This review (2019), for a psychiatry audience, summarizes our current understanding of how psychedelics work, from 5HT2a agonism to more bottom-up processing.
Abstract
“Purpose of review Psychedelics are reawakening interest from psychiatry, cognitive neuroscience and the general public with impressive outcomes in small-scale clinical trials, intriguing human brain imaging work and high-impact journalism. Recent findings This brief opinion piece offers a perspective on how psychedelics work in the brain that may help contextualize these developments. It attempts to link various scales of action, from the molecular (serotonin 2A receptor agonism) through to the anatomical and functional (heightened plasticity) and up to the dynamic (increased brain entropy), systems level (network disintegration and desegregation) and experiential. Summary It is proposed that psychedelics initiate a cascade of neurobiological changes that manifest at multiple scales and ultimately culminate in the relaxation of high-level beliefs. The purpose of psychedelic therapy is to harness the opportunity afforded by this belief-relaxation to achieve a healthy revision of pathological beliefs.”
Author: Robin L. Carhart-Harris
Notes
This paper is included in our ‘Top 10 Articles for Psychedelic Novices‘
Key points according to the author:
- Psychedelics relax high-level priors or ‘beliefs’ through a hierarchically high-level locus of action.
- 5-HT2AR-initiated belief-relaxation begets potential belief-revision that, if properly mediated, can be conducive to improvements in mental health.
- Trauma and associated uncertainty may trigger the tightening of certain implicit beliefs that express as symptoms of psychiatric disorder.
- Psychedelic therapy has the potential to remediate such aberrant beliefs via a process of belief relaxation and revision.
Summary
Robin L. Carhart-Harris a,b
Psychedelics are unique among brain drugs, inspiring interest across a broad range of disciplines. They have impacted on Western culture significantly, spawning a new approach in psychiatry, genre of music and art, and perhaps even a way of thinking and living.
CLASSICAL PSYCHEDELICS
The effects of classical psychedelics can be traced to an initial action at the molecular level (5-HT2AR), and if this receptor is blocked, none of their fantastical effects can occur.
5-HT2A receptors are most densely expressed in the cortex, especially on layer 5 pyramidal neurons, and 5-HT2AR-induced plasticity is most pronounced in the cortex.
5-HT2AR agonism has been found to induce an asynchronous mode of glutamate release and a spike-to-field decoherence, which may account for dysregulation appearing at the population level, and for the compromised functional integrity of canonical ‘resting-state’ or ‘intrinsic’ networks.
The entropiac brain hypothesis predicts that a more functionally interconnected brain reflects a more globally interconnected state of consciousness. This hypothesis has been replicated by independent teams and correlates with high-level psychological phenomena such as ego-dissolution and the unitive experience.
The ‘entropic brain hypothesis’ states that entropy-related metrics of population or network level brain activity index the richness-of-content of subjective experience in any given state of consciousness. This hypothesis originates from psychedelic research and speaks to the fundamental relevance of entropy for understanding the relationship between mind and brain.
PROCESSING
Until recently, there was no unified account of how psychedelics worked in the brain. However, predictive processing has emerged as the leading unified model.
The first focused attempt to provide a predictive processing account of psychedelics’ action appeared in 2017 in an intriguing article by Pink-Hashkes et al. 5-HT2ARs are expressed on high-level prediction units in high-level cortex.
Psychedelics have been shown to effectively treat depression, obsessive-compulsive disorder, end-of-life existential distress and addictions, and there is anecdotal evidence of ayahuasca being used to treat eating disorders.
Addictions are manifestations of unhealthy implicit beliefs that have become overly dominant and resistant to revision. The mnemonic TIghtened BEliefs in Response to uncertainty (TIBER) is offered to capture this phenomenon.
Psychedelics induce serotonin 2A receptor agonism, heightened plasticity and brain entropy, mirrored by the relaxation of high-level beliefs. This belief-revision may underlie the rapid and enduring improvements in mental health that are being widely reported with psychedelics.
The TIBER and REBUS models are largely conceptual, and more empirical work is needed to clarify how they interrelate.
LSD reduces low-frequency oscillations in the rat prefrontal cortex, and antipsychotic drugs reverse this effect. The paradoxical psychological effects of LSD are revealed by multimodal neuroimaging, and lifetime experience with psychedelics predicts pro-environmental behavior through an increase in nature relatedness. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action, and LSD increases primary process thinking via serotonin 2a receptor activation.
A multimodal neuroimaging model using serotonin receptor maps explains how the spatial distribution of serotonin 2A receptors can predict the functional brain effects of lysergic acid diethylamide.
Psychedelics promote structural and functional neural plasticity, and selective 5-HT2A and 5-HT2C receptor antagonists inhibit serial spatial reversal learning in rats.
Serotonin and brain function: a tale of two receptors. 5-HT1AR agonism aids stress moderation, whereas 5-HT2AR agonism is the main action of psychedelics.
A high-resolution in vivo atlas of the human brain’s serotonin system was made using 5-HT2AR layer 5 pyramidal neurons, and a new unifying principle was found in 5-HT2AR distribution in the living human brain.
Alpha oscillations carry visual and language-related priors. Psilocybin and MDMA affect resting state functional connectivity in healthy volunteers. Psychedelics modulate connectivity in the default mode network and ego dissolution is correlated with increased global functional connectivity. Moreover, the complexity of multidimensional spontaneous EEG decreases during propofol induced general anaesthesia is reduced to plain common sense. Pezard L, Nandrino JL, Saxe GN, Calderone GN, Morales LJ, Friston K. Exploration, novelty, surprise, and free energy minimization.
Psychedelics increase brain entropy, and this is evident in studies of spontaneous MEG signal diversity and Shannon entropy of brain functional complex networks. A narrative review of the research on the brain action of psychedelics, including a review of the entropic brain theory, a review of the self-evidencing brain, and a review of the default-mode, ego-functions, and free-energy: a neurobiological account of Freudian ideas.
Psilocybin was studied in 9 patients with obsessive-compulsive disorder and in 5 patients with advanced-stage cancer.
Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer. A rigorous double blind randomised control trial showed clear positive outcomes.
Psilocybin treatment reduced anxiety and depression in patients with life-threatening cancer, and improved alcohol dependence in a proof-of-concept study.
Several studies have examined the role of psychedelics in the treatment of depression, including ayahuasca, psilocybin, and music therapy. These studies have found that psychedelics may enhance suggestibility, and that music may help patients feel more connected and accept themselves.