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Neurons are the basic building blocks of our nervous system and are responsible for sending and receiving sensory information between other neurons through an electrochemical process. If a neuron is stimulated, it generates an electrical impulse and if that impulse reaches the end of the neuron, it stimulates the release of chemical messengers called neurotransmitters. These neurotransmitters are released into the synapse or the space between two neurons, then bind to receptors found on the surface of the second neuron to complete the transmission of the message. When a neurotransmitter is bound to a receptor the fit is very similar to a key fitting into a lock that unlocks that receptor function.
Psychedelics act as a key fitting into specific ‘locks’ or receptors. Psychedelics have an affinity for and fit into 3 primary receptors (1) adrenaline receptors, which increases attention, focus and excitement, (2) dopamine receptors, which is involved in motivation, movement, learning and mood, and (3) serotonin receptors which is often associated with memory, learning, and happiness.
When you ingest a psychedelic, it primarily binds to serotonin receptors, namely, subtype 5-HT2A (ref). This interaction between the psychedelic and the serotonin receptor seems to result in profound changes in perception, cognition, and many other bodily systems. The 5-HT2A receptor is the most abundant 5-HT receptor in the cerebral cortex and is predominantly found in the cortical versus subcortical brian regions (ref). The cerebral cortex, the outermost layer of the brain, is where higher order activities take place such as decision making and problem solving but also plays a key role in memory, learning, reasoning, emotion regulation, consciousness and functions related to your senses. The subcortical (i.e beneath the cortex) regions are the more primitive brain regions which are constantly processing and relaying information to multiple brain regions including the cortex on an ongoing basis. There is relaying and processing of information from the cortical to subcortical regions referred to as top-down processing and from subcortical to cortical regions referred to as bottom-up processing.
Functionally, the brain is anatomically linked by neurons arising from multiple different brain regions and organized into networks. The communication between these networks is referred to as the functional connectivity and measured by fMRI BOLD (blood-oxygen-level-dependent imaging) signals, which detect changes in blood flow and oxygenation within the brain. These changes in blood flow and oxygenation correspond to neuronal activity in these brain network (ref). In scientific studies looking at the effects of psychedelics on functional connectivity, a subject’s resting fMRI BOLD signal is measured to establish a baseline. The subject lies on their back, is moved into the fMRI scanner, and that baseline data is collected. After a psychedelic is administered, another scan is done, and by comparing the data set with and without the drug present, scientists can make inferences about what might be happening in these networks based on the changes they see and how they map onto the subjective experience (ref). Beyond looking at fMRI BOLD signals, subjects are also asked about depression, anxiety, quality of life, and the Mystical Experiences Questionnaire (ref) to name a few to see if changes in BOLD signal are correlated with subject reported outcome measures.
Now the 5-HT2A receptor density appear to be relatively high in regions that serve the default-mode network (DMN), a network of brain regions that are most active when we are not engaged in a task, hence, the default mode. The DMN is active during mental processes such as mind wandering, rumination, mental time travel (i.e. reflecting on the past and the future), thinking about oneself, and thinking about others (ref). After a single dose of a psychedelic, studies report significant reductions in activity within DMN which often coincides with less negative thinking, relaxed beliefs, less rumination, and more perceived unity (ref, ref). In days and even weeks after the psychedelic experience, many individuals often report being more patient, feeling less stressed, and a notable elevation in mood. These acute changes are often referred to as a ‘brain reboot’. It is this ‘reboot’ and changes in the functional connectivity of the DMN where psychedelics may create this sea of therapeutic potential. However, there may be other brain regions that mediate activity in the DMN such as the dorsolateral prefrontal cortex (DLPFC) that are also undergoing a ‘reset.’ To create a more holistic view as to how psychedelics exert their proposed therapeutic potential, there is growing support in the cognitive neuroscience literature surrounding entropy (ref) and predictive processing (ref, ref).
Negative thoughts patterns are a hallmark feature of many mental health conditions such as depression (ref) anxiety (ref) and eating disorders (ref). Reductions in DMN activity correspond to less repetitive negative thinking and enable capacity for change (i.e neuroplasticity) to form new mental habits (ref). Negative thinking is a normal part of a person’s day to day, which likely has important benefits (i.e. threat detection) from an evolutionary perspective, but it can lead to needless suffering and even mental health problems when engaged too often. There is a growing body of evidence that psychedelics provide a temporary window of time for less negative thinking and a relaxation of prior beliefs which allows for enhanced mental flexibility (ref, ref), a chance for new perspectives to be realized, new narratives to be formed (ref), and short to longer term reductions in depression and anxiety (ref). Similar to a fresh blanket of snow filling deeply rutted ski tracks, the psychedelic creates a mountain of potential where forming new tracks becomes possible and new areas can be explored.
In summary, classic psychedelics such as psilocybin and LSD primarily bind to serotonin receptors, although there are other binding sites. Activation of the serotonin receptors leads to a reboot of the default mode network and other brain structures that may govern it. It is this reboot that may create a window of opportunity to take new perspectives and form new narratives during the integration process. This explanation is simple and reductionist, and by its nature will leave out other lines of inquiry and rationale, but it is a common narrative that has held over the years.
