Pharmacological, Neural, and Psychological Mechanisms underlying Psychedelics: A Critical Review

This review (2022) explores three analysis levels of psychedelic therapeutic mechanisms; 1) biochemical (e.g. neuroplasticity), 2) neural (e.g. less top-down signalling), and 3) psychological level (e.g. belief change). The review then maps out how the levels can be bridged and provide directions for future studies.


“This paper provides a critical review of several possible mechanisms at different levels of analysis underlying the effects and therapeutic potential of psychedelics. At the (1) biochemical level, psychedelics primarily affect the 5-HT2a receptor, increase neuroplasticity, offer a critical period for social reward learning and have anti-inflammatory properties. At the (2) neural level, psychedelics have been associated with reduced efficacy of thalamo-cortical filtering, the loosening of top-down predictive signaling and an increased sensitivity to bottom-up prediction errors, and activation of the claustro-cortical-circuit. At the (3) psychological level, psychedelics have been shown to induce altered and affective states, they affect cognition, induce belief change, exert social effects and can result in lasting changes in behavior. We outline the potential for a unifying account of the mechanisms underlying psychedelics and contrast this with a model of pluralistic causation. Ultimately, a better understanding of the specific mechanisms underlying the effects of psychedelics could allow for a more targeted therapeutic approach. We highlight current challenges for psychedelic research and provide a research agenda to foster insight in the causal-mechanistic pathways underlying the efficacy of psychedelic research and therapy.”

Authors: Michiel van Elk & David B. Yaden


This paper provides a critical review of several possible mechanisms underlying the effects and therapeutic potential of psychedelics. It highlights current challenges for psychedelic research and provides a research agenda to foster insight in the causal-mechanistic pathways underlying the efficacy of psychedelic research and therapy.

  1. Introduction

Psychedelic drugs are psychoactive substances that produce substantial alterations to perception, cognition, and emotion. They have been used in ritual and religious contexts across several cultures for hundreds of years, and are increasingly used recreationally in Europe and the US.

We are currently witnessing a psychedelic revival in scientific and clinical research, with preliminary data suggesting that psychedelics may have a strong therapeutic potential for the treatment of several psychiatric disorders, including severe depression, addiction, obsessive-compulsive disorder, anxiety related to a life-threatening medical diagnosis, and cancer-related anxiety disorders.

Several different explanations have been offered as to how psychedelics could exert their therapeutic effects, including mystical-like or self-transcendent experiences, a loosening of prior beliefs, and an increase in brain-derived neurotrophic factor. However, an integrative perspective is lacking.

In this paper, we review the evidence regarding the different potential mechanisms of action of psychedelics at the pharmacological, neural and psychological levels. We conclude by highlighting current challenges for psychedelic research.

Our model could be extended to include social, contextual, and cultural levels of analysis as well, but we limit ourselves to discussing contemporary research on the pharmacological, neural, and psychological mechanisms involved in psychedelics.

Classic psychedelics are serotonergic hallucinogenic substances, such as LSD, psilocybin, and DMT, which have a common mechanism of action, consisting of partial agonism for the serotonin 5-HT2a G protein-couple receptors. Ketanserin, a 5-HT2A receptor antagonist, prevents the typical subjective effects associated with psychedelics to occur.

Psychedelics affect many cognitive, perceptual, and emotional functions through the partial agonism of the 5-HT2A receptor, which can be found in the pyramidal neurons in layer 5 of the neo-cortex, in the thalamus, and in the reticular nucleus.

Recent findings suggest that 5-HT2a receptor antagonism may not be the primary therapeutic mechanism of psilocybin, and that the therapeutic impact of psilocybin may be conveyed through other pharmacological mechanisms.

LSD and other psychedelics bind to many different receptors, including the 5-HT2A receptor. However, pre-treatment with the 5-HT1AR agonist buspirone reduced the effects of LSD on visual hallucinations.

LSD has been shown to activate the 5-HT2A and D2 receptors in different phases, but no study has directly evaluated the effect of blocking dopamine receptors on the subjective effects of LSD.

Psychedelics may affect the sensitivity to reward and stress by activating the trace amine-associated receptor (TAAR).

Psychedelics induce several pharmacological processes, including the 5-HT2A receptor activation, the critical period for social reward learning model and the anti-inflammatory model.

Classic psychedelics increase synaptic growth and complexity of the dendrites and the number of synapses in the brain, thereby increasing the number of connections between neurons. This is due to the increased expression of genes that encode for proteins that foster neuroplasticity and learning.

Psychedelics might increase neuroplasticity, which might have a therapeutic effect by fostering adaptive rewiring of neural circuits. However, more research is needed to establish the robustness of psychedelic-induced changes in BDNF and the downstream effects on neural plasticity.

Based on the observations of increased synaptic growth and density of neurons, psychedelics could be considered “psychoplastogens”, or substances capable of promoting rapid neural plasticity both structurally and functionally. People microdose psychedelics for a variety of different reasons, including cognitive enhancement, depression and anxiety. However, the psychoplastogen model is limited by its lack of specificity, and the actual efficacy of psychedelic microdosing remains a topic of ongoing debate.

Classic psychedelics like LSD and DOI increase levels of oxytocin, which is a hormone that results in strong feelings of empathy, connectedness and sociability. However, MDMA also induces strong pro-social and emotional effects, though possibly only for in-group members.

MDMA may open the critical period for social reward learning in rodents, which then results in oxytocin release, and may also be the case in classic psychedelics. However, this model may not account for the acute anti-depressant effects that have frequently been observed.

2.3 Anti-inflammatory model

Psychedelics affect genetic transcription through the activation of 5-HT2a receptors, which in turn activate an anti-inflammatory mechanism. This mechanism could potentially help to explain why psychedelics already have therapeutic effects after a single session with a classic psychedelic.

Psychedelics stimulate the 5HT2a receptor, increase glutamate and oxytocin levels, produce BDNF, and have an anti-inflammatory effect. This combination of effects may explain why psychedelics are effective for a wide range of disorders.

  1. Neurocognitive Mechanisms

There are several neuroscientific explanations for the effects of psychedelics at a brain-level, including the thalamo-cortical filter theory and the relaxed beliefs under psychedelics model.

Before presenting these different neural models, we briefly discuss the effects of psychedelics on cognitive and attentional processing. Psilocybin has an attention-disrupting effect, which is likely mediated by the 5-HT1AR receptor. Psychedelics impair cognitive and executive control, as well as working memory, and motor performance. The different neural theories discussed in this section each provide clues as to why this might be the case.

Psychedelics act by releasing sensory filters, which control the amount of sensory information sent to higher-level cortical regions. This causes the prefrontal cortex to have a reduced inhibitory control over the thalamic reticular nucleus, thereby resulting in an overload of information sent to other sensory brain regions.

The CSTC model suggests that the reduced gating of the thalamus is associated with different neural mechanisms, including excessive stimulation of the 5-HT2a receptors, blockade of NMDA receptors and increases in dopaminergic and GABAergic projections. This model fits well with the attentional impairments associated with psychedelics.

The CSTC model, which includes increased metabolic activity of the thalamus, may explain some of the neural and phenomenological effects observed under psychedelics, including an intensification of sensory processing bearing similarities to the psychotic state.

Psychedelics loosen prior predictions, while increasing sensitivity to bottom-up prediction error signaling, according to the REBUS model, which integrates the so-called entropic brain hypothesis with the free-energy principle.

Low doses of psychedelics induce perceptual effects, which may be related to the high density of 5-HT2a receptors in the visual system. These effects are exemplified by the phenomenon of breathing walls and the absence of correct prediction error updating under psychedelics.

Psychedelics affect the Default Mode Network (DMN), a set of strongly interrelated brain regions, which is involved in task-free processing, such as mind-wandering, self-referential processing and daydreaming. The strength of the decrease in DMN activity is related to self-reported ego-dissolution.

However, the decrease in DMN activity observed in this study is in apparent contrast with the earlier studies showing an increased activity in prefrontal areas associated with the psychedelic experience. This could be due to methodological differences between studies.

The REBUS model integrates insights from the entropic brain hypothesis, which states that the brain is in an increased state of disorder or entropy during psychedelic experiences. This increased entropy may explain the synesthetic experiences that are typically reported under psychedelics. The increased connectivity of the brain makes it more unpredictable which specific processing route information will take, which may account for the unpredictable effects of the psychedelic experience. The REBUS model can account for the disruptive effects of psychedelics on attention, as less precise prior expectations result in impaired attentional processing.

The REBUS model suggests that psychedelics may help treat disorders characterized by maladaptive hyperpriors, by temporarily loosening the grip of these rigid beliefs and by opening the door to new beliefs and insights. Psychedelics can loosen one’s prior beliefs and directly induce a new embodied experience of connectedness and self-transcendence, which can challenge one’s prior beliefs. The REBUS model has been criticized for its conceptual and methodological shortcomings, including the fact that the notion of entropy is not well defined and that the REBUS model suggests increased prediction error signaling under psychedelics.

The effects of psychedelics on the default mode network (DMN) are too generic to provide a sufficiently specific account, and additional confirmatory research is needed to test the predictions from the REBUS model.

The claustro-cortical-circuit (CCC) model is based on neuroimaging observations and proposes that the claustrum supports cortical network states, which is shown by the observation that direct activation of the claustrum through optogenetic imaging results in widespread cortical activation.

Psychedelics may cause a destabilization of canonical brain network states through the direct activation of 5-HT2a neurons in the claustrum and a decoupling between prefrontal areas and the claustrum. This may contribute to the decrease in cognitive control observed under the acute influence of psychedelics.

The CCC model is a promising theory that potentially accounts for some of the widespread effects of psychedelics on different brain networks, but more advanced imaging techniques, including ultra high field fMRI, are necessary to more clearly elucidate the flow of information between the claustrum and other brain regions.

Three prominent theoretical frameworks have been proposed to account for the psychedelic experience, which could involve inhibition of sensory gating, relaxed beliefs under psychedelics, or disengagement of executive control networks.

  1. Psychological Mechanisms

Psychedelics are often reported to induce complex, dynamic, and multifaceted experiences. These effects include altered and affective states, changes in cognition, belief change, social effects, and behavior change.

4.1 Altered and Affective states

Psychedelics induce an altered state of consciousness that is characterized by mystical experiences, feelings of awe, ego dissolution, and an enhanced perception of emotions. The concept of mystical experience was first used by William James in 1902, and is often rated in the same top-five life events as the birth of a child or the loss of a loved one. The psychedelically induced mystical state is difficult to put into words, and is best experienced from a first person perspective. However, the experience often yields specific insights, which are sometimes impossible to put into words. The psychedelic experience provides the person with a different perspective on their life, which enhances the perceived meaning and purpose. However, the mystical experience is a multi-dimensional construct that contains multiple cognitive and affective processes.

At higher doses, psychedelics can also occasion the experience of ego-dissolution, which is characterized by a complete loss of self-awareness. This experience has been related to an increased global connectivity between high-level association areas and the thalamus, a reduced alpha power in the posterior cingulate cortex, and a decreased activation of the default mode network.

Awe is a psychological construct that is elicited by the perception of vastness and results in a need to mentally accommodate the experience into one’s schemas. The sensory effects of psychedelics are a driving factor underlying the experience of awe.

In previous studies, it has been found that awe-experiences are characterized by a similar decrease of the default mode network (DMN) as has been observed for psychedelic experiences, suggesting some potentially similar underlying mechanisms. However, it remains to be determined how psychedelic-induced awe compares to nature-induced awe experiences.

Psychedelic experiences typically involve strong positive emotions, but some negative emotions as well. Psychedelics can bring hidden thoughts and cognitions to the surface, which can have an intense emotional valence.

Psychedelics are characterized by acute subjective effects that are transient and challenging, yet overall positive and meaningful with persisting positive effects. These effects are in stark contrast to psychosis, which tends to last for days/weeks and is mostly negative and has largely detrimental effects.

While public messaging around psychedelics was overly negative in valence and alarmist for several decades, recent literature on psychedelics seems to emphasize the positive aspects of the psychedelic experience.

The Challenging Experiences Questionnaire was developed to capture the effects that could occur during a bad trip. It has been found that a bad trip can ultimately have a positive outcome, as it may have helped people in the longer-term to come to terms with specific personal issues.

4.2 Cognition

Psychedelics have been shown to increase psychological flexibility, which is an adaptive response to different stressors that promotes value-driven action. Psychological flexibility mediated the effects of psychedelic-induced experiences and decreases in anxiety and depression.

A psilocybin study showed that cognitive flexibility was increased from baseline, and persisted for 4 weeks, but the increase in cognitive flexibility was not correlated with previously reported decreases in depression using this sample.

Psychedelic-induced changes in cognitive and psychological flexibility could potentially explain the trans-diagnostic effects of psychedelics, although some studies have shown that psychedelics can acutely impair cognitive flexibility.

There is no clear evidence that psychedelics enhance creativity, although several studies have shown that ayahuasca and psilocybin microdosing result in more original and fluent answers. This could be because psychedelics increase associative thinking while impairing the ability to select the best alternative from all the different associations that are activated.

Psychedelic substances can increase mindfulness and being present in the here-and-now, and there is a synergistic relationship between psychedelics and meditation. Prior experience with meditation can help people navigate their psychedelic experience, and psychedelic use can also trigger and facilitate meditative depth.

Psychedelics and mindfulness meditation may share a commonality at a deeper level, as both have been characterized as “mind-revealing experiences”. They may even fulfill complementary roles in clinical practice, metaphorically speaking as compass and vehicle.

4.3 Beliefs

Psychedelic experiences can trigger supernatural encounters and increase suggestibility, which can lead to changes in metaphysical beliefs, worldviews, and the perception of enhanced feelings of meaning. Participants can report God encounters during psychedelic experiences.

Psychedelics may help people deal with their psychological problems, but they may also foster spiritual bypassing, grandiosity and narcissism. A careful approach to psychedelic therapy and research is necessary, which involves empathic resonance and intersubjective validation and mediation with the participant.

Experimental research has shown that psychedelics can change one’s personal beliefs, and can increase one’s belief in dualism and afterlife beliefs. Many participants who first considered themselves atheists changed their minds after experiencing DMT.

Psychedelics can have a profound impact on people’s worldview, and may cause an ‘ontological shock’. This raises additional challenges for psychedelic research and therapy, as well as recommending a metaphysically agnostic approach.

LSD acutely increases suggestibility and the strong prior expectations that many people have about psychedelics contribute to the psychedelic experience. This results in a prolonged and enhanced perception of meaning and significance.

Psychedelics exert strong social effects, including feelings of connectedness, communitas and empathy. Several measures of connectedness and unity are available, including the mystical sub-scale of the mystical experience questionnaire and the oceanic boundlessness sub-scale of the five dimensional altered states of consciousness scale.

Feeling connected to others may contribute to a more conscious way of living, a more environmentally aware lifestyle, and the relief from depression and death anxiety, as well as having an effect on one’s personality.

Psychedelics are frequently used in structured social contexts, such as group ritual settings, which can impact the outcomes of psychedelic use.

Psychedelics may impact feelings of social connection and empathy, and may decrease narcissism and increase compassion. The multifaceted empathy test (MET) is one common measure of empathy.

4.5 Behavior

Psychedelics have been shown to increase neuroplasticity and can be used to learn new healthy habits, such as improved diet, physical exercise, and mindfulness practices.

Although there is no systematic research on psychedelic-induced changes in habits and behavior, several clinical trials with psilocybin have found self-reported positive changes to behavior.

Despite the profound acute effects of psychedelics on subjective experience, most studies rely on self-report measures and are thus prone to socially desirable responding, demand effects, and suggestibility. Specifically, participants scoring high on the personality trait of absorption may be prone to suggestibility effects.

This section highlighted different psychological explanations for the therapeutic efficacy of psychedelics, including altered and affective states, changes in cognition, belief change, social effects and behavior change.

The integration view, which argues that different levels of analysis converge on a similar causal mechanism, and the pluralistic view, which argues that integration between different levels of analysis is not possible.

5.1 The Integration View

Psychedelics can be helpful in the treatment of depression, anxiety, addiction, and obsessive-compulsive disorder, suggesting a common pathway underlying these biomedical disorders.

In psychopathology, a tendency for a rigid and persistent vs. a more associative and flexible processing style may be a common factor. This ability may be impaired in psychopathological disorders such as depression, addiction, or post-traumatic stress-order.

Psychedelic-assisted psychotherapy may break through rigidity by introducing enhanced meta-control, which results in a more flexible and open processing style. This is mediated by serotonergic, dopaminergic and glutamergic activity, which in turn induces neurogenesis.

On this integrative account, different types of psychedelic-assisted psychotherapies act at different explanatory levels. Microdosing with LSD or psilocybin, ketamine-infusions for the help of treatment-resistant depression, and psychoplastogens are examples of approaches that act at different levels of analysis.

A robust integrative account of psychedelics has the virtue of bridging levels of analysis that have proven difficult to bring together in any subject in the psychological and brain sciences.

5.2 Pluralistic Causation

While we support efforts to discover a comprehensive theory of how psychedelics exert their effects, there is also reason to believe that instead of grand unifying theories, the field may need to look to pluralistic models of causation.

Pluralistic theories of causation are common in psychiatry and the psychological sciences, and may be drawn from other mental phenomena such as mental illness in psychiatry. However, different levels of analysis have yet to be coherently integrated into a single explanatory theory.

Psychedelic effects are too psychologically and socially situated for a single theory to prove satisfactory. Multiple causal pathways, including social, cultural and historical factors, are necessary for a pluralistic account of psychedelic effects.

A pluralistic account of psychedelics has been proposed, and this account suggests that psychedelics might have beneficial effects on depression by increasing neuroplasticity for one patient, but not for another patient.

Psychedelics involve a number of psychological and social factors, but the trigger is a particular, well-characterized molecule, which separates it from many vaguer and more multi-dimensional psychological topics.

Understanding the different explanatory levels of psychedelic effects is important in order to provide a more targeted therapeutic approach. Comparative studies between different therapeutic practices may shed light on the question whether psychedelic experiences are unique in the effects they exert.

A different research approach could be to administer psychedelics to vegetative state patients to study the effects of the drugs at a pharmacological and neurocognitive level, without the accompanying psychological experiences.

The psychedelic state is a complex and multifaceted experience, characterized by different features and characteristics. These characteristics may be accounted for by different pharmacological, neurocognitive, and psychological mechanisms.

In order to do justice to the dynamic nature of the psychedelic experience, we need more refined measurement instruments, such as the microphenomenological approach, which aims to provide an in-depth assessment of different stages and aspects of an experience through a carefully crafted interviewing method.

Many of the findings presented in this review are still preliminary, and there is a potential for researcher bias. Additionally, many published studies are underpowered, and it is not always clear to what extent theoretically important effects are actually supported by empirical data.

Several steps have been taken to improve scientific practices within mainstream psychology and neuroscience research, which should soon be implemented in psychedelic research as well, in order to increase the credibility of this important research field.

  1. Conclusion

Classic psychedelics induce a wide range of different effects at the pharmacological, the neurocognitive, and the psychological level. A pluralistic theory of causation may be needed to fully account for the multifaceted and dynamic nature of the psychedelic experience.


Authors associated with this publication with profiles on Blossom

David Yaden
David Bryce Yaden (Ph.D.) is a Research Fellow at Johns Hopkins University School of Medicine. His research focus is on the psychology, neuroscience, and psychopharmacology of psychedelics and other positively transformative experiences. Specifically, David is interested in understanding how brief experiences can result in such long-term changes to well-being.

Michiel van Elk
Michiel van Elk is an Assistant Professor at the unit Cognitive Psychology of the Institute of Psychology, at Leiden University.

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