By Chloe West, MS Neuroscience, PhD Candidate at Georgia State University
What is it about psychedelics that make them so therapeutically beneficial for depression? This is arguably one of the most debated topics in the field of psychedelic research.
Some researchers argue that the psychoactive experience, or psychedelic “trip”, is necessary for treating depression.1,2,3 Others say that neurobiological mechanisms alone, and not those involved in the psychoactive trip, are responsible for alleviating symptoms of depression in psychedelic users. 4
It is important to note that the psychoactive experience and its effects on the brain are one in the same. All psychoactive effects of psychedelics are the result of neurobiological mechanisms. So, the answer to this question is complex, and it will certainly have implications on the legalization and use of psychedelics as a therapeutic tool.
How Do Psychedelics Affect the Brain?
Psychedelics interact with many different neurons and receptors all over the brain. Scientists have been able to pinpoint the exact mechanism of action responsible for their psychoactive effects: serotonin 5HT-2A/5HT2C receptor agonism. 5,6
When serotonergic psychedelics like DMT, LSD, and psilocybin enter the brain, they mimic the neurotransmitter-receptor activity of the naturally occurring neurotransmitter serotonin. Serotonergic psychedelics bind to the 5HT-2A/5HT2C serotonin receptor subtypes in place of serotonin. This process ultimately leads to the complex, downstream mechanisms that underlie a psychedelic trip.
There is strong evidence that the psychedelic trip depends on 5HT-2A/5HT2C receptor agonism. Consequently, when a substance blocks 2A/5HT2C receptors, and psychedelics cannot bind to these receptors, the psychoactive trip does not occur. 5,6
Psychedelics and Depression: What We Know So Far
A 2021 study, published in Proceedings of the National Academy of Sciences of the United States of America found that blocking psilocybin-5HT2A/5-HT2C binding, and thus the psychoactive effects of psilocybin did not reduce its antidepressant effects in mice with depression markers, induced by chronic stress.4 These types of mice are used in depression research because they model various symptoms of depression in humans.
This initial work supports the idea that psilocybin’s antidepressant effects are the result of some other receptor interaction, not implemented in the psychedelic trip. However, further study is needed to parse out the driver of these antidepressant effects.
Proponents of this perspective might argue that the psychoactive experiences elicited by psychedelic substances are merely by-products of the underlying neurobiological mechanisms. In other words, every measurable behavioral effect of psychedelics has neurobiological underpinnings. These neurobiological mechanisms are the ultimate drivers of the antidepressant effects.
For example, psychedelics promote synaptic plasticity through 5-HT2A receptor-mediated mechanisms.7 Synapses allow our neurons to communicate with each other. Synaptic plasticity refers to the ability of synapses to strengthen and adapt over time.8 The reduced activity of proteins necessary for synaptic plasticity can damage important brain areas in patients with depression. So, psychedelics may alleviate depression through synaptic plasticity.
Psychedelics and the default mode network
Psychedelics’ influence on the default mode network (DMN) may also contribute to their antidepressant effects. The DMN is a network of brain regions that seems to be overactive in depressed patients. Psychedelics work to temporarily disrupt DMN activity. This process may lead to ego dissolution.
The ego dissolution experience is positively correlated with the therapeutic benefits of psychedelics. However, it could just be a by-product of the underlying reduced DMN activity and not inherently necessary. The truth remains a mystery. (For now.)
DMN overactivity could result in an overemphasis on the self. Ego dissolution could bring that self-emphasis to a healthier baseline.
Self-focused attention (SFA) refers to excessive and rigid self-focus, and SFA is closely related to depression.9 In his influential (yet controversial) model of chronic depression, McCullough argued that chronically depressed patients, particularly those with an early onset of the disorder, feature a particularly pronounced self-focus.10
When ego dissolution occurs, a person’s focus shifts outward on the perceptual environment. This shift facilitates objective problem-solving. Thus, it is plausible that psychedelics reduce SFA, which underlies their antidepressant effects.
Why Are Psychedelic Trips So Essential?
There have been many influential studies suggesting that psychedelic-induced alterations in consciousness are essential to the antidepressant response.
A study published in the Journal of Psychotherapy Integration found that psychedelic-induced religious, spiritual, and mystical experiences (RMSEs) are positively correlated with the therapeutic benefits of psychedelics. Specifically, scores on the mystical experiences questionnaire (MEQ), which quantifies the strength of psychedelic induced RSMEs, positively correlate with therapeutic benefits.3 However, these experiences are also dose-dependent. 11,12
While these findings are promising, there are still so many unanswered questions. Namely, why is the trip so necessary?
The increased propensity to change belief structures could be a key aspect of the psychedelic trip’s antidepressant effects. In fact, many beliefs that are foundational to an individual’s sense of self and world perspective are impacted as a result of psychedelic use. 13,14,15 16 Interestingly, these changes in beliefs tend to follow a similar pattern across individuals, regardless of prior beliefs.13,16,17,18
The Relationship Between Spirituality and Psychedelic Trips
It is plausible that psychedelics change negative beliefs into more positive ones, which has implications for alleviating symptoms of depression or anxiety. A 2021 study published in Nature found that psychedelic use leads to shifts from hard-materialist beliefs (the idea that thoughts, behaviors, and menta states result from physical world interactions) toward more dualistic beliefs (the thought that another realm influences our thoughts and behaviors) and that this shift away from hard-materialism was positively correlated with self-reports of well-being.13
In 2020, researchers at Johns Hopkins University’s Center for Psychedelic and Consciousness Research conducted the largest-ever DMT study. Among 2,561 suvey participants, 28 perent self-identified as atheists before their DMT experience, but only 10% identified as atheists after the experience. Furthermore, while only 36 percent of participants believed in an “ultimate reality, God, higher power, or Universal Divinity” before the experience, 58 percent believed so afterward. In 60 percent of participants, having a DMT experience altered their fundamental conception of reality in a desirable way.18
In another study, researchers found that people who have experienced “God-encounters” while under the influence of psychedelics have reported feelings of connectedness and oneness with “God” and the universe, and the majority of them endorsed encountering a God that was benevolent, intelligent, sacred, conscious, eternal, and all-knowing, rather than malicious. 16
Taken together, emerging research supports the idea that the psychedelic experience allows one to adopt beliefs that may promote well-being. In 2013, researchers Carhart-Harris and Friston proposed that psychedelics work to de-weight pathologically over-weighted beliefs that underlie various expressions of mental illness, such as negative self-perception and fearful, pessimistic, or paranoid outlooks.20 The underlying mechanism of psychedelic belief-change remains to be fully elucidated, but it seems, from initial studies, that the psychoactive trip may be necessary for this.
The subjective psychedelic experience is an extremely profound and introspective experience. It is common for people to gain insight into personal behaviors, emotions, relationships, or life purpose from their psychedelic experiences. We also know that the psychedelic experience is extremely impactful, with many people rating it as the single most personally, spiritually, or psychologically meaningful experience in their life.16,18
So, even if one day we learn that the subjective psychedelic experience is not necessary to alleviate mental disorders like depression, anxiety, and PTSD, that does not mean there is no benefit to the trip at all.
Depression, as with all psychiatric disorders, is complex and multifactorial. There is not just one underlying mechanism. The many effects of psychedelics, both neurobiological and psychoactive, might work together to broadly target the different symptoms and underpinnings of depression.
Chloe West, M.S.
Neuroscience PhD Candidate, Graduate Research Assistant, Georgia State University
Chloe West received her Master’s in Neuroscience from Georgia State University in 2020. GSU is also where she is currently pursuing a PhD in neuroscience, with a concentration in neuroethics. Her research focuses on the neurobiological and psychological underpinnings of psychedelic mediated changes in belief and creativity. Outside of research, Chloe teaches an undergraduate neuroscience course on Drugs & the Nervous System at Georgia State. In her spare time, she creates science communication content about psychedelics. To contact Chloe, learn more, or participate in psychedelic research, you can visit her website Neuro-Psychedelic.com.
2. D. B. Yaden and R. R. Griffiths, “The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects,” ACS Pharmacology and Translational Science, vol. 4, no. 2. American Chemical Society, pp. 568–572, Apr. 09, 2021. doi: 10.1021/acsptsci.0c00194.
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