What happens when we take psilocybin?
Many may understand psilocybin, the core psychoactive component of “magic mushrooms”, as a compound that induces powerful, mind-bending, and even theistic hallucinations - much akin to other classic psychedelics such as LSD (lysergic acid diethylamide), DMT (N, N-dimethyltryptamine), and mescaline. But what does this all mean - down at the molecular level? How do psychedelics modulate our brain? Can science close the explanatory gap between the subjective, phenomenological experiences of psilocybin and our current objective understanding of the neuropharmacology of these compounds?
Maybe, if we lend enough credence to the best approximations that science can come up with. Psychedelic research is still in its infancy, beset with a lot of epistemic issues, but so far, it has seemed to provide adequate approximations. Just in the last decade, research published by multiple academic teams and institutions have significantly furthered our understanding of psilocybin on both the experiential level and the neurobiological level. On the experiential front, three component parts exist for every experience: the visual/physical, the cognitive, and the emotional. On the neurobiological front, many state-of-the-art modalities and methodologies have enabled the mapping of these component parts to processes in the brain.
The visual/physical part of the psilocybin experience can include visual, auditory, or tactile hallucinations, synesthesia (i.e. integration of the sensoria such as seeing music notes), pupillary dilation, altered bodily perception (e.g. feeling the body is unusually light), uncoordinated movements, headaches, and temperature, heart rate and energy fluctuations . These can be generally explained by psilocybin’s action on the serotonergic system. It also indiscriminately binds to serotonin (5HT) receptors found throughout the body outside of the brain, accounting for a host of downstream physiological effects. The mind-altering properties of the compound can also shift our subjective interpretations of these physiological changes (or lack thereof).
Recently, a growing body of evidence has borne out the claim that psychedelics, in altering the way we conceive of reality, serve to expand our mind and increase our openness to new experiences and ideas. . During conscious wakefulness, our brain activates a circuit called the default mode network (DMN), which engages in activities such as daydreaming, mind-wandering, reminiscing about the past, and envisioning the future. These functions essentially serve to buttress our brain’s conception and narratives of ourselves - namely, our ego. The narrative of the ego is built and fortified by decades of experience and knowledge about the world, and ourselves in relation to the world, so that our inferences based on our experiences enable us to make the best choices for our own survival. Simply put, the ego is an operating system that relies heavily on its past inputs to minimize prediction errors about the world. Although vital to our survival, the ego can go awry and do us strong disservice, such as in the cases of psychiatric illnesses. Many disorders such as depression, obsessive-compulsive disorder, and eating disorders have been linked to hyperactivity of the DMN. Indeed, those afflicted with the disorders tend to be entrenched in ego-driven, inflexible mental patterns and a resistance to new information that may aid in recovery. The nature of the ego is inherently an existential defense against the future unknown. However, it is not always adaptive, and eventually renders our defense weak.
Psychedelics have the power to reverse this maladaptation. By quieting the DMN and therefore the ego, psychedelics invite novel sensory, cognitive, and emotional experiences to modify and refine the possibly outdated system in ways that enable us to be more adaptive to our surroundings . Another model posits that psychedelics, by stimulating the 5HT2A receptor, allow a greater amount of sensory information (i.e. novel inputs) to enter the higher centers of the brain via the thalamus . Yet another theory suggests that psychedelics increase and rewire communications between neurons, termed neuroplasticity, facilitating the encoding of new information or re-coding of old information . Indeed, neuroplasticity is at the root of all learning, via neurons making new connections with other neurons. Neuroplasticity, therefore, can serve to relax our rigid priors perpetuated by the DMN and prioritize new inputs. Note that ‘novel inputs’ do not necessarily denote new information that has never been acquired; it could also refer to interpreting and analyzing old information in new ways. Hence, these models in aggregate illuminate the mechanistic bases of openness and cognitive flexibility that are widely observed with psychedelics.
The most powerful and awe-inspiring effect of dampening the DMN is what is known as ‘ego dissolution’. This phenomenon can be occasionally experienced in the clinical setting, although it is usually provoked by higher doses. When the ego, or the sense of self, dissolves, people report being left with “the experience of unity”, in that “the boundaries between myself and my surroundings seemed to blur,” “and it seemed to me that my environment and I were one” . Another theme is the continuity of time: “I experienced a touch of eternity,” and “I experienced past, present and future as an oneness” . An overflowing sense of existential serenity, gratitude, wonder, and even mysticism, accompanies this experience.
The emergence of new insights, another fascinating aspect of the cognitive dimension, points to another key feature of the psychedelic brain: global integration . Under the influence of psychedelics, regions in our brain display greater interconnectedness with one another (see figure). This perhaps explains why revelatory thoughts are often encountered, as insight generation entails creativity and synthesis of various phenomena - and furthermore, synesthesia, the integration of the sensoria (e.g. hearing the drift and breathing of one’s visuals). This integrative process also accords with the above-mentioned cognitive models whereby greater emphasis is placed on new inputs, or bottom-up flow, as the latter similarly occasions new insights.
Upon detaching from our entrenched beliefs of the past, and perhaps even our conception of the self altogether, we become better able to manipulate and adapt our cognitive models to our own flourishing - a pivotal part of which is our connections to other humans. We are able to recognize and reimagine the importance of our attachments to loved ones. Numerous studies have borne out this prosocial effect . For one, the amygdala is implicated in anxiety and emotional processing of fearful stimuli. Researchers have found that psychedelics decreased the reactivity of the amygdala to negative stimuli in a dose-dependent manner for up to one month after dosing. Further, people have overwhelmingly reported increases in emotional empathy, interpersonal closeness, decrease in sensitivity to social rejection, as well as decrease in social withdrawal. The power of psychedelics in suppressing the DMN and inducing ‘ego dissolution’ may underlie these shared experiences of emotional healing, via evoking a sense of unity that erodes the boundaries previously erected between the self and others.
Science has given us some clues in unifying the neuropharmacological underpinning of psychedelics with the experiential. In essence, psychedelics can recondition our previous maladaptive cognitive models via engagement with new ideas and restore us back to our consciousness armed with more robust models. But this still leaves much to be desired. As the field of psychedelic research becomes less and less bottlenecked by legal and financial constraints, more and more questions will surely be answered here at TrPR. Stay tuned!
 Nichols, D., 2016. Psychedelics. Pharmacological Reviews, 68(2), pp.264-355.
 Nutt, D., King, L. and Phillips, L., 2010. Drug harms in the UK: a multicriteria decision analysis. The Lancet, 376(9752), pp.1558-1565.
 Carhart-Harris, R. and Friston, K., 2019. REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics. Pharmacological Reviews, 71(3), pp.316-344.
 Vollenweider, F. and Preller, K., 2020. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nature Reviews Neuroscience, 21(11), pp.611-624.
 Aleksandrova, L. and Phillips, A., 2021. Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics. Trends in Pharmacological Sciences, 42(11), pp.929-942.
 Bayne, T. and Carter, O., 2018. Dimensions of consciousness and the psychedelic state. Neuroscience of Consciousness, 2018(1).
 Carhart-Harris, R., 2019. How do psychedelics work?. Current Opinion in Psychiatry, 32(1), pp.16-21.