further evidence of the gut brain connection. The Effect of LSD On Brian Entropy and The Personality Trait ‘Openness

The Effect of LSD On Brian Entropy and The Personality Trait ‘Openness’

Nathaniel Green

In the paper “LSD-Induced Entropic Brain Activity Predicts Subsequent Personality Change,” the relationship between brain entropy while taking Lysergic acid diethylamide (LSD), and the personality trait of openness two weeks later was examined (Lebedev et al. 2016). Classic psychedelics such as psilocybin have been known to change aspects of adult personality, despite being relatively fixed past the age of 30 (MacLean, Johnson, and Griffiths 2011). Nineteen healthy individuals, all of whom had prior experience with LSD, were given a dose of 75µg of LSD. These individuals then underwent three 7.5 minute fMRI scans to observe change in brain entropy. The first and third scans were in silence while the second was while listening to music. After each scan, subjects were questioned on the extent of ego dissolution experienced. Two weeks later the levels of ‘openness’ were assessed compared to a baseline previously taken. The results showed that LSD significantly increased openness, as well as global brain entropy, affecting all hierarchal levels of the brain, but most importantly the upper levels. Increases in entropy accurately predicted the increase of openness two weeks later, especially during and after the music listening session, and when ego dissolution was achieved. These findings illuminate the medium-term positive effects of psychedelics and correlates these with acute brain circuit changes. These findings support emerging arguments that LSD and other psychedelics could have a role in treatments for illnesses including treatment-resistant depression and PTSD.

Background and introduction

The human use of psychedelics for ritual and recreation dates back thousands of years (“The Medical History of Psychedelic Drugs”, 2007). These early psychedelics included peyote, which contained mescaline, and psilocybin. It wasn’t until 1938 that LSD, a psychedelic originally synthesized from the poisonous fungus ergot, was synthesized by Albert Hofmann (Williams, 1999). Early research included by the Central Intelligence Agency into the potential use of LSD as a truth serum, alongside other therapeutic uses. At the same time, the counterculture movement started welcoming and encouraging its (and other psychedelics) use (Carhart-Harris and Goodwin 2017). As the use of psychedelics in counterculture progressed into the 1960s, in part lead by Harvard professor Tim Leary, fear of the negative cultural side effects grew until the US government severely regulated its use and halted research (Williams, 1999). After 40 years, research into the therapeutic use of psychedelics began again (Carhart-Harris and Goodwin, 2017). Since emerging from the psychedelic dark age, research has made great strides in the classification of LSD and other psychedelics’ effects and mechanisms. LSD, psilocybin, and mescaline act as 5-HT2A (serotonin receptor) agonists, secondarily increasing glutamate release and effecting subjective perception and sense of self (Kraehenmann et al., 2017; Carhart-Harris and Friston, 2019). These changes are understood as being related to the brain’s functional hierarchy in a new theory called ‘Relaxed Beliefs Under Psychedelics’ (REBUS) (Carhart-Harris and Friston, 2019). In normal brain function, information is gathered from the environment and filtered through the progressive hierarchy to multimodal associative areas. As it enters through sensory areas of the brain and moves through the brain’s hierarchy, it is compared to predictions using an approach employing Bayesian statistics: predictive coding (Friston, 2010). Predictions are formed from priors encoded in the upper echelons –higher cortical structures - of the brain's hierarchy (Carhart-Harris and Friston, 2019). New sensations and data from the World are weighed against these predictions and are either confirmed true (confidence) or false (surprise). False predictions may reshape priors if those priors are malleable enough, and the surprise significant (Carhart-Harris and Friston, 2019). Psychedelics act to decrease the activity of high levels of the brain, disrupting the influence of these prior on lower input, therefore increasing malleability and the surprise factor. This theory has been supported by high concentrations of 5-HT2A receptors in high level regions, such as the default mode network (DMN) (CarhartHarris and Friston, 2019). Another aspect of the REBUS theory is the property of increased brain entropy under psychedelics, known as the entropic brain hypothesis (Carhart-Harris and Friston, 2019). Brian entropy is a measure of the activity of brain networks differing from its natural order (Carhart-Harris et al., 2014). For example, the networks in the brain that contribute to the supposed default mode network, which is responsible for a stable sense of self and day-dreaming states, shows reduced co-activity, resulting in increased connections between brain regions that would otherwise be relatively muted (Carhart-Harris et al., 2014; Carhart-Harris and Friston, 2019). Interestingly, increased entropy is correlated with the intensity of the psychedelic experience (Carhart-Harris and Friston, 2019). This phenomenon is studied in the paper “LSD-Induced Entropic Brain Activity Predicts Subsequent Personality Change,” as it shows a correlation between increase in both brain entropy and the personality trait of openness. This paper connects the two concepts of the entropic brain hypothesis and the free energy principle in a real-world example, as increased levels of brain entropy show less input from priors. Brian entropy was measured three times using fMRI, once with music playing. These scans were done under LSD and placebo conditions. After each scan, it was determined whether ego dissolution had occurred. Ego dissolution is the loss of understanding of ‘self’ and is correlated with the global connection of brain regions such as the DMN (Tagliazucchi et al., 2016). Openness was measured two weeks after taking LSD using the NEO-PI-R test which measures five main categories of personality (Carhart-Harris and Friston, 2019; “NEO Personality Inventory-Revised | NEO PI-R” n.d.).

Major results

The results of the target paper demonstrate that LSD had a significant effect on 11 of 17 functional systems of the brain (figure 1), showing there was increased global entropy, as predicted by the REBUS model. Another significant result that was supported by past research (Carhart-Harris and Friston, 2019) was a significant increase in the personality trait of openness, despite the fixation of personality once adulthood is reached. This effect is logical concerning the free energy principle, as priors are relaxed during psychedelic use. A significant correlation was found between increased brain entropy and increased personality change, demonstrating LSD-induced increase in global brain entropy is a predictor of personality change two weeks later. Interestingly, the correlation was strongest during and after listening to music (figure 2). Also, those with high ego dissolution showed greater personality change. These two results provide important information that could allow for more future success in psychedelic therapy (Kaelen et al., 2018; Carhart-Harris, 2019).

Conclusion and discussion

Administration of LSD caused a significant increase in global brain entropy, correlating with increased openness, indicating that brain entropy may predict personality change. This effect was especially strong during and after music listening, as well as when ego dissolution had occurred, offering evidence that music and ego dissolution may play an important role in the therapeutic use of LSD. The findings of the target paper that state that LSD increased brain entropy is significant to the newly resurrected field of psychedelic therapy and research. LSD acts on the brain’s higher levels, decreasing the influence of priors on incoming sensory data streams. This allows for more information entering the brain to be interpreted without the constraining lens of prior assumptive understanding, potentially aided by

increased entropy in high-level brain networks such as the DMN (Carhart-Harris and Friston, 2019). Considering this, the result that individuals showed increased openness begins to make should be studied. It is important to note that government regulation of LSD and other classic psychedelics is extremely strict,

sense. While this effect is not well understood, the paper theorizes that through mystical experience or ego dissolution, prior understanding of the world may begin to unravel, allowing the individual to question their assumptions of the World and accept what they may have denied without psychedelic aid. Increased openness is a well-recognized effect of psychedelics, and was seen even one year after use (MacLean, Johnson, and Griffiths, 2011). Another aspect of the psychedelic experience that may play a role in personality change is the registered value of the experience. While personality is mostly fixed in adulthood, significant life experiences may have a transformative effect (MacLean, Johnson, and Griffiths, 2011; Lebedev et al., 2016). In one study, a majority of psychedelic naïve volunteers who took psilocybin reported that their psychedelic experience was deeply profound and spiritual, over 60% rating it in their top 5 most meaningful encounters. (Griffiths et al., 2006). The importance of the experience may cause a greater change in personality. These findings are supported by the biological processes of stress modulated serotonin release to the 5-HT2A receptors, causing a change in perspective and neuroplasticity (Murnane, 2019).

Music and ego dissolution were shown to affect openness by increasing change in personality and predictive power of entropy change. Music may trigger the change of personality as these effects were only found during and after listening to music. One explanation the paper proposes is that music may guide changes in brain entropy that affect personality. Both music and ego dissolution have been discussed in prior research. Music has been linked with increased mystical experiences, and positive therapeutic results (Kaelen et al., 2018) while ego dissolution has been regarded as an effect of increased brain entropy and dysregulation of the DMN and has also been linked to therapeutic benefit and increased openness (Carhart-Harris and Friston, 2019).

Critical analysis

REBUS is largely theoretical and somewhat speculative. While experiments such as the one conducted in the target paper support the REBUS model, much is still disputed and unknown. One issue posed by the target paper was that brain entropy correlated strongly with increased personality change during or after listening to music. However, in the experiment, music listening was always done 7.5 minutes after the first silent fMRI, and before a third silent fMRI. This was not controlled for, as the order of listening to music was not changed. This means that the predictive power increase is possibly a result of the timing rather than the music. Another notable problem with this study is that all participants had taken LSD in the past, though not within two weeks of the experiment. While it is unlikely that this discredits the results of the study, it is important, as individuals were aware of the effect of the drug, and most likely felt a level of comfort and expectation. LSD may have different effects

Future direction

Because of the novelty of these experiments and theories, there are many directions research into this field could be taken. The results of this paper offer a reason to explore the possibility of LSD and other psychedelics as therapeutic aids. Such research has already begun, and promising results have been documented for diseases such as treatment-resistant depression, PTSD, addiction and even eating disorders (CarhartHarris and Friston, 2019). Psychedelic therapy has the potential to treat disorders that have evaded members of the medical community for years. The methods continue to be refined through research and critique, improving the safety and utility of psychedelics. To strengthen the results of the target paper, the experimenters could change the order of music listening sessions or exclude music altogether. This experiment would still demonstrate that music had an important effect, as other sources have shown this phenomenon to some extent (Kaelen et al. 2018). In the case that music did not show a meaningful effect, it would discredit the theory that music may aid in how the brain increases entropy. It may also support evidence that indicated that the benefit of music is variable and may not affect everyone equally (Kaelen et al., 2018). The possibility that music may “guide” LSD users in a particular way proposes an important aspect of psychedelic treatment: the subjective experience. It is already known that the environment and mental attitude of the individual plays a role in the unique experience that each LSD experience offers (Carhart-Harris and Friston, 2019). However, the mechanism of this is still not well understood. This information is essential in standardizing LSD research, as different environments may affect each experimenter's results significantly (Unger, 1963). It is also important to gauge environments that could improve therapeutic results. In an attempt to verify that LSD-naïve and experienced people would have the same outcome from this, both groups on LSD naïve people than in people with experience.

and it is difficult to ethically enter naïve individuals into a psychedelic study. Had this study been completed, however, I predict that the results would be the same. In the case results were different, I predict a possibly stronger effect for LSD naïve individuals, as psychedelics can have lessening effects with repeated use, and because personality change may decrease from repeat use. This information would be important when exploring the possibility of using psychedelics therapeutically, as it would allow therapists to weight the benefit of undergoing this novel therapeutic method. The results of this study provide evidence of the possible benefit of psychedelics in a therapeutic way, as well as offering ways to predict the medium-term effects of LSD use. With increased research and testing, it is highly plausible that psychedelics will soon play a role in the treatment of many psychological diseases.

Figure 1

Boxed numbers depict brain networks with increased entropy after LSD exposure 1. Secondary Visual; 2. Primary Visual; 3. Superior Sensorimotor; 4. Inferior Sensorimotor; 5. Superior Parietal; 6. Posterior Sensorimotor; 7. Posterior Salience; 8. Anterior Salience; 9. Anterior MTL; 10. Orbitofrontal; 11. Precuneus; 12. Inferior Frontoparietal; 13. Superior Frontoparietal; 14. Auditory; 15. Hippocampal; 16. Default Mode Network; 17. Frontotemporal (Lebedev et al. 2016).

Figure 2

red = first fMRI; green = second fMRI; blue = third fMRI. These data demonstrate the effect of music on the predictive power of entropy and openness. Green took place while listening to music, and blue after music. These results demonstrate the increase of predictive power during and after listening to music (Lebedev et al. 2016).

10.

11. 12.

13. 14.

15. Carhart-Harris, R. L., and K. J. Friston. 2019. “REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics.” Edited by Eric L. Barker. Pharmacological Reviews 71 (3): 316–44. https://doi.org/10.1124/pr.118.017160. Carhart-Harris, Robin L. 2019. “How Do Psychedelics Work?” Current Opinion in Psychiatry 32 (1): 16–21. https:// doi.org/10.1097/YCO.0000000000000467. Carhart-Harris, Robin L, and Guy M Goodwin. 2017. “The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future.” Neuropsychopharmacology 42 (11): 2105–13. https://doi.org/10.1038/npp.2017.84. Carhart-Harris, Robin L., Robert Leech, Peter J. Hellyer, Murray Shanahan, Amanda Feilding, Enzo Tagliazucchi, Dante R. Chialvo, and David Nutt. 2014. “The Entropic Brain: A Theory of Conscious States Informed by Neuroimaging Research with Psychedelic Drugs.” Frontiers in Human Neuroscience 8. https://doi.org/10.3389/fnhum.2014.00020. Friston, Karl. 2010. “The Free-Energy Principle: A Unified Brain Theory?” Nature Reviews Neuroscience 11 (2): 127–38. https://doi.org/10.1038/nrn2787. Kaelen, Mendel, Bruna Giribaldi, Jordan Raine, Lisa Evans, Christopher Timmerman, Natalie Rodriguez, Leor Roseman, Amanda Feilding, David Nutt, and Robin Carhart-Harris. 2018. “The Hidden Therapist: Evidence for a Central Role of Music in Psychedelic Therapy.” Psychopharmacology 235 (2): 505–19. https://doi.org/10.1007/s00213-017-4820-5. Kraehenmann, Rainer, Dan Pokorny, Helena Aicher, Katrin H. Preller, Thomas Pokorny, Oliver G. Bosch, Erich Seifritz, and Franz X. Vollenweider. 2017. “LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation.” Frontiers in Pharmacology 8 (November). https://doi.org/10.3389/fphar.2017.00814. Lebedev, A. V., M. Kaelen, M. Lövdén, J. Nilsson, A. Feilding, D. J. Nutt, and R. L. Carhart‐Harris. 2016. “LSD-Induced Entropic Brain Activity Predicts Subsequent Personality Change.” Human Brain Mapping 37 (9): 3203–13. https://doi.org/10.1002/ hbm.23234. MacLean, Katherine A., Matthew W. Johnson, and Roland R. Griffiths. 2011. “Mystical Experiences Occasioned by the Hallucinogen Psilocybin Lead to Increases in the Personality Domain of Openness.” Journal of Psychopharmacology (Oxford, England) 25 (11): 1453–61. https://doi.org/10.1177/0269881111420188. Murnane, Kevin Sean. 2019. “Serotonin 2A Receptors Are a Stress Response System: Implications for Post-Traumatic Stress Disorder.” Behavioural Pharmacology 30 (2-): 151–62. https://doi.org/10.1097/FBP.0000000000000459. “NEO Personality Inventory-Revised | NEO PI-R.” n.d. Accessed June 12, 2020. https://www.parinc.com/Products/Pkey/276. Tagliazucchi, Enzo, Leor Roseman, Mendel Kaelen, Csaba Orban, Suresh Muthukumaraswamy, Kevin Murphy, Helmut Laufs, et al. 2016. “Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution.” Current Biology 26 (April). https://doi.org/10.1016/j.cub.2016.02.010. “The Medical History of Psychedelic Drugs.” 2007, 52. Unger, Sanford ML. 1963. “Mescaline, LSD, Psilocybin, and Personality Change a Review † .” Psychiatry 26 (2): 111–25. https://doi.org/10.1080/00332747.1963.11023344. Williams, Luke. 1999. “Human Psychedelic Research: A Historical And Sociological Analysis.” MAPS. MAPS. 1999. https:// maps.org/index.php.