Correlates of Ego Dissolution on Classical Psychedelics (5HT2A Agonists)


By Trey Brasher & David Rosen, Ph.D.   | 22 minute read


Few discoveries in history have changed psychology more than the 1943 discovery of the profoundly psychoactive nature of lysergic acid diethylamide (LSD).  The ability of LSD to reliably occasion the boundary dissolving peak experience colloquially called ‘ego death’ catalyzed a revival in interest in studying consciousness [6][10]. LSD belongs to a class of compounds known as classical psychedelics, along with the phenethylamine mescaline, and tryptamines psilocybin and dimethyltryptamine (DMT) [18]. The designation ‘classical psychedelic’ refers not only to their historically prominent use, but also their overlapping effects that are mediated by semi-selective agonist affinity at the 5HT2A receptor. 5-hydroxytryptamine (5HT) is the chemical name of the neurotransmitter serotonin, of whose structure the classical psychedelics are simulacra. All classical psychedelic 5-hydroxtryptamine (serotonin) 2A receptor agonists mediate profound changes in consciousness and a change in the individual’s self perception in particular. The ‘ego death’ or ‘peak experience’ archetypal of classical psychedelics involves partial or total dissolution of the cognitive boundaries between subject and object, self and other, and internal and external. Colloquially used terminology reflects historical psychological frameworks used to characterize these experiences; the ‘peak experience’ from the peak of Maslow’s Hierarchy of Needs, self-transcendence, and ‘ego-death’ from the disintegration of the Freudian Ego construct [3][12].  Dissolution of one’s usual sense of self, and an experience of union with something greater than one’s self, are regularly and reliably produced by high dose experiences on classical psychedelics, both in clinical and naturalistic settings [5][6][14][21].  


Modern Research on the Neural and Cognitive Correlates of Ego Dissolution


To understand modern research on the neural and cognitive correlates of ego dissolution on classical psychedelics, it is critical to understand what is meant by the term ‘ego dissolution’. The term ego derived its modern meaning from the work of psychologist Sigmund Freud. In this blanket term, he encompassed one’s sense of self, a conscious construct delineated spatially and temporally by the properly functioning human mind [19]. Psychology imprinted this concept of self and the term ego is commonly used today to indicate those conscious boundaries. Soon after the discovery of LSD, the emergence of the psychotomimetic model linked the concept of ego inexorably to the classical psychedelics. In this model, classical psychedelics mimicked schizophrenic psychosis by causing disturbances in the ego [1][4]. Although long discredited, the psychotomimetic model laid the groundwork for cognitive correlates of a healthy sense of self to be observed by single dissociation. Today, with the invention of fMRI, researchers are beginning to map these cognitive correlates to neural correlates, physiological hallmarks of the functioning ego. They are going about this using the classical psychedelics, which occasion ‘mystical-experiences’ defined by ego dissolution [6]. Based on current research on neural correlates of ego dissolution on classical psychedelics, there is evidence that this dissolution results from decreases in activity of primary connector hubs in the brain, as well as temporary disintegration of the Default Mode Network (DMN) and Salience Network (SN).  Feelings of a dissolution of the boundaries between self and other, subject and object, the self and the external world, and a sense of union with something larger than one’s self are cognitive correlates of ‘ego dissolution’ and implicate these systems in the regular functioning of ‘ego’ or self-identification. These networks are correlated with the highest densities of 5HT2A receptor sites, upon which classical psychedelics are known to primarily act. The evidence suggests the resulting feeling of ‘oneness’, ‘ego death’, or ‘ego dissolution’ results from decreases in aforementioned systems, resulting in increased functional global connectivity [2][13][20].   


In the groundbreakings study ‘Neural Correlates of the Psychedelic State as Determined by fMRI studies with Psilocybin,’ Carhart-Harris et al. (2012) applied modern fMRI technology to directly measure physiological changes precipitated by classical psychedelics for the first time. Using a within-individual placebo-controlled design, blood-oxygen level dependent (BOLD) fMRI, a cerebral blood flow (CBF) indicator, was used to map changes in two groups of 15 psychedelically experienced participants as they underwent the psychedelic experience [2]. Contrary to commonly held presumptions and previous studies focusing on glucose metabolism, significant decreases in brain blood flow and venous oxygenation were observed in the BOLD signal, these decreases directly correlated with measured intensity of subjective effects. These observed decreases in brain activity where also highly concentrated to particular brain structures including the thalamus, angular and supramarginal gyrus (IPL), posterior cingulate cortex (PCC), anterior cingulate cortex (ACC), and medial prefrontal lobe (mPFC). All the affected regions represent major connection hubs in the brain. Decoupling of the PCC and the mPFC/ACC showed a regression suggesting that the psychedelic state tipped the balance in this system more toward bottom-up processing. These two key structural hubs, the PCC and the mPFC/ACC, represent the primary axis of the Default Mode Network (DMN), along with the IPL, all structures showing consistent deactivation and decoupling during the psychedelic state. DMN components have been shown to be active during self-referencing and handle other higher-level processes involving sense of self [2]. Carhart-Harris et al. explicate that it is currently unclear what specific synaptic mechanisms are causing these deactivations. Since deactivation and decoupling are seen in higher-level association regions of the DMN which contain the most cortico-cortical connections in the brain, neuronal messages are suggested to travel by more complex routes, increasing overall global connectivity and allowing an ‘unconstrained style of cognition’ [2].  


In 2015, a team of scientists, including Carhart-Harris conducted a within-subject placebo controlled fMRI study specifically looking at neural changes compared to subjective ratings of ego-dissolution phenomena. ‘Finding the Self by Losing the Self: Neural Correlates of Ego-Dissolution under Psilocybin’ corroborated Carhart-Harris et al., 2012 indicating decreases in BOLD signal, concentrated at connective network hubs for all 15 psychedelically experienced participants [13]. Lebedev et al. indicate ego-dissolution is a constellation of phenomenon including awareness of existence, self-agency, multi-modal phenomenon being interpreted as integrated experience, differentiation of self from the outside world, and ‘I’ as a narrative across time, as well as a method for ‘reality testing’ [9]. Subjective measures of experience were gathered along with a subjective judgment of whether ego-dissolution was experienced. Measures most strongly correlated with ego-dissolution were: I – I lost all sense of ego, II – My imagination was extremely vivid, III – The experience had a spiritual or mystical quality. These subjective judgments correlated with concentrated decreases in BOLD signal, particularly in the dorso-medial prefrontal cortex (dmPFC), and a decoupling of the medial temporal lobe (MTL)/parahippocampel gyrus (PHG) system with the neo-cortex. These represent primary nodes of the ‘Salience Network’, which chooses important stimuli and regulates attention. Decreases in the MTL/PHG had previously been linked to ego-dissolution [13]. Particularly, the decoupling of the MTL and PHG is thought to represent a loss of the contextual feed into the stream of consciousness, considering this system is associated with the ‘what’ of object recognition. Considering its memory retrieval function as the ‘gateway to the hippocampus’ further supports Carhartt-Harris et al., 2012 in asserting ‘unconstrained cognition’, as subconscious aspects of the mind become conscious. Findings also indicate a decreased inter-hemispheric connectivity via decreased activity of the mPFC/ACC system associated with the DMN. Lebedev et al. (2015) indicates PCC decreases in this study did not correlate strongly with ego dissolution as they did in Carhart-Harris et al., 2012 [2][13].


The study, ‘Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution,’ which used LSD instead of psilocybin, represents the most prolific modern application of fMRI technology to the heavily studied LSD induced state of ego-dissolution [20].  This study introduces the concept of functional connectivity density (FCD), an fMRI-based measure of intra-structural connections. The study focused on global trends, as opposed to previously mentioned studies that focused on the localized concentrated decreases observable in DMN and Salience Network association hubs. Tagliazucchi et al. (2016) utilized the same within-individual placebo controlled experimental design as the previous studies and also used 15 psychedelically experienced participants. Local decreases were observed in the precuneus/PCC, angular gyrus of the IPL, dmPFC, MTL areas, as well as insular cortices, substantiating previous models of ego-dissolution involving decreased integrity of the DMN and Salience Network. Increases in functional connectivity density correlated both with decreased connector hub function as previously found, and also strongly correlated with subjective intensity of ego-dissolution. As observed by Lebedev et al. (2015), administration of a classical psychedelic precipitates what appears to be a collapse of the hierarchical functioning of the brain, connecting high-level association areas and low-level sensory areas. In subjective cognition, this FCD increase blurs the distinction between what is experienced as within self and what is experienced as anchored in an external world. Tagliazucchi et al. revealed an increase in the brain’s global integration but decreases in integrity within-locales known to host high densities of 5HT2A receptors [20]. 



Understanding the Research


These studies add to a foundational knowledge of the original function of deactivated networks and structures. Decreased activity of the Default Mode Network appears universally correlated with ego dissolving experiences [2][13][20] validating the evidence that the DMN is critical in the neural signature of self-awareness.  Both the mPFC and PCC of the DMN, which show the largest decreases in function, show the highest energy usage anywhere in the brain under normal consciousness, indicating exactly how critical these systems are in typical perception. In ego-dissolution, set teleology regularly attributed to external objects ceases and a universal importance is felt to imbue all objects, as would be suspected from a cessation of Salience Network integrity, specifically the MTL/PHG, the system usually responsible for indicating the purpose of objects. The precuneus/PCC, which showed decreased activity in two of the studies, has been linked to the representation of the human body in time and space, autobiographical memory retrieval, and self-referencing as well as measures of implicit spiritually [16][20]. The IPL showed consistent deactivation across studies and has been linked to perceptual distinction between self and other [20]. Further studies, which should be conducted with larger sample sizes, will compound understanding of these systems deactivated by classical psychedelics, strengthening functional correlations. 


All three of the aforementioned studies used psychedelically experienced volunteers, a design aspect that easily could be misconstrued as needing to be fixed. This concern is explicitly stated in both Carhart-Harris et al., 2012 and Tagliazucchi et al., 2016. It is possible that the volunteers experienced greater prevalence of ego disturbance than normal at administered doses because of the expectancy effect. However, selecting experienced psychedelic users for participants is a feature, not a defect, despite appearing deceptive. Ego dissolution is perhaps among the most intense subjective experiences possible for a human being to have, often causing profound and permanent changes in personality and consistently being rated by participants as among the most meaningful experiences of their lives [6] [15]. The subjective intensity of experiencing ego dissolution precipitated by a high dose psychedelic experience, while inside a confining fMRI machine, should never be underestimated. Studies of ego dissolution on classical psychedelics using fMRI should never be conducted with psychedelically naïve volunteers, or participants other than expert psychedelic users. Adverse reactions while in the fMRI machine are nearly certain for inexperienced users.  


A Potential Profound Paradigm Shift


These studies represent a renascent wave of scientific research with psychedelics.  Findings from these second wave studies shatter fundamental presumptions made by first wave progenitors. First wave psychedelic research and the reemergence of interest in consciousness brought about by the 1943 discovery of the psychoactivity of LSD incorrectly assumed that classical psychedelics functioned by increasing brain activity. This presumption is logical to make in the absence of fMRI imaging because the psychedelic state, and ego-dissolution in particular, is the most complex known state of human cognition and contrasts in dipolar fashion with states where brain activity appears reduced, such as during sleep or anesthesia [20]. Modern research applying fMRI technology rejects this presumption, repeatedly demonstrating a strong correlation between decreased brain activity and peak experiences of ego dissolution on classical psychedelics. The decreased activity, concentrated in critical nodes of the DMN and Salience Network, appears to increase the brain’s global functional connectivity, resulting in unconstrained cognition and hierarchical breakdown, giving rise to the subjectively perceived complexity of the psychedelic state.  


This research potentially constitutes a profound paradigm shift and represents the only evidence to date that increased brain activity does not necessarily constitute intensified experience. Modern philosophy and psychology seem divided into two camps; the religious or spiritual view that sees consciousness as existing independent of the brain, and the current scientific paradigm, which sees brain activity as constituting experience. Both camps seem eager to bend these findings to their view of consciousness. CNN reported on Tagliazucchi et al., 2016 on the front page of their site, misrepresenting the information by saying the brains of participants on LSD appeared “lit up with activity” as would be expected from the psychedelic experience if brain activity actually constituted experience. The chart CNN used actually showed large swaths of decreased BOLD signal [11]. Those who view consciousness as existing independent of the brain often see consciousness as a wave signal and the brain as a receiver, an idea propagated by chemist Albert Hofmann who discovered both LSD and psilocybin. They take this emerging body of evidence as an indication that the brain does not generate consciousness, as decreasing its activity increases subjective intensity of experience [11]. The findings presented in these papers do not clearly validate either claim regarding the nature of consciousness. What does seem evident is that the function of the brain is somewhat akin to Aldus Huxley’s idea of a ‘reducing valve’ [8], a Bayesian inference machine which selects stimuli for conscious awareness and delineates an ego construct, filtering out a massive quantity of thoughts, memories, and stimuli which the brain is fully capable of perceiving. This ‘reducing valve’ effect occurs not because some stimuli are innately more salient or because a ‘self’ innately exists, but because they are highly adaptive functions. In the words of psychologist Donald Hoffman, “Evolution has given us an interface that hides reality and guides adaptive behavior” [7].  That interface is called the ego.  


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[1] Carhart-Harris, R. (2007). Waves of the unconscious: The neurophysiology of dreamlike phenomena and its implications for the psychodynamic model of the mind. Neuro-Psychoanalysis, 9(2), 183-211.


[2] Carhart-Harris, R. L., Erritzoe, D., Williams, T., Stone, J. M., Reed, L. J., Colasanti, A., … & Hobden, P. (2012). Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proceedings of the National Academy of Sciences109(6), 2138-2143.


[3] Carhart-Harris, R. L., & Friston, K. J. (2010). The default-mode, ego-functions and free-energy: a neurobiological account of Freudian ideas. Brain133(4), 1265-1283


[4] Evarts, E. V. (1957). A review of the neurophysiological effects of lysergic acid diethylamide (LSD) and other psychotomimetic agents. Annals of the New York Academy of Sciences66(3), 479-495.


[5] Goodman, N. (2002). The serotonergic system and mysticism: could LSD and the nondrug-induced mystical experience share common neural mechanisms?. Journal of psychoactive drugs34(3), 263-272.


[6] Griffiths, R. R., Richards, W. A., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology187(3), 268-283.


[7] Hoffman, D. (2015, March). Do We See Reality as It Is? Lecture presented at TED2015.


[8] Huxley, A., & Huxley, A. (1954). The Doors of Perception & Heaven and Hell. London: Harper & Brothers.


[9] Jaspers, K. (1913): Allgemeine Psychopathologie: English translation of the 7th edition: General Psychopathology. Baltimore: Johns Hopkins University Press; 1997.


[10] Johnson, M. W., & Griffiths, R. R. (2017). Potential therapeutic effects of psilocybin. Neurotherapeutics14(3), 734-740.


[11] Kastrup, B. (2016). The LSD Study: You’re Being Subtly Deceived (Again). Retrieved from LIST&utm_campaign=5c024a0f3e-Reality_Sandwich_7_31_A_B_Split_7_30_2015&utm_medium=email&utm_term=0_321db437f5-5c024a0f3e-313175233&mc_cid=5c024a0f3e&mc_eid


[12] Klavetter, R. E., & Mogar, R. E. (1967). Peak experiences: Investigation of their relationship to psychedelic therapy and self-actualization. Journal of Humanistic Psychology7(2), 171-177.


Peak Experiences

[13] Lebedev, A. V., Lövdén, M., Rosenthal, G., Feilding, A., Nutt, D. J., & CarhartHarris, R. L. (2015). Finding the self by losing the self: Neural correlates of egodissolution under psilocybin. Human brain mapping36(8), 3137-3153.


[14] Lyvers, M., & Meester, M. (2012). Illicit use of LSD or psilocybin, but not MDMA or nonpsychedelic drugs, is associated with mystical experiences in a dose-dependent manner. Journal of psychoactive drugs44(5), 410-417.


[15] MacLean, K. A., Johnson, M. W., & Griffiths, R. R. (2011). Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. Journal of Psychopharmacology25(11), 1453-1461.


[16] Miller, L., Balodis, I. M., McClintock, C. H., Xu, J., Lacadie, C. M., Sinha, R., & Potenza, M. N. (2018). Neural Correlates of Personalized Spiritual Experiences. Cerebral Cortex.


[17] Nichols, D. E. (2004). Hallucinogens. Pharmacology & therapeutics101(2), 131-181.


[18] Nichols, D. E. (2012). Structure–activity relationships of serotonin 5HT2A agonists. Wiley Interdisciplinary Reviews: Membrane Transport and Signaling1(5), 559-579.


[19] Ostow, M. (1959). The structural model: ego, id, and superego. Annals of the New York Academy of Sciences, 76(4), 1098-1134.

Tagliazucchi, E., Roseman, L., Kaelen, M., Orban, C., Muthukumaraswamy, S. D., Murphy, K., … & Bullmore, E. (2016). Increased global functional connectivity correlates with LSD-induced ego dissolution. Current Biology26(8), 1043-1050.


[21] Trichter, S., Klimo, J., & Krippner, S. (2009). Changes in spirituality among ayahuasca ceremony novice participants. Journal of Psychoactive Drugs41(2), 121-134.

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