Introduction Part II: Cellular and Molecular Mechanisms of Psychedelics

Written By Michael Angyus

Introduction and basics of neurons

 Welcome curious friends to Psychedelic Neuroscience, where we use advances in psychedelic research to learn about brain, mind, and soul. I’m your host, Michael Angyus, and today we’re going to talk about the cellular and molecular research on psychedelics. This means we’re going to dive into the amazingly complex behavior of individual cells, tracking what happens within a neuron when a psychedelic activates its receptors, and how that affects the larger networks of the brain.

To start, let’s review some of the basic characteristics of a neuron and appreciate the beauty of your body, brain, and mind. Your nervous system is more than just the brain. It innervates the entire body creating a network of information flow that helps you dynamically interact with and feel connected to your environment. The experience you’re having now is manifested through an interactive process between the complex computations of the brain and the information coming in from the senses of the body. Some people feel like this view of consciousness as a computer-generated simulation is reductionistic, but we have to remember that the simulation that we call reality is the product of everything in the universe. It is the  culmination of every dynamic force in the world, every law of physics, every transfer of energy, and every bumping and bouncing of molecules against each other to unfold as the electrochemical communication center that is the universe observing itself. This is the scientific perspective of the brain. The fundamental unit of this system is the neuron, of which there are around 100 billion in the brain (von Bartheld et al., 2016). Each neuron in the brain averages around 15,000 connections to other neurons, forming a vastly complex network that is currently trying to understand itself.

Each neuron’s structure can be thought of like a tree that is taking information from the roots and sending it out through the branches. The roots of this neuron tree are called dendrites, which receive information from other cells, while the branches are called axons, which send information to other cells. The trunk of this tree is called the soma. The soma of our tree-like neuron is a bulging, swollen trunk which contains various organelles including the nucleus and DNA. Like in all cells, the nucleus acts as the command center of the cell, where molecules help other molecules copy their arranged sequence and float that copy through the dense cellular mush to cellular factories (which are just bundles of other molecules that help the molecules produce more molecules). Within the neuron, the molecules that are produced in these factories are neurotransmitters, receptors, and structural materials. The structural materials create the scaffolding around the neuron, assembling that basic shape of swollen trunk-like soma and the network of branch-like axons and root-like dendrites necessary for communication with other neurons. This complicated network is given more complexity through the use of different neurotransmitters, which basically allow neurons to speak different languages with each other. Neurotransmitters are small molecules held in the tips of axonal branches that are specialized to release under specific conditions. These small molecules find their way into receptors that position themselves on the dendrites of the next cell. The receptors are specialized proteins that only respond to specific neurotransmitters, allowing a multi-lingual discussion between neurons of the brain. The variation in what languages each neuron can use allows different neurons to act differently within the network, adding to the complex interaction of cells that sets goals, falls in love, and, in this moment, wonders curiously about how it wonders curiously.

Our scientific understanding of how an individual neuron works is much more concrete than our understanding of how they make up our mind. Through studies of individual neurons grown in the lab, and through studies of individual neurons of animals, researchers have explored how psychedelics are affecting the receptors of neurons and triggering cascades of responses within the cell and subsequently its network. With this brief introduction on these beautiful fundamental elements of the mind, we can now dive into how psychedelics interact within these tiny systems.

 

The 5HT-2A receptor

In this episode and the introductory series more broadly, I’m going to focus on what have been called “Classic Psychedelics” which includes but is not limited to LSD (otherwise known as acid), psilocybin (the active molecule in magic mushrooms), DMT (the active compound in Ayahuasca), and Mescaline (the active molecule in peyote and san pedro cacti). Classic psychedelics does not include drugs like Ketamine, MDMA, or salvia although some of these trigger similar mechanisms in the brain, though not through as clean of a fashion.

There appears to be a single receptor that explains the majority of classic psychedelic effects: the serotonin subtype 2A (5HT-2A) receptor (5HT stands for 5 hydroxy-tryptamine which is the molecular name for serotonin). In human studies, subjective effects of classic psychedelics have been blocked by the administration of 5HT-2A antagonist ketanserin (Vollenweider et al., 1998; Preller et al., 2017). An antagonist is a molecule that fits into a specific receptor without activating it, meaning when we block the 5HT-2A receptor, people don’t trip. Additionally, researchers have related 5HT-2A receptor occupancy, that’s the percentage of 5HT-2A receptors that that are filled with the psychedelic, to the intensity of subjective effects (Madsen et al., 2019). These studies have led researchers to elect the 5HT-2A receptor as the primary route by which psychedelics generate their profound and often mystical subjective effects (To be dramatic, I sometimes call this receptor: the ‘God button’).

The 5HT-2A receptor is one of at least 14 serotonin receptor subtypes, each of which responding differently to the neurotransmitter serotonin. While the function of serotonin is complex, researchers have primarily understood it as it relates to our response to stress. A simplified view of the serotonin system proposed by Carhart-Harris & Nutt, 2017 – journal of psychopharmacology divides the response to stress into two categories: passive coping, which is the reduction or suppression of an emotional response to stress, and active coping, which is directing attention towards the processing of emotions. They then offer that two of the 14 receptors are primarily responsible for activation of these different stress responses, with 1A receptors primarily facilitate passive coping while the 2A system facilitates active coping.

This two-receptor view offers a mechanistic explanation for the known differences in patient responses to traditional antidepressants vs. psychedelics. While daily consumption of a traditional antidepressant may primarily act on the 5HT-1A system to facilitate passive coping with depressive symptoms, high-dose psychedelic sessions could act on the 5HT-2A system to promote active coping with depressive symptoms. I want to highlight that both medicines can be useful tools if combined properly with therapy, but this distinction is one of the reasons psychedelics are shaking up psychiatry.

The discovery of antidepressants brought with it the idea that mental illness is simply an imbalance in the ratios of chemicals within our brains, something that could be solved by the daily consumption of a pill. For decades research, psychiatry, and the broader culture have shaped themselves around this perspective, but mental illness is far more complicated than the idea of a chemical imbalance in the brain (Moncrieff et al., 2022). Yes, the brain is the mechanism behind the person, and with increasing understanding of the brain we can develop molecular tools that leverage those mechanisms and help the person have a better relationship with their emotions. However, there will never be a pill or a mushroom that completely abolishes the need to attend to the human on a personal level.

 

Molecular keys to spiritual manifestation

Before we get into the specific features of psychedelic molecules that help them activate the 5HT-2A receptor, we first have to get these drugs into the brain. This generally depends on the charge of the molecule, which affects its ability to cross the blood brain barrier, which protects the brain by keeping much of what is in the blood out of the brain. In the world of drug development where crossing the blood brain barrier is necessary, researchers have established a “Rule of Three” which classifies molecules that are likely capable of entering the brain. The Rule of Three is that the molecules are small, relatively hydrophobic, and possess few hydrogen-bond donors and acceptors (Congreve et al., 2003). This basically means that if they’re small and have the right overall electric charge, they’ll be able to enter the brain. Psychedelics often abide by this rule, and they additionally have a pKa close to that of blood (7.4) which means that electrical charge won’t be altered by the blood, further improving the chances of entering the brain. This step makes it difficult to develop new drugs that treat mental illness. With the fortunate discovery of psychedelics, we can learn from this natural class of drugs. Using the basic shape of psychedelics, we can explore how variations to this structure can help serve different applications. Some people are alarmed by humans manipulating molecules which will eventually enter the body, but I don’t think human intervention with something natural is necessarily wrong. Science is an extension of nature, not independent of it. A tree is experimenting with the molecules within it the same way it experiments with the limbs it grows. Branches weave in all directions and some remain while others fail, meaning all molecules of nature are the results of experimentation. Our scientific approach is indeed an accelerated version of this process, but that does not eliminate the possibility of a genuinely positive discovery. The technologies and medicines that stand the test of time are an extension of nature just as we are. When learning from what has been produced by nature, such as the case with psychedelics, we can invent new technologies that help us survive in and interact positively with nature.

Once the drug has crossed into the brain, there are common molecular structures shared between psychedelics that help them activate the 5HT-2A receptor. Classic psychedelics all maintain a basic shape, which coincidentally resembles that a traditional key with a circular handle, a long shaft, and a uniquely shaped tip (If you visit psychedelicneuroscience.org you can see a figure from Kwan et al., (2022) for a collection of molecular diagrams for various classic psychedelics). At the tip of this key is an amine group, which has a positively charged nitrogen atom that forms a salt bridge with a negatively charged aspartate residue within the binding pocket of the 5HT-2A receptor. You can think of this like the tip of the key moving into the lock and turning the specific tumblers necessary to activate the receptor. The handle of the key is composed of a cyclic aromatic group, which can either be a phenyl group (phenethylamines) or an indole group (Benzene and Pyrrole combo - tryptamines and ergolines). This cyclic ‘handle’ forms important hydrogen bonds with other residues of the 5HT-2A receptor which hold the molecule in place. This stability helps the key remain in position the same way the handle of a usual key would. The amine ‘key tip’ is separated from the aromatic ‘handle’ by a two-carbon linker which makes up the shaft of the key.

Figure 1: The classic psychedelic molecular family copied from Kwan et al., (2022)

Shortening this ‘shaft’ creates an antagonist (Froldi et al., 2004), while lengthening it reduces affinity (Glennon et al., 1978). This tells me that if the key is too short, the amine can’t reach the aspartate residue and ‘unlock’ the receptor. If the key is too long, the cyclic handle sticks out and can’t form stable hydrogen bonds. Another aspect of potency can come from rigidity of the key. In LSD, the bulging ergoline backbone around the key’s shaft adds to potency because the molecule cannot change into incompatible shapes; the key cannot be bent (Nichols, 2018). Potency can also be increased by adding structures to the amine (the key tip) that improve its fit into a secondary binding pocket (aka tripping more tumblers within the lock). Finally, we can increase duration of drug experience by preventing metabolic degradation of the molecule. This can be done by adding a methyl group to the carbon linker key shaft.

These are the basic features that lead psychedelics to activate that oh-so-special 5HT-2A receptor, and numerous research groups are in the process of editing these features for distinct effects (Kaplan et al., 2022). By artfully cutting new keys to the God button, we may modify the experience duration, intensity, and quality for unique therapeutic and research applications, bringing more of the soul into the grasp of the scientific approach.

 

Other receptors related to psychedelic action

While evidence points toward the 5HT-2A receptor for primary effects (and specifically subjective effects) of classic psychedelics, they also target several other receptors in the brain. LSD appears to have the most promiscuous activity of the classic psychedelics, with affinity for other serotonin receptors, as well as receptors for dopamine and adrenaline (Kroeze et al., 2015), but we’re unclear on how these receptors are contributing to the subjective experience. Rodent studies have linked some alternative effects to these receptors (Marona-Lewicka et al., 2005; Grailhe et al., 1999; Marona-Lewicka et al., 2009), but a human study asking participants about the different subjective effects of LSD and Psilocybin in a controlled setting did not show significant differences in the reported experience except for in duration (Ley et al., 2023). This does not mean the experiences are identical because our subjective questionnaires may still lack sufficient detail, but it does tell us that the fundamental effects of these drugs are fairly similar, which may be due to their common mechanism of the 5HT-2A receptor.

Psilocybin and DMT also activate more than the 5HT-2A receptor (Klein et al., 2021), and these other receptors may contribute to the differences in subjective experience. For instance, two studies by the research group at the University of Zurich in Switzerland have suggested that 5HT-1A receptor activity can reduce visual hallucinations in humans (Pokorny et al., 2016; Preller et al., 2020). This early work glimpses what could be an exciting research avenue. Delineating the contributions of each receptor to the psychedelic experience could help us fill mechanistic connections between our understanding of molecular, cellular, and network level components of perception and psychology.

 

5HT-2A induced neuroplasticity

Research on the downstream molecular and cellular effects of 5HT-2A agonism has shown psychedelics can induce neuroplasticity. Dr. David Olson’s lab at UC Davis demonstrated psychedelic induced neural growth in vitro, which relied on 5HT-2A receptor activation (Ly et al., 2018). This paper sits center stage in the neuroplasticity subfield of psychedelic research, which has since replicated these results in vivo, in rodents (Shao et al., 2021; Cameron et al., 2023; Olson, 2022; Jefferson et al., 2023). This promotion of neuroplasticity aligns with the general idea that psychedelics are agents of change. Unfortunately, replication of these cellular and molecular studies is not possible in humans, and studies using secondary markers of neuroplasticity in humans have yielded mixed results (Olson, 2022). Understanding psychedelic induced neuroplasticity in humans is a nascent area of research in which novel imaging tools and markers will likely bring insight in coming years.

 

Can we remove the subjective effects from psychedelics?

While subjective effects have been linked to therapeutic outcomes, and the 5HT-2A receptor has been linked to subjective effects and neuroplastic effects, it is still unknown whether subjective effects are necessary for successful therapy. Further work by Dr. David Olson has focused on the development of non-psychedelic psychedelics which he calls neuroplastogens (Olson, 2022). At the root of this approach is the idea that psychedelics might produce their therapeutic effects by inducing neuroplasticity, which can be separated from the subjective effects of the drug. Head twitches in rodents are highly correlated with their ability to determine whether they are under the influence of the drug (Halberstadt et al., 2020), suggesting a strong proxy for subjective effects of psychedelics. Hesselgrave et al., (2021) showed that blocking the 5HT-2A receptor with ketanserin reduced the head twitch response without inhibiting neuroplastic effects of psychedelics, suggesting distinct mechanisms for subjective and neuroplastic effects. Additionally, a recent paper published in nature neuroscience demonstrated that classic psychedelics LSD and psilocybin manifest their neuroplastic effects by binding to TrkB, an effect that is independent of 5HT-2A activation (Moliner et al., 2023). The involvement of TrkB was already shown by previous plasticity studies, but this study showed that psychedelics bind directly to TrkB at extremely high affinities, triggered plasticity without the activation of 5HT-2A. In humans, a recent study found that ketanserin administration one hour after LSD reduced the duration of subjective effects from 8.5 hours to 3.5 hours (Becker et al., 2022). This reduction in duration creates the opportunity to see if subduing subjective effects hinders the therapeutic capabilities of psychedelics. If psychedelic assisted psychotherapy is feasible without the hallucinogenic drug effects, our understanding of the role perception and experience plays in recovery would be drastically questioned. However, removal of psychological and social components from the treatment of mental illness has historically created problems for therapy (Sarafino & Smith, 2014), so it’s important that we don’t rush into reducing the full therapeutic experience to a molecular description of plasticity.

 

Where is the 5HT-2A receptor?

5HT-2A receptors are distributed widely throughout the brain (see the figure below from Beliveau et al., (2017) for receptor distribution maps). However, 5HT-2A receptors are densely expressed in layer V pyramidal neurons across the entire cortex. This facilitates broad connections between cortical regions as well as project cortical information to deeper brain regions (Aru et al., 2019; Larkum, 2013). Stimulation of these neurons appears to drive the effects of psychedelics but understanding how specific functional alterations in different cortical and subcortical regions relate to subjective and therapeutic effects will take decades to disentangle. 5HT-2A receptor agonism increases the likelihood that a neuron will fire, while 5HT-1A agonism decreases it (Whitaker-Azmitia, 2001). However, the overall excitatory or inhibitory effect on neuronal populations is dependent on the neurotransmitters of different cell types. A mixture of excitatory (glutamatergic) or inhibitory (GABAergic) cells make the downstream population level activity of psychedelics less clear (Wood et al., 2012). 

 

5HT-1A and 5HT-2A receptor distributions. Originally from Beliveau et al., (2017)

While the chemistry and neurobiology of psychedelics provides us with some much-needed footing in this mysterious and mystical field of science, it is still a very long way from unification with the other levels of study. To call the 5HT-2A receptor the “God Button” is a reductive simplification. In reality we are nowhere close to uncovering the brain basis of spirituality, and research continues to emerge around other receptors and mechanisms that might be contributing to the things we find special about psychedelics. What I’m aiming to portray with my cheeky use of the term “God button” is that there is potentially a biological basis for spirituality, a fundamental process of transformation used by the brain to develop the deeper self. The finer details of how this process is experienced may depend on the persons background and perspective of the world. Some may see it through the lens of their religious upbringing, and others through the perspective of emotional or psychological development. I see psychedelics as an opportunity to look beneath the language that an individual uses, opening the door for us to respect various interpretations of a potentially common phenomenon, regardless of religious or philosophical background.

This was the second episode of a four-part introduction series, where I’m giving you an overview of the field from the molecule up to the mystery. This episode was science heavy, covering the cellular and molecular cascades of activity that psychedelics trigger, giving you a feel for the ways in which this level of research can connect to and influence our understanding of brain, mind, and soul. In the next episode, I will move up a level to the neuroimaging work and cover the three leading models of psychedelic action. Thanks for tuning in to Psychedelic Neuroscience, see you next time.

 

You can find the script for this episode with in-text citations at psychedelicneuroscience.org (that’s psychedelic neuroscience .org, not .com). If you enjoy the show, subscribe on your listening platform or sign up for the email list through the website. If you’d like to contact me with questions, recommendations, or guests you’d like me to invite on the show, you can email me at psychedelicneuroscience@gmail.com. Additionally please email me if you feel I’ve made an error or misinterpreted the science in any way. This podcast is a place for us to learn together, so I will announce any previous mistakes at the beginning of future episodes. Finally, if you’d like to support this completely free podcast financially, you can do so by donating at psychedelicneuroscience.org. As always, thank you for stretching your mind to harmonize science and spirit, catch you next time.

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Michael Angyus
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Introduction Part I: Psychedelic Neuroscience in a Nutshell
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Introduction Part III: Neuroimaging and Models of Psychedelic Action