT_2A activation is required for their effects to occur (Ray, 2010, 2016).

How does psychedelic drug-induced 5-HT_2A receptor agonism change the behavior of the host neuron? Generally, 5-HT_2A 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-HT_2Aactivation 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.

In mammalian brains, neurons tend to ‘fire together’ in synchronized rhythms known as temporal oscillations (brain waves). MEG and EEG equipment measure the electromagnetic disturbances produced by the temporal oscillations of large neural populations and these measurements can be quantified according to their amplitude (power) and frequency (timing) (Buzsáki and Draguhn, 2004). Specific combinations of frequency and amplitude can be correlated with distinct brain states, including waking ‘resting’ state, various attentional tasks, anesthesia, REM sleep, and deep sleep (Tononi and Koch, 2008; Atasoy et al., 2017a). In what ways do temporal oscillations change under psychedelic drugs? MEG and EEG studies consistently show reductions in oscillatory power across a broad frequency range under ayahuasca (Riba et al., 2002, 2004; Schenberg et al., 2015; Valle et al., 2016), psilocybin (Muthukumaraswamy et al., 2013; Kometer et al., 2015; Schartner et al., 2017), and LSD (Carhart-Harris et al., 2016c; Schartner et al., 2017). Reductions in the power of alpha-band oscillations, localized mainly to parietal and occipital cortex, have been correlated with intensity of subjective visual effects—e.g., ‘I saw geometric patterns’ or ‘My imagination was extremely vivid’—under psilocybin (Kometer et al., 2013; Muthukumaraswamy et al., 2013; Schartner et al., 2017) and ayahuasca (Riba et al., 2004; Valle et al., 2016). Under LSD, reductions in alpha power still correlated with intensity of subjective visual effects but associated alpha reductions were more widely distributed throughout the brain (Carhart-Harris et al., 2016c). Furthermore, ego-dissolution effects and mystical-type experiences (e.g., ‘I experienced a disintegration of my “self” or “ego”’ or ‘The experience had a supernatural quality’) have been correlated with reductions in alpha power localized to anterior and posterior cingulate cortices and the parahippocampal regions under psilocybin (Muthukumaraswamy et al., 2013; Kometer et al., 2015) and throughout the brain under LSD (Carhart-Harris et al., 2016c).

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).

In what ways does brain network connectivity change under psychedelic drugs? First, functional connectivity between key ‘hub’ areas—mPFC and PCC—is reduced. Second, the ‘strength’ or oscillatory power of the DMN is weakened and its intrinsic functional connectivity becomes disintegrated as its component nodes become decoupled under psilocybin (Carhart-Harris et al., 2012, 2013), ayahuasca (Palhano-Fontes et al., 2015), and LSD (Carhart-Harris et al., 2016c; Speth et al., 2016). Third, brain networks that normally show anticorrelation become active simultaneously under psychedelic drugs. This situation, which can be described as increased between-network functional connectivity, occurs under psilocybin (Carhart-Harris et al., 2012, 2013; Roseman et al., 2014; Tagliazucchi et al., 2014), ayahuasca (Palhano-Fontes et al., 2015) and especially LSD (Carhart-Harris et al., 2016c; Tagliazucchi et al., 2016). Fourth and finally, the overall repertoire of explored functional connectivity motifs is substantially expanded and its informational dynamics become more diverse and entropic compared with normal waking states (Tagliazucchi et al., 2014, 2016; Alonso et al., 2015; Lebedev et al., 2016; Viol et al., 2016; Atasoy et al., 2017b; Schartner et al., 2017). Notably, the magnitude of occurrence of the above four neurodynamical themes correlates with subjective intensity of psychedelic effects during the drug session. Furthermore, visual cortex is activated during eyes-closed psychedelic visual imagery (de Araujo et al., 2012; Carhart-Harris et al., 2016c) and under LSD “the early visual system behaves ‘as if’ it were receiving spatially localized visual information” as V1-V3 RSFC is activated in a retinotopic fashion (Roseman et al., 2016, p. 3036).

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-HT_2A 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.

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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).

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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.

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Predictive Processing

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).

What is FEP? “In this view, the brain is an inference machine that actively predicts and explains its sensations. Central to this hypothesis is a probabilistic model that can generate predictions, against which sensory samples are tested to update beliefs about their causes” (Friston, 2010). FEP is a formulation of a broader conceptual framework emerging in cognitive neuroscience known as predictive processing (PP; Clark, 2013)¹⁰. PP has links to bayesian brain hypothesis (Knill and Pouget, 2004), predictive coding (Rao and Ballard, 1999), and earlier theories of perception and cognition (MacKay, 1956; Neisser, 1967; Gregory, 1968) dating back to Helmholtz (1925) who was inspired by Kant (1996; see Swanson, 2016). At the turn of the 21st century, the ideas of Helmholtz catalyzed innovations in machine learning (Dayan et al., 1995), new understandings of cortical organization (Mumford, 1992; Friston, 2005), and theories of how perception works (Kersten and Yuille, 2003; Lee and Mumford, 2003).

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Conclusion

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.

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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.