Unifying theories of psychedelic drug effects

This review (2018) investigates historic and current theories on how psychedelics work. The work is first grounded by describing the (subjective) effects of psychedelics. The paper concludes that a commonality between theories is that ‘normal’ brain processes are disturbed. Thus leading to more unconstrained thoughts under psychedelics.


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.”

Author: Link R. Swanson


This paper is included in our ‘Top 10 Articles for Psychedelic Novices



Western science began its systematic investigations into the unique effects of mescaline 125 years ago, and expanded to include drugs like DMT, LSD, and psilocybin in a ‘second wave’ of psychedelic science. A ‘third wave’ of psychedelic science has recently emerged with its own set of sleuths on the trail.

Existing theoretical hurdles span five major gaps in understanding of psychedelic drugs, including how they produce such a broad diversity of subjective effects, and how they cause large-scale changes in brain activity.

The third gap is that we do not know how psychedelic drug-induced brain activity maps onto acute subjective phenomenological changes in perception, emotion, cognition, and sense of self.

Scientists try to produce a single theory that can account for many phenomena using a minimal set of principles. Unfortunately, there is no existing unifying theory of psychedelic drug effects, but there are enduring abstract principles that recur across more than a century of theoretical efforts.

Cognitive neuroscience offers formalized frameworks and general principles designed to track and model the neural correlates of perception, emotion, cognition, and consciousness. These frameworks can be used to explain psychedelic drug effects at intermediate levels somewhere between pharmacology and phenomenology.

I review theories of psychedelic drug effects, including acute subjective phenomenological properties, long-term clinical outcomes from psychedelic-assisted therapies, and recent neurophysiological research in humans under psychedelic drugs. I also review select 21st-century theories of psychedelic effects that have been developed within cognitive neuroscience frameworks.


There are dozens of molecules known to cause psychedelic-like effects, but this review focuses on four classic psychedelic drugs: LSD, DMT, psilocybin, and mescaline. Effects unfold temporally over a drug session, and are influenced by non-drug factors such as personality, pre-dose mood, drug session environment, and external stimuli.

The subjective phenomenology of psychedelic effects can be characterized using validated psychometric instruments consisting of self-report questionnaires and rating scales, though some of these rating scales may be in need of further validation using modern statistical techniques.

Perceptual Effects

Perceptual effects include intensification, distortion, illusion, mental imagery, elementary hallucination, and complex hallucinations. The external world is experienced as if in higher resolution, seemingly more crisp and detailed, often accompanied by a distinct sense of ‘clarity’ or ‘freshness’ in the environment.

Perceptual distortions and illusions are extremely common, and can affect motion perception, object completion, binocular rivalry, and many other areas of perception.

In complex hallucinations, the visual field can become permeated with elaborate structural motifs, landscapes, cities, galaxies, plants, animals, and human (and non-human) beings.

Psychedelic drugs cause visual hallucinations that can be augmented and intensified, and are intimately linked with emotional and cognitive effects. These visual hallucinations can be modulated by both verbal and musical auditory stimuli, but classification of these effects as ‘true’ synaesthesia is actively debated.

Somatosensory perception can be drastically altered, including body image, size, shape, and location, and sense of time and causal sequence can be lost.

Emotional Effects

Psychedelics induce unique states of euphoria characterized by involuntary grinning, uncontrollable laughter, silliness, giddiness, playfulness, and exuberance. Negatively experience emotions are often accompanied by a general sense of losing control, however, the majority of emotional psychedelic effects are experienced as positive.

Classic psychedelic drugs can promote feelings of trust, empathy, bonding, closeness, tenderness, forgiveness, acceptance, and connectedness. These effects can be modulated by all types of external stimuli, especially music.

Cognitive Effects

Precise characterization of cognitive psychedelic effects has proven enigmatic and paradoxical. Microdoses of the drug have been anecdotally associated with improvements in cognitive performance, but this claim urgently requires empirical verification through controlled research.

Psilocybin and LSD increase divergent thinking, use of unlikely language patterns or word associations, expansion of semantic activation, and attribution of meaning to perceptual stimuli, especially musical stimuli. These effects can remain for up to 2 weeks after the main acute drug effects have dissipated.

Ego Effects and Ego Dissolution Experiences

Under peyote, the line of demarcation between object and subject seemed to be changed. The body, the ego, became objective and the objects became subjective. Effects on sense of self and ego occur along a dose-dependent range spanning from subtle to drastic. Psychedelic drugs can cause ego dissolution experiences, which are described as the dissolution of the sense of self and the loss of boundaries between self and world. These experiences can be driven and modulated by external stimuli, most notably music. Subjects who experienced ‘complete’ ego dissolution in psychedelic-assisted therapy were more likely to evidence positive clinical outcomes and long-term changes in life outlook.

Clinical Efficacy and Long-Term Effects

Mescaline-assisted therapies showed promising results during first-wave psychedelic science, and second-wave psychedelic research on LSD-assisted therapies has produced significant evidence for the therapeutic utility of psychedelic drugs in treating a wide range of mental health issues.

A single psychedelic experience can increase optimism for at least 2 weeks and can produce lasting changes in personality trait openness. Regular ayahuasca users report improved cognitive functioning and increased positive personality traits compared with matched controls.


Classic psychedelic drugs produce broad diversity of acute subjective effects in perceptual, emotional, cognitive, and self-related domains. These effects are related to long-term changes in mental health, personality, and behavior.


First-wave and second-wave psychedelic scientists observed that psychedelic drugs produce hallucinations, altered self-reference, and perceptual distortions, and they also observed that psychedelic drugs expand the total range of contents presented subjectively in our perceptual, emotional, cognitive, and self-referential experience.

Model Psychoses Theory

Lewin (1894, 1927) reported that the peyote cactus had psychedelic properties, and scientists began consuming the cactus and observing its effects. Later, Klüver (1926) ingested peyote and completed standard psychophysical measures, but the pathology aspect became the dominant focus of ensuing mescaline research paradigms.

Model psychoses theory began long before any of the classic psychedelic drugs became known to Western science. Kraepelin founded “pharmacopsychology” by dosing himself and his students with various psychoactive drugs, and later argued that mescaline was the ideal chemical agent for model psychoses.

Model psychoses theory was an idealistic paradigm for researching psychoses that was already in use before Western science ‘discovered’ classic psychedelic drugs. It inspired a search for common neural correlates and led to the hypothesis that serotonin might play a role in regulating mental function.

At the 1955 Second Conference on Neuropharmacology, the whole class of drugs was dubbed psychotomimetic. However, psychotomimetic drugs do not share functional or structural properties in their underlying biology or phenomenology with psychoses, and thus we still need a theory of how psychotomimetic drugs work.

Model psychoses theory was challenged by the fact that drugs capable of inducing psychotic symptoms could simultaneously be capable of treating them. Osmond declared ‘psychotomimetic’ an outmoded term, arguing that the effects of these drugs could not be captured wholly in terms of psychopathology.

Filtration Theory

Osmond (1957) argued that the ‘psychotomimetic’ class of drugs needed a more appropriate name. Aldous Huxley (1953) described the core idea of psychedelic effects as ‘mind-manifesting’.

Huxley’s letter can help unpack Osmond’s new term psychedelic, which he saw as a “device” engaged in a continuous process of elimination and inhibition.

After psychological maturity, a cerebral reducing valve emerges which limits waking life to a world fabricated by our everyday, biologically useful and socially conditioned perceptions, thoughts and feelings.

Huxley borrowed the core idea from 19th-century filtration theory accounts of various mental phenomena, including nitrous oxide’s peculiar state of mind. He convinced Osmond that it was important to reflect this principle in scientific descriptions of the effects of LSD and mescaline.

Osmond’s (1957) proposed name-change for drugs was intended to capture the spirit of filtration theory. This new descriptive model was highly applicable to first-person experiences with mescaline and LSD.

Osmond argued that the pharmacological disruption of hypothetical inhibitory brain mechanisms could explain the diverse range of psychedelic effects and their relationship to psychotic symptoms.

The brain’s selective filtration mechanisms can develop pathological characteristics in two fundamentally distinct ways: either a chronically overactive filter limits too much of the mind, or a chronically underactive filter allows too much ‘Mind at Large’ to enter conscious awareness.

Filtration theory addressed the paradoxical “hair of the dog” issue by suggesting that psychedelic drugs temporarily disable brain filtration mechanisms, which can allow patients and therapists to work outside of the patient’s everyday (pathological) inhibitory mechanisms.

Osmond and Huxley argued that filtration theory concepts were consistent with the subjective phenomenology and therapeutic efficacy of psychedelic drugs. According to Huxley, LSD and mescaline inhibit the normal self and ordinary brain activity, thus permitting the ‘other world’ to rise into consciousness. Osmond’s ‘mind-manifesting’ (psyche) (delic) name suggests that these drugs permit latent aspects of mind to rise into conscious awareness.

Psychoanalytic Theory

Freud (1895) developed an elaborate theoretical account of mental phenomena which placed great emphasis on inhibition mechanisms in the nervous system. He divided the psyche into two fundamentally distinct modes of activity: the primary process and the secondary process.

The ego is a secondary process that emerges during ontogenetic development and solidifies with adult maturity. It is required for certain aspects of perceptual processing, directed attention, reality-testing, sense of linear time, and higher cognitive processes.

Psychedelic drugs produce dreamlike visions and modes of cognition that feature symbolic imagery, conceptual paradox, and other hallmark characteristics of the primary process. This allows the primary process to spill into conscious awareness, resulting in perceptual instability, wildly vivid imagination, emotional intensity, conceptual paradox, and loss of usual self-boundaries.

Psychedelic drugs disrupt the structure of the ego by altering perception. These disturbances make it impossible for the ego to integrate the evidence of the senses and to coordinate its activities.

Freud hypothesized that the ego is sustained by a delicate balance of ‘neuronal energy’. Psychedelic drugs perturb integrative mechanisms that normally bind and shape exogenous and endogenous excitation into the structure of the ego.


The above analysis of first-wave and second-wave theories suggests that psychedelic drugs inhibit a core brain mechanism that normally functions to reduce or filter mental phenomena into an evolutionarily adaptive container. This mechanism can behave pathologically, and psychedelic drugs have therapeutic utility via their ability to temporarily inhibit it.

A psychedelic drug molecule affects a neuron by binding to and altering the conformation of receptors on the surface of the neuron. This alteration produces subjective psychedelic effects. When the 5-HT2A agonist activity of psychedelic drugs is intentionally blocked using 5-HT2A antagonist drugs, the subjective effects of these drugs are blocked or attenuated in humans under psilocybin, LSD, and ayahuasca. However, 5-HT2A activation may not be the sole neurochemical cause of all subjective effects.

Psychedelic drug-induced 5-HT2A receptor agonism changes the behavior of the host neuron by making it more excitable. However, this does not necessarily mean that the excitation will have an overall excitatory effect throughout the brain.

MEG and EEG equipment measures the electromagnetic disturbances produced by large neural populations, and these measurements can be correlated with distinct brain states, including waking ‘resting’ state, various attentional tasks, anesthesia, REM sleep, and deep sleep.

Studies consistently show that the power of alpha-band oscillations is reduced under ayahuasca, psilocybin, and LSD, and that this power reduction is correlated with intensity of subjective visual effects, ego-dissolution effects, and mystical-type experiences.

fMRI imaging of the brain reveals temporal correlations of activity occurring in spatially remote regions of the brain that form highly structured patterns (brain networks). The default mode network (DMN) is a type of RSN that increases activity in the absence of tasks and decreases activity during task performance.

Under psychedelic drugs, the functional connectivity between key ‘hub’ areas is reduced, the strength of the default mode network is weakened, the anticorrelation between networks becomes active, and the overall repertoire of explored functional connectivity motifs is substantially expanded compared with normal waking states.

Taken together, the neurophysiological correlates of subjective psychedelic effects present a puzzle for 21st-century neuroscience. 5-HT2A receptor agonism leads to desynchronization of oscillatory activity, disintegration of intrinsic integrity in the DMN, and increased signal diversity.


Recent theoretical efforts to understand psychedelic drug effects have taken advantage of existing frameworks from cognitive neuroscience, which are designed to track the key neurodynamic principles of human perception, emotion, cognition, and consciousness. These frameworks suggest that psychedelic drugs interfere with the integrity of neurobiological information-processing constraint mechanisms.

EBT proposes that hallmark psychedelic effects can be mapped directly onto elevated levels of entropy/uncertainty measured in brain activity, and that the difference between psychedelic states and normal waking states is positioned on a scale between the two extremes of order and disorder. Criticality is a transition zone between order and disorder, in which the brain exhibits increased sensitivity to perturbation, hypersensitivity to external stimuli, and rapidly shifting mental contents. Entropic Brain Theory (EBT) uses the notion of criticality to characterize the difference between psychedelic states and normal waking states, and hypothesizes that psychedelic drugs interfere with ‘entropy-suppression’ brain mechanisms which normally sustain sub-critical brain dynamics.

Carhart-Harris and Friston (2010) hypothesized that Freud’s primary process was a high-entropy brain dynamic that operated at criticality, while Freud’s secondary process was a lower-entropy brain state that sustained a sub-critical dynamic via a key neurobiological entropy-suppression mechanism – the ego.

Psychedelic drugs weaken the DMN, which constrains cortical and subcortical activity, and allow the emergence of more uncertain primary consciousness. This is reflected in the increased levels of between-network functional connectivity and the greater variety of explored functional connectivity motifs.

Carhart-Harris et al. (2014) argue that the DMN’s organizational stronghold over brain activity can be both an evolutionary advantage and a source of pathology, and that increased DMN activity and connectivity in mild depression promotes concerted introspection and an especially diligent style of reality-testing.

Psychedelic drugs work by dismantling reinforced patterns of negative thought and behavior by breaking down the stable spatiotemporal patterns of brain activity upon which they rest.

EBT formulates all four theoretical features identified in filtration and psychoanalytic accounts, but uses 21st-century empirical data plugged into the quantitative concepts of entropy, uncertainty, criticality, and functional connectivity.

Integrated Information Theory

Using Integrated Information Theory (IIT) to describe the relationship between consciousness and its physical substrates, Gallimore (2015) develops a model of psychedelic effects that is consistent with EBT. This model describes the brain’s continual challenge of minimizing entropy while retaining flexibility.

Each mechanistic state of the brain has a cause-effect repertoire that limits the set of past states that could have causally given rise to it, and limits the set of future states that can causally follow from it.

Human brains exhibit a larger overall repertoire of neurophysiological states under psychedelic drugs, exploring a greater diversity of states in a more random fashion. This increases flexibility but decreases precision and control as the subjective boundaries which normally demarcate distinct cognitive concepts and perceptual objects dissolve.

Predictive Processing

Modern brain imaging measurements in humans under psilocybin yielded somewhat unexpected results: reductions in oscillatory power and cerebral blood flow correlated with the intensity of subjective psychedelic effects.

FEP is a formulation of a broader conceptual framework emerging in cognitive neuroscience known as predictive processing, which has links to bayesian brain hypothesis, predictive coding, and earlier theories of perception and cognition.

The brain works to minimize its own prediction error by matching the expected bottom-up synaptic activity at lower-level areas with top-down predictions that adequately explain the bottom-up (evidence) signals. Mismatches generate prediction error signals that propagate upward to be explained away by yet higher levels of processing anatomy. This recurrent neural processing scheme approximates Bayesian inference, as the brain continually maps measured bodily effects to different sets of possible causes. Prior constraints allow the system to narrow the hypothesis space, and hyperpriors allow the system to rule out large swaths of possibilities, drastically narrowing the hypothesis space, making explanation more tractable. PP states that brains are neural generative models built from linked hierarchies of priors.

PP holds that our perceptions of external objects recruit the same synaptic pathways that enable our capacity for mental imagery, dreaming, and hallucination. This simulation of our own virtual reality is crucial to our ability to perceive the external world.

Psychedelic molecules perturb predictive processing by causing hyperexcitation in layer V pyramidal neurons, which causes endogenous simulations to ‘run wild’ and awareness to become more imaginative, dreamlike, and hallucinatory.

PP ties into filtration theories and psychoanalytic accounts by describing rampant internal simulations of reality, not revealing more of the external world. However, active inference, a key principle of FEP, resolves the apparent tensions between Osmond’s ‘mind-manifesting’ model and Huxley’s ‘world-manifesting’ model.

Internal generative models could expand our inner world of feelings, thoughts, and mental imagery, and could explain the perception-hallucination continuum of psychedelic drug effects.

Muthukumaraswamy et al. (2013) described a recurrent back-and-forth give-and-take between colliding top-down and bottom-up signals, and Corlett et al. (2009) hypothesized that LSD hallucinations result from noisey, unpredictable bottom-up signaling in the context of preserved and perhaps enhanced top-down processing.

Several hypotheses exist about how psychedelic molecules perturb top-down processing, including hyperactivation, reduced influence of signals from higher cortical areas, interference with multisensory integration processes, and changes in the composition and level of detail specified by top-down signals.

In normal adult waking states, higher-level cortical structures can successfully predict and explain the activity of lower-level areas, but in non-ordinary states, this function may be perturbed, compromising the hierarchical organization and suppressive capacity of the intrinsic networks.

Similar PP-based theories of psychedelic ego dissolution have been proposed without invoking Freud. Letheby and Gerrans (2017) use the PP framework to recast the psychoanalysis-based theories of LSD ego effects, which argue that psychedelic drugs cause an unbinding of stimuli that are normally processed according to self-binding multisensory integration mechanisms.

Pink-Hashkes et al. (2017, p. 2907) argue that psychedelic drugs cause the brain to issue more detailed (less abstract) ‘decomposed’ predictions that “fit less data than the ‘usual’ broad prediction”. These more detailed predictions lead to more prediction error.

In summary, the current state of predictive processing-based theories of psychedelic effects reveals a divergent mix of heterogeneous ideas and conflicting hypotheses. Yet there seems to be a core intuition that transcends the conceptual variance here: psychedelic drugs interfere with established priors that normally constrain perception and cognition.


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: psychedelic drugs perturb adaptive mechanisms that normally constrain perception, emotion, cognition, and self-reference, and these adaptive mechanisms can develop pathologies rooted in either too much or too little constraint.

In this review, I have highlighted a handful of formalized frameworks that are just beginning to be used to account for psychedelic effects. These frameworks propose that psychedelic drugs inhibit neurophysiological constraints in order to produce their diverse phenomenological, psychotomimetic, and therapeutic effects.

Psychedelic drug effects are complex and evolve under diverse environmental circumstances. Many doubt the possibility of a grand unified theory of brain function, and PP in particular threatens metaphysical disaster if taken as a unified theory.

Psychedelic drugs offer a unique way to iteratively develop and test big-picture explanatory frameworks for brain function, since they can be used to probe the links between neurochemistry and neural computation across multiple layers of neuroanatomy and phenomenology.

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