Key Insights

• Modern imaging techniques (fMRI, EEG) help us understand through which mechanisms psychedelics have their influence on the brain. This helps us understand both the acute (psychedelic) effects, and how they can lead to long-term positive outcomes.
• Through the disruption of abhorrant mechanisms, for instance activity in the Default Mode Network (DMN), psychedelics can have therapeutic effects that are evident for up to years later. Several encompassing theories such as the entropic brain and its descendant REBUS help explain how this can happen at different levels.
• Neuroscience can help validate how psychedelics work and help regulators make choices about the safety (and efficacy) of psychedelics.

What is Neuroscience?

Neuroscience is the scientific study of the body’s nervous system. The nervous system is comprised of a complex network of nerves and cells that are tasked with coordinating actions and sensory information by relaying signals to and from different parts of the body. Originating in the brain, the nervous system controls one’s movements, thoughts and responses to both internal and external stimuli. Furthermore, the nervous system helps to control all other body systems.

The nervous system is subdivided into two main systems: the peripheral nervous system and the central nervous system. The central nervous system is comprised of the brain and the spinal cord. The peripheral nervous system consists of nerves that branch out from the spinal cord which connect other parts of the body to the central nervous system. Importantly, the brain is the main organ of the nervous system, acting as the body’s command centre.

The brain is a complex organ that controls thought, memory, emotion, touch, motor skills, vision, breathing, temperature, hunger and every process that regulates our body. The brain works by receiving and sending both chemical and electrical signals throughout the body as necessary. Each different region of the brain is responsible for controlling other bodily functions. For example, the hippocampus supports memory, learning and perception of space, whereas the amygdala regulates emotion and memory and is associated with the brain’s reward system [1].

Given the central role the brain plays in almost every aspect of our bodily functions, scientists are always seeking to better our understanding of this complex organ. To do so, scientists are always searching for new tools to peer deeper into the brain. Now, however, scientists are successfully combining modern technologies like MRI machines and EEGs with a class of psychoactive drugs that have been used throughout history, psychedelics.

Psychedelics and Neuroscience

Psychedelics are proving to be valuable tools in the realm of neuroscience. By utilizing modern technology and techniques, scientists are not only unearthing how psychedelics have the ability to produce such profound effects in the brain, but they are also helping us to better understand how psychedelics exert their therapeutic effects.

However, given that this research is in its infancy, much of the exact science remains speculative. As we progress through the psychedelic renaissance, scientists are gradually transforming these speculations into solid scientific evidence. For instance, scientists are now fairly certain that classical/serotonergic psychedelics exert their therapeutic effects, in part, by altering the brains’ default mode network (DMN).

The DMN is a network of interacting brain regions that is active when a person is not focused on the outside world, when the brain is at wakeful rest, such as during daydreaming and mind-wandering [2]. The collection of pathways within the DMN govern our self-image, our autobiographical memories, and our deeply ingrained beliefs and thought patterns [3].

Abnormal functioning of the DMN has been implicated in numerous mental disorders. For example, in depression, the DMN has been shown to be hyperactive using functional MRI (fMRI). Hyperactivity in this region can lead to negative rumination, the process of continuously thinking about the same thoughts [4]. fMRI techniques have shown that psychedelics have the ability to disrupt these engrained patterns of rumination within the DMN.

By stimulating 5-HT2A receptors, psychedelics like psilocybin downplay hyperactivity in the DMN which in turn, allows patients to work through their issues with more ease. Additionally, it appears that activation of these receptors can have long-lasting effects on brain function which enhances therapeutic outcomes [5]. Though this view is held by many researchers, this isn’t the only mechanism at work nor should be taken as being solely responsible as a causal mechanism of psychedelics’ therapeutic effects.

Modern psychedelic neuroscience research

The research team at Imperial College London’s Centre for Psychedelic Research have been using neuroimaging techniques like fMRI to explore the effects of psychedelics on the brain for the past decade. Led by Dr. Robin Carhart-Harris, the team at Imperial have used functional neuroimaging to examine the brain under the influence of psilocybin, LSD, MDMA and DMT, as well as conducting various clinical trials into the effects psychedelics have on mental disorders.

In a 2014 seminal paper, Carhart-Harris and colleagues proposed a theory of conscious states in the brain informed by neuroimaging studies of psychedelic drugs; entropic brain theory. In short, by incorporating principles of physics, neurobiology and psychoanalysis, the theory proposes that there are two different forms of cognition that the researchers term the ‘primary’ and ‘secondary’ states.

The secondary state is our normal waking state, in which we try to limit our surprise and uncertainty about the world, or limit ‘high entropy.’ In ‘primary states,’ such as the psychedelic state, the downregulation of the DMN creates less entropy and in turn, causes the brain to enter a more critical state. In this more critical state, normal patterns of brain activity, such as those associated with mental disorders, are broken down which allows people to gain therapeutic benefit from the psychedelic experience.

Carhart-Harris and colleagues revisited their entropic brain theory in a 2018 paper, offering further evidence for this hypothesis. In 2019, Carhart-Harris combined this entropy hypothesis with a leading model of global brain function, hierarchical predictive coding. Working with Karl J. Friston, the pair termed this formulation ‘relaxed beliefs under psychedelics (REBUS) and the anarchic brain.’

The Centre for Psychedelic and Consciousness Research at Johns Hopkins University is another research group that is using psychedelics to delve into human consciousness. The centre’s director Dr. Roland Griffiths, and associate director Dr. Matthew Johnson, are two of the biggest names in the world of psychedelics.

In 2006, Griffiths and colleagues published one of the first research papers since the blanket ban on psychedelic research in the 1970s. Not only did they find that psilocybin can occasion mystical-type experiences, but these findings were also associated with long-lasting positive changes in people’s mood, attitudes and behaviour [6].

The findings from this study had neuroscientists across the globe wondering what the nature of these mystical experiences is and how do they elicit positive changes in people’s behaviour. In 2015, the team at Johns Hopkins were able to further validate their findings by revising the Mystical Experience Questionnaire which was developed by Walter Pahnke during the first wave of psychedelic research.

Dr. Fredrick Barrett has led numerous neuroimaging studies at Johns Hopkins investigating the effects psychedelics have on the brain. Barrett and colleagues found there to be lower functional connectivity within the DMN in trial participants who received a high dose of psilocybin. Changes in brain function were also present one day after their psilocybin experience [7].

Interestingly, using neuroimaging techniques, Barrett and colleagues also showed that serotonin receptor (5-HT2RA) signalling is responsible for the neural changes that occur in response to music when a person is under the influence of LSD [8].

More research centres exploring the effects psychedelics have on the brain, like those at Imperial and Johns Hopkins, are emerging as we progress through this third wave of psychedelic research.

A team at the University of California Davis showed that psychedelics promote structural and functional neuroplasticity in both in vitro and in vivo models [9]. Neuroplasticity refers to the brain’s ability to modify, change, and adapt both structure and function throughout life and in response to experience and therefore, the aforementioned findings could be beneficial for mental disorders.

In March 2021, the University of California San Francisco launched The Neuroscape Psychedelic Division. Led by Dr. Robin Carhart-Harris, the team aim to investigate the positive influence of psychedelics on long-term neuroplasticity and neural network dynamics in healthy human research participants using various neuroimaging techniques.

Working with Harvard University, Massachusetts General Hospital recently opened its Center for the Neuroscience of Psychedelics to better understand how psychedelics enhance the brain’s capacity for change, optimize current treatments and create new treatments for mental illness.

Understanding the neuronal basis of how psychedelics affect the brain is essential for realizing the therapeutic potential of psychedelics. Findings from such research not only inform scientists but also regulatory bodies who are tasked with determining the safety and efficacy of psychedelic treatment models so that they can be brought to market.

References

1. Hopkins Medicine. (n.d). Brain Anatomy and How the Brain Works. Baltimore: Johns Hopkins Medicine. https://www.hopkinsmedicine.org/health/conditions-and-diseases/anatomy-of-the-brain

2. Voelcker-Rehage, C., Nienmann, C., Hübner, L., Godde, B., & Winneke, A. (2016). Sports and Exercise Psychology Research: From Theory to Practice. Academic Press. https://www.sciencedirect.com/science/article/pii/B9780128036341000030

3. Buckner, R., Andrews-Hanna, J., & Schacter, D. (2008). The brain’s default network: anatomy, function, and relevance to disease. Annals of The New York Academy of Sciences. https://pubmed.ncbi.nlm.nih.gov/18400922/

4. Sheline, Y., Barch, D., Price, J., Rundle, M., Snyder, A., Mintun, M., . . . Raichle, M. (2009). The default mode network and self-referential processes in depression. Proceedings of the National Academy of Sciences. https://www.pnas.org/content/106/6/1942

5. Nutt, D. (2019). Psychedelic drugs-a new era in psychiatry? Dialogues in Clinical Neuroscience, 139-147.

6. Griffiths, R., Richards, W., McCann, U., & Jesse, R. (2006). Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology.

7. Barrett, F., Johnson, M., & Griffiths, R. (2017). Psilocybin in long-term meditators: Effects on default mode network functional connectivity and retrospective ratings of qualitative experience. Drug and Alcohol Dependence. https://www.sciencedirect.com/science/article/pii/S0376871616302988

8. Barrett, F., Preller, K., Herdener, M., Janata, P., & Vollenweider, F. (2020). Serotonin 2A Receptor Signaling Underlies LSD-induced Alteration of the Neural Response to Dynamic Changes in Music. Journal of Contextual Behavioural Science.

9. Ly, C., Greb, A., Cameron, L., Wong, J., Barragan, E., Wilson, P., . . . Olson, D. (2018). Psychedelics Promote Structural and Functional Neural Plasticity. Cell Reports.