The Biology of Psychedelics: Part II
“Your head is a granite rock of neural impulses; get some dynamite if you need it.”
-Abbie Hoffman, Revolution for the Hell of It
In today’s newsletter you will learn:
How psychedelics alter neuronal activity
How psychedelics alter gene expression
A common human experience...
...is the one where you get old and life seems to become more and more mundane. We may have been naive as kids, but don’t you think there was a sort of wisdom in the way we viewed the world back then? As we age, our brains settle; our neurons establish their connections, and their flexibility diminishes. We formulate most of our habits and worldview by our mid-twenties, and then we coast through life riding on the bet that we got it right.
Hate to tell ya, but that dent in your couch, formed under the weight of the TV-watching habit you formed at 23, was made by the same neurotransmitters hitting the same receptors on the same neurons, day after day. There is hope for you yet. Psychedelics are molecular defibrillators that can jumpstart the flexibility of your brain. Just like mixing up your workout routine is good for your fitness and long-term physical health, working out your neurons in different ways is good for your mental well-being and long-term cognitive health. Psychedelics can’t give you a new couch, but they can make you feel like you’re sitting on it with a new ass.
Learning the biology of psychedelics will help you understand why participants in psychedelic studies report long-term, positive benefits in mental health1, and why psychedelic-assisted therapy can reduce suicide ideation in as little as one session.2 So then, what do psychedelics do in the brain?
Psychedelics alter neuronal activity.
The coordinated networks of neurons in your brain form the basis of your entire perception of reality and sense of self. Sweet. Your neurons are organized into circuits, like the wires in your computer, and those circuits are organized into brain regions, like the different modules in your computer. Neurons communicate by releasing neurotransmitters to each other, and are often described by the type of neurotransmitter they release. For example, neurons that release serotonin are “serotonergic”, while neurons that release dopamine are “dopaminergic”. A serotonergic neuron can receive inputs from dopaminergic or glutamatergic (releasing glutamate) neurons, as long as it has the receptors to bind those neurotransmitters.
When psychedelics bind to neuronal receptors, they cause it to fire with new patterns and frequencies. Neuronal “firing” means that it releases neurotransmitters to other neurons. Those receiving neurons will then fire with new frequencies and patterns, and so on. This creates a cascade effect around the brain, altering global brain activity, and manifesting in your consciousness as a “trip”.
The classical psychedelics (LSD, psilocybin, DMT, mescaline, etc.) primarily bind to a receptor called serotonin 5-HT2a. Neurons with this receptor are found throughout the brain, but are concentrated in our cerebral cortex.3 Our cortex is the outermost layer of our brain (you know, the squiggly part 🧠). This part of our brain plays huge role in creating our perception of the world by blending together signals from all over the brain.
When psychedelics bind to the 5-HT2a receptors in this area, it initiates a cascade of neuronal firing that alters the activity of major networks in the brain. Feelings of ‘oneness’, ‘inter-connectedness’ and ‘ego-dissolution’ are correlated with the disintegration of our usual brain connectivity, and the strengthening of connections between brain regions that usually do not communicate.4 5 The nature of these brain states and their relation to the psychedelic experience are active areas of research. They have the potential to help us understand what the hell this thing we called consciousness even is.
Psychedelics alter gene expression
Every cell in an organism contains the entire DNA code of that organism. However, any one cell only activates the genes that it needs to perform its duties. So, an immune cell will express different genes than a skin cell, which will express different genes than a neuron. Gene expression is an ongoing and dynamic process because cells exist in extremely dynamic environments. The ability to switch genes on and off allows cells to adaptively respond to their environment in the pursuit of keeping us, the organism, at a stable level.
The brain is one of the most stable environments in the body, however, neurons are constantly switching genes on and off in response to their environment. Serotonin 5-HT2a receptors are G-protein coupled receptors (See Biology Part I) which, when activated, initiate a number of different process in cells. Some of these processes trigger the expression of genes in neurons that promote the growth of new branches of neurons. Other genes triggered by psychedelics promote the rearrangement of neuronal connections, a phenomenon called called neural plasticity.6 The ability to promote the growth and plasticity of neurons is most likely what underlies the long-term therapeutic benefits of psychedelics.7
Put them together and…
You get some damn cool molecules that have the power to mold your mind and jostle you out of the mind-ruts you may find yourself in. Psychedelics are a 🔥 hot 🔥 topic in neuroscience and mental health research right now for this reason. They have shown stunning clinical outcomes for treating mental illnesses and are basically our only tool for understanding the nature of human consciousness. Psychedelic decriminalization movements around the U.S. signal that one day, anyone who desires to explore their own mind and view the world with fresh eyes may be able to do so without having to hide it. That, my friends, smells like freedom.
From around the Psychosphere
🥊 Shports
UFC x Johns Hopkins Psychedelic Study? Read up on what might shape up to be the first professional sport to integrate psychedelics into athlete care
⚖️ Ethics:
The North Star Ethics pledge is something to be aware of as psychedelic companies start vying for your dollars. We need to hold psychedelic companies accountable for their impact on society. Spend and invest wisely friends.
🧪 Science:
Go deep on the Serotonin 5-HT2A receptor with an excellent psychedelic science communicator:
Follow The Psychedelic Scientist here:
Tunes for your next flow state:
🔥 ARTBAT - BBC Radio 1 Essential Mix 2019-07-13
🍯 Khruangbin @ Villain | Pitchfork Live
⚗️ Stay tuned Friday for a breakdown of this weeks psychedelic research article.
Aday, J. S., Mitzkovitz, C. M., Bloesch, E. K., Davoli, C. C. & Davis, A. K. Long-term effects of psychedelic drugs: A systematic review. Neurosci. Biobehav. Rev. 113, 179–189 (2020).
Ross, S. et al. Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer. ACS Pharmacol. Transl. Sci. acsptsci.1c00020 (2021).
Carhart-Harris, R. L. How do psychedelics work? Curr. Opin. Psychiatry. 32, 16–21 (2019).
Carhart-Harris, R. L. et al. Neural correlates of the LSD experience revealed by multimodal neuroimaging. Proc. Natl. Acad. Sci. 113, 4853–4858 (2016).
Petri, G. et al. Homological scaffolds of brain functional networks. J. R. Soc. Interface11, 20140873 (2014).
Ly, C. et al. Psychedelics Promote Structural and Functional Neural Plasticity. Cell Rep. 23, 3170–3182 (2018).
Martin, D. A. & Nichols, C. D. The Effects of Hallucinogens on Gene Expression. in Brain Imaging in Behavioral Neuroscience 137–158 (2017).
Great post Tyler! To what are you comparing the brain here? Or on which dimension?
"The brain is one of the most stable environments in the body"
Are you referring to the blood-brain barrier keeping things out maybe?
Awesome info, thanks, Tyler! It would be really great to know when studies are recruiting for volunteers, or to know what types of treatments are becoming available as psychedelics are decriminalized.