Today we are going to talk about the mechanisms of action of psychedelics from a neuro-biological perspective, uhhh big words…you know! All those jungled up filaments you have in your head skull that get chemically stimulated by the LSD, psilocybin, MDMA and a few others, have what we call neuro-transmitters receptors, oh shit! Another big word! But keep cool and we are going to make sense of this stuff.
So whenever you hear the word neuro we are referring to nerves of the nervous system, this pretty extensive network of communication you have in your body! Ok? So neuro-transmitter means something that transmits, communicates, pass on a message from one nerve to another. The receptor is what receives this transmission, so, neuro, nerve, transmittter, communicator, receptor, receiver, nerve-transmitter-receiver.
So now back to what I want to talk about today, which is the MECHANISMS OF ACTION, and by this we mean “What are the mechanics that get triggered by these nerve transmission receptions? How does the brain engine get to move when we inject into its blood stream a psychedelic?” That’s what we are talking about today. Parenthesis “why is this important? Well, listening to technicalities about the functioning of your brain does two things:
1 It provides you with images, words, logics, a grammar to aid you in negotiating your intentions with yourself and others.
2 It shows you that some people out there are looking at this microscopically, correlating all of their observations with a very large database of observations about the brain, it’s chemistry, and its structure in general.
3 Understanding the Mechanics of Action and getting a grasp of the technical terms used in this field should shield you from hyper-polarised-narratives.
Ok, let’s get into it, and let’s list first of all the kind of mechanisms of action psychedelic drugs have been observed to trigger under experimental conditions:
1 Increased Neuroplasticity, which means increased flexibility of action in those nerves we talked about earlier, or increased ability of the brain to form and reorganize its connections
2 Alterations in the reward processing centres of your brain, some of which I have talked about in relation to light exposure in the video on Seasonal Affective Disorder. So alterations in the brain structures that drive the way we seek rewards, e.g. sexual organsms, kissing, hugging, chocolate!, lottery winnings, and even light itself
3 A decrease in neuroinflammation, which a growing body of evidence suggests is involved in psychiatric conditions such as depression, and others
4 The more typically talked about alterations of the Serotonin Receptors often involved in memory recall, learning and cognition in general.
Ok, before you get too excited, Dr. Katrin Peller, from whose conference talk I took most of this info, makes it clear from the get go that despite there being quite a few mechanisms for actions, none of them have been investigated enough to be sure of what exactly it is that makes psychedelic substances therapeutically beneficial. The data is just simply not in yet.
Now all of these mechanisms for action can be often correlated (NOTE!: correlated, NOT proven, or CAUSALLY associated) to:
1 Increased insight into one’s dysfunctional behaviour
2 Increased awareness of our social environment and the impact we have on it or it has on us.
That is, all of the above observed mechanisms for action, observed often in rats I shall specify, come down to a short term increase in alertness to patterns, your ability to see how things connect to each other, and an increased sensitivity to sense perception in general, which also helps in perceiving patterns.
So what happens in the brain when we ingest psychedelics?
We have talked about what gets triggered at large in the brain, the mechanisms for action, but we haven’t talked about the micro-activity taking place, how exactly the chemical compound acts on your brain.
Well, first of all the stimulation of the serotonin receptors that are on the surface of neurons changes the pattern of communication these neurons have, what we call their firing. And since serotonin receptors are mainly excitatory receptors, their stimulation increases the firing rather than decreases it. Now you may ask, “Is this happening just in the brain?” Good question folks! No, although serotonin receptors are distributed across different brain regions in different densities, there are more of these guys all along the nervous system, which means that our sense-perception is enhanced at all levels of our sensory system, including the skin. We become more sensitive to touch all over our bodies.
What is more important for us here, though, is to know that certain brain regions are going to be firing more than others.
“What are these brain regions?” You ask again! God you are a good student! ><
The sensory regions of your brain, the thalamus, and the posterior cingulate cortex (PCC).
"Ok, what the heck!" you now say. I am with you! ><
Ok, remember that in these regions there is now a serotonin receptor bias, correct? The serotonin receptors have been given a boost of excitation, so the neurons that fire do so not only in relation to this particular neurotransmitter called Serotonin, but the brain regions where there are more of them are also more active than those where there are normally less, and since brain regions specialise in the processing of different kinds of information, the processing that is going on here is skewed towards serotonergically dense brain-regions.
And why is this important? Because although we are now so excitedly fixated on the serotonergic molecules activating the brain’s serotonergic system, we must acknowledge that whatever we are getting out of it, says that super cool hallucinatory experience where you dive into your toilet and find it to be a gateway to the ocean depths, is essentially just the result of an amplified bias we have just introduced into the brain system!
And talking of biases, let’s not forget that these observations are done in laboratories, an environment of colors (or non colors), smells (or non-smells), textures (or non textures), etc., that communicates with our entire nervous system while under the serotonergic bias. So keep that in the back of your mind when we focus on “what we know”, because of course the results we get from our experiments are connected to these unavoidable interactions across the nervous system and across the space in which it functions. How these sterile environments skew the observed results by amplifying them or attenuating them, we just don't know.
Actually on this point Rob Coffey, psychotherapist and founder of the Irish Inwardbound Retreats, speaks of one of his most difficult psychedelic experiences he had in the presence of a veteran Shapebo grandmother guide in Peru, and says “I was going trough the most horrendous horrors of my own psyche, and she came and she sang with me, and she sang and sang and sang, and she sang until I was better, so substance is not enough”. And on a similar note, Dr. Martha Havenith tells us of a study done at Oxford with mice, whereby significantly different behaviours were observed in their reaction to psychedelic states when experiencing them in the comfort of their known cage, as opposed to completely new environments. When we look so closely at something it seems always good to pull back a little and look at the broader picture!
Ok ok, backtracking from this environmental tangent I got into, we get back to the microscopic world of chemical interactions and Dr. Katrin Preller assessed one model of the changes taking place under psychedelic influence called the Thalamus Filter Model. You don’t need to remember this, because there is a simple way to understand what the model stands for.
So here you have these sensory information processing regions of the brain, but prior to them there is the Thalamus. The Thalamus is like a traffic police agent that filters incoming information from the body and directs it to one or other region. The Thalamus Filter Model basically hypothesises that the traffic police agent is behaving differently when psychedelic molecules are around.
So how does Dr. Keller find this to be different for the brain?
Well according to her research, brain scans show that under psychedelic influence:
1 The sensory regions are hyper activated as well as hyper connected and in touch with one another, while the integration regions, the regions that integrate sound, vision, smell and so on and would normally make sense of these, are hypo-activated. In other words, there is an increase in sensory traffic (TRAFFIC SOUND), but the brain regions that would normally organise this traffic are not talking to one another anymore, except, funnily enough, for the posterior cingulate cortex (PCC), towards which the Thalamus seems to be sending more information than when it is in its sober state. The PCC has been implicated in human awareness in numerous studies, as well as in pain and retrieval of a type of long-term memory that involves conscious recollection of previous experiences, their context in terms of time, place, emotions, etc so this changes in communication with the PCC affect the way in which the brain is processing deep memories, perhaps particularly those with a traumatic quality.
2 Another line of observations comes back to this very central area called the amygdala, the emotion processing centre of our brain, the fear processor. Under psychedelic influence the activity of the amygdala seems to be reduced, showing that participants in studies give less credit to negative emotions.
For instance there is this interesting Social Exclusion experiment that has been replicated several times outside the scope of psychedelic research that shows that when someone is exposed to a game whereby two characters are passing each other a ball, first including the participant, and then excluding him or her, the emotional pain that is triggered in this process can be predictably placed in the amygdala and very much resembles the pattern of physical pain. What is more, is that people suffering from mental illnesses often tend to react a lot more strongly to this situation. Well, it turns out that under the influence of psilocybin participants suffering these forms of social pain, report significantly lower levels of negativity towards the experience of exclusion. And this does not impact the capacity of the participant to actually perceive the rejection, as in, to recognise that he or she is actually being excluded from receiving the ball. In other words, psilocybin, in its way of amplifying sensory input and decreasing regular connectivity, seem to open opportunities for re-connecting with the social environment in a different way.
In summary, at least in the short term, psychedelic assisted therapy is an interaction between pharmacological and non-pharmacological mechanisms that support the processing of negative life events, and the finding of new ways of looking at things, including new ways of interpreting our social connections and environments. These pharmacological effects happen principally through increased connectivity in the sensory processing areas, increased connectivity of one of the regions responsible for our views of self with the filtering system of the thalamus, and finally a decreased connectivity with the associative areas as well as the fear processing centres.
Ok what’s left uncharted here? Everything really! Dr. Keller is open to admit that the sample sizes of all the results presented to date are still very much too small and have not been tested in clinical populations, so we do not know if the effects we are seeing have something to do with the clinical mechanisms of action, all of which are important for any claims about predictability of efficacy in therapeutic settings. And Dr. Keller's stance is not unique. At the psychedelic conference in Berlin in 2020, over and over, the professionals at the INSIGHT conference reiterated that we just don’t have enough data to make any conclusive remarks.
Nonetheless, to conclude, and more broadly speaking, a critique of the overall research that I want to put forward, is that often times these pharmacological approaches take for granted depression, clinical anxiety, and a deep sense of isolation as normal features of our modern lives. These are not, as they would have it, byproducts of systemic social features, such as hyper individualism, hyper productivity, and hyper consumption of social media, which we know increases isolation and loneliness and consequently depression and relational anxiety. These are just neuro-chemical mechanisms.
But my point here is that, sure, depressive states manifest in rigid neural structures, and psychedelics seem to disrupt these rigid neural networks in our brains, but depression, high level anxiety and these deep feelings of exile are features of our hyper-productive, hyper-consumeristic, western-hegemonic individualistic societies, just as much as diabetes, heart attacks, obesity, and anorexia are byproducts of certain economic environments and not others. It is thus very hard, if not impossible, to argue that these issues are reducible, to any extent, to a chemical compound we could just swallow up! This is scientific reductivism in its pure form. In other words, do not assume that there really is a disease, that this disease is a fixed feature of our societies, and that the only point of leverage is bio-technological innovation. No way!
Well, that’s it from me folks, until next time!
Wishing you Well,
Your Shrink in Bansko
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