Psilocybin and Depression: A Review of how Assisted Therapy and External Factors Guide Emotion

Author's Bio

Elijah Valerjev is a recent graduate with the class of 2024, obtaining his degree in Microbiology with a double minor in Professional Writing and Education. He enjoys writing and learning about various science topics associated with the brain and substances. Additionally, he has an interest in free-form writing and intends to publish several novels about introspective stories, both fiction and nonfiction. In his free time, he enjoys boxing, baking, and buying books.

Author’s Note

This was the paper that started it all. I was in my second year exploring courses I needed to graduate, completely unfamiliar with the UWP series and its rigour. I enrolled in UWP 102B, Writing in the Disciplines for Biology, and was hooked at just how creative I could be with any science topic. After spending two years in college taking rigid chemistry, biology, and math courses, the freedom granted by the choice to write a literature review about almost any science topic of interest was both profound and scary. I remember approaching my professor, Amy Goodman-Bide, nervous about writing a paper about literal shrooms.. To my surprise, she was all for it, and even supported me to take it in specific directions. To this day, I find reading and writing, especially when it considers science, to be a deeply ingrained passion of mine. Though I am still figuring out the course of what my life will look like, this paper served as a wonderful stepping stone in a positive direction.

Introduction

Since the recent decriminalization of psilocybin in many states across America (1), new research provides insight on the effects of psychedelics to treat mental illness. Prescribed antidepressants are a prevalent source of care for depression, however, they produce various side effects and are unavailable to some treatment-resistant individuals. Moreover, 10% to 30% of depression-diagnosed patients are emotionally unaffected after attending regular therapy (2), suggesting a need for further intervention. Psilocybin is a psychedelic compound naturally produced by fungi with a similar chemical resemblance to the feel-good neurotransmitter serotonin, which has shown promise in fighting depression. The active chemical compound in psilocybin, known as psilocin, functions by activating the 5-hydroxytryptamine-2A (5-HT2A) serotonin receptor in the brain (3). This is the main contributor to the change in patients’ mindset that causes cascading emotional effects primarily described as “insightful” (2). Studying the brain regions of interest (ROI) affected by this receptor activation could support directions for research. The combined intervention of this drug and the guidance of experts in assisted therapy reveals decreased depressive symptoms in patients. The results of different methods of assisted therapy could be synthesized to pursue new therapeutic concepts. Furthermore, external factors such as the therapeutic setting as shown in Figure 1, affect the psychedelic experience (4). This review explores the nature of psilocybin’s effects, the variables that play a role in its treatment against depression in assisted therapy, and external factors that draw questions to the expansion of further research.

(Reproducible Graphic) Figure 1: Psilocybin reacting with 5-HT2A serotonin receptor, combined with the effects of dose and environment on user experience. Link: https://www.mdpi.com/1424-8247/14/10/985

Neural Effects of Psilocybin

Psilocybin’s interaction with the brain’s serotonin receptors causes an altered emotional and creative mindset. Changes to psychological perception are observed in patients with depression, including increased connection to life and meaning behind decision making (5). Functional Magnetic Resonance Imaging (fMRI) and resonance scans of brain activity under psilocybin’s influence generate a schematic of its nature.

Through assessing brain scans, studies have hypothesized that prefrontal cortex deactivation is linked to the effects of psilocybin. The prefrontal cortex regulates the limbic system, a complex set of nerves in the brain. The increased expression of the limbic system, due to prefrontal cortex deactivation, dissolves any regular routine-set feelings of users’ consciousness (6). A resonance scan reveals deactivation of the prefrontal cortex in a study where depression-diagnosed subjects recollected vivid life memories under psilocybin’s influence (6). The ability to reflect on past experiences in an altered state of consciousness could be a gateway to healing trauma. Tasks that further explore memory recollection could be implemented with psilocybin in curated therapy sessions.

(Reproducible Graphic) Figure 2: Diagram of location of prefrontal cortex and amygdala. Link: https://www.linkedin.com/pulse/understanding-executive-function-unravelling-role/ 

The amygdala is another area of the brain that may provide insight into the drug’s properties. As shown in Figure 3, this structure is a region of the limbic system responsible for regulating the emotional perception of negative responses in individuals with depression (8). Though a high dose of psilocybin (25mg) in fMRI readings of subjects with depression shows a decrease in amygdala activity, normal function rebounds shortly after (5) which highlights the temporary neural effects of psilocybin. A decrease in the negative stimulus of emotionally stirring facial images was also observed (8), validating that psilocybin may boost a surrender to positive emotion by briefly interfering with the amygdala. The upkeep of amygdala function should be considered when dosing psilocybin during this short window of emotional vulnerability.

(Reproducible Graphic) Figure 3: Diagram showing the interaction between fear, a strong emotional response, and amygdala intervention. Link: https://www.simplypsychology.org/amygdala.html

In the same study that presents lowered amygdala function, fMRI data revealed increased amygdala response one day post-trial (8). Immediate amygdala activation one day after intervention exemplifies the spontaneous nature of psilocybin on the brain. The speculated cause of this re-expression, or re-living, of the psychedelic trip results from the 5-HT2A receptors’ connection to both positive and negative emotions (5). Due to the amygdala’s link with memories and intense emotions, the patients’ emotional re-living is likely to have caused the increased amygdala response (5 & 6), which supports that experiences associated with psilocybin usage may have lasting effects. More observations of amygdala activity and patient behavior should be conducted to validate the uncertainty behind these re-livings. Changes to assisted therapy can be implemented where guides focus their patients on unwinding past trauma to form behavioral changes. The mapped fluctuation pattern of the amygdala response will allow for a better understanding of how to treat people under the influence of psilocybin to generate a positive experience.

Forms of Assisted Therapy

Understanding the subjects’ responses in experiments of assisted therapy introduces new ideas for treating depression. Revisiting positive life memories while under psilocybin’s influence produces fewer depressive symptoms in depression-diagnosed patients (6). As proposed by viewing prefrontal cortex deactivation, subjects restructured their views on recalled past life events to obtain a different perspective. These behavioral observations with memory recollection are consistent with the understanding of amygdala function. Patients reported that the vividness of the recollected memories was strong, noting a sense of enlightenment (6). An idea of furthering this form of assisted therapy could be by guiding users in revisiting both negative and positive memories. Though the positive memory cues generated less depressive symptoms, negative stimuli may bring up confounding results in further studies.

A way of reflecting on these stimuli could be through guided meditation. Trained meditation experts have reported feeling ego-dissolution and an increase in visual perception while taking psilocybin (7). A more detailed analysis of psilocybin’s effects can be experienced by its users due to the focused mental reflection. Amygdala changes due to psilocybin are also consistent with the heightened visual responses expressed by the meditation experts. This qualifies the notion for more research on the amygdala under the effects of psilocybin. Aside from this finding, ego-dissolution is also associated with the effects of meditation. A neural response to meditation is the lowering of the default mode network (DMN), which relates to awareness and ego-identity. The DMN was disintegrated in fMRI readings of ROI in the meditation trial (7), presenting increased neural effects of meditation. The increased connection to self-identity could be useful in subjects’ reflection on their state of well-being during meditation. The lowering of psychological defenses (Figure 4) is an acknowledged risk of deeper thoughts under psilocybin due to reportings of negative relivings (6). However, patients with depression primarily reported decreased depressive symptoms consistently at various time intervals leading up to six months after drug administration (4). Experiments with psilocybin meditation should be continued with untrained depression-diagnosed individuals instead of meditation experts. The link to self-identity is a considerable behavioral effect of psilocybin  in assisted therapy when guiding the emotions of patients. The neural connection to memories and mindful regulation of emotions through meditation may control the overwhelming effects of psilocybin, heralding new ideas for assisted therapy.

(Reproducible Graphic) Figure 4: A simple explanation of how ego provides a form of self-identity. Ego dissolution can rewrite the outlook one may have on their place in the world. Link: https://www.thezag.com/self-justification/ 

External Factors and their Effects

The relation between therapeutic setting and mindset is frequently reassessed across experiments when considering limitations (7). A large portion of these experiments with assisted therapy take place in hospitals or neutral settings with little stimulation of the study’s environment. To observe the psychedelic-induced consciousness in a controlled space, an exaggerated setting including changing lights and illusions was designed to mimic psilocybin’s visual effects (9). Placebo users, having no history of mental illness, expressed feelings of insightfulness and mental bliss as if they had taken psilocybin (9). These behavioral results are consistent with the depression-diagnosed patients in the experiments of assisted therapy–despite the absence of a psychedelic drug. Further experimentation of this idea on depression-diagnosed participants is necessary to certify whether a placebo drug will be effective in a therapeutic environment. Despite this limitation in Olson’s experiment, the positive experience of the placebo users is steady with the increased mindfulness of the individuals with depression. The combination of setting and placebo drugs could be harnessed to treat patients with depression who may also negatively react to psychedelics (2).

Another external factor that may affect the psychedelic experience is music. Depression-diagnosed participants under psilocybin’s influence reported increased feelings of guidance, welcomeness, and emotional intensification when listening to a playlist designed by psychedelic therapists (10). Including music in assisted therapy could further alter patients’ moods and serve as a mental guide through the psychedelic trip. This must be employed with caution, as subjects of this experiment also expressed feelings of unwelcomeness and misguidance (10). The cause of the uncomfortable feelings could be due to the unfamiliarity the participants had with the music being played (10). Constructing a guided therapy session where users choose their own music could provide more positive results and evoke more comforting emotions. Despite both negative and positive feelings expressed by the participants in the music-guided therapy, the discovery that music is a delicate factor in psilocybin’s effects is noteworthy for future assisted therapy sessions.

Though there are factors that may heighten the experience, a variable that causes concern on the health effects of psilocybin is whether it may be taken in conjunction with prescribed antidepressants. Depression-diagnosed participants ingested the antidepressant escitalopram in combination with the hallucinogen; a decrease in the negative acute effects of psilocybin was noted when compared to a placebo group (3). Decreased negative effects included lessened anxiety about psychedelic trip expectations and decreased gastrointestinal discomfort (3). Though the results establish a safe relationship between both drugs, escitalopram represents a small section of the large variety of antidepressants utilized to treat depression. Participants were also consistently taking escitalopram for briefly two weeks prior to psilocybin administration (3). This small time frame limits the ability to determine how psilocybin may affect depression-diagnosed candidates who also take prescribed antidepressants long-term. More studies with resonance scans of brain ROI under psilocybin’s effects combined with various antidepressants should be observed to qualify its safety. If future studies show no critical interaction between both drugs, credible harm-reduction information about psilocybin could be constructed to generate a more welcoming outlook on assisted therapy.

Another issue that challenges the acceptance of psilocybin therapy is the risk of psychosis. One case study presents the discussion around a case where a woman who ingested psilocybin in a recreational setting experienced mania and suicide for a prolonged length of time (11). Furthermore, 31% of clinical patients were uncomfortable with the length of the experience, and 39% of recreational users felt the experience was critically challenging (11). Moreover, with psilocybin’s research becoming more accepted, there is a cultural push for recreational use which threatens further research due to the increased possibility of negative experiences in recreational users (11). It was noted that though cases like this exist, the risk of psychological trauma from psilocybin is rare in clinical trials, and only 11% of recreational users felt they have put themselves at risk under the drug’s influence (11). Moreover, setting has been crucial for guiding these experiences and promoting a positivity for users (11). It was found that the risk of a negative experience is heightened in recreational users likely because of a lack of guiding positive resources, which provides more of a reason to explore how assisted therapy settings could be improved (11). If legalized, the experience must be advertised as mentally intense. This has been a gray-area of determination when it comes to placing regulations on the legalization of psilocybin, and will likely take more trials and time to discover a clear criteria for risk-assessment (11). 

Conclusion

The neural models of psilocybin activity reveal specific areas of the brain that are impacted. Guided therapists can understand the way the drug functions from these models and expand research in assisted therapy. The slight uncertainty behind some of the brain activity presents ideas for future studies to gain more information on brain ROI. Combining psilocybin with other mindful practices, such as memory reflection and meditation, reveals consistent behavioral and neural effects of the hallucinogen. External factors introduce new variables that may increase the efficiency of assisted therapy including environment, music, and the combination of antidepressant use.

References

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