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Study Applications of Psilocybin Studies

Kasey Devitt

Capella University

PSYC-FPX4310 Biological Psychology

Jeremy Owens

December 2021
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Study Applications of Psilocybin Studies

Introduction for Study Proposal of Psilocybin to Treat Depression

This paper includes a proposal and a detailed summary of a research plan for a study on

psilocybin for depression. It will also include a brief outline of the major themes and the theories

used in current studies on psilocybin for depression. Psilocybin (4-PO-HO-DMT) and psilocin

are the compounds found in psilocybin mushrooms or magic mushrooms. Religious and spiritual

ceremonies of indigenous cultures use psilocybin, but researchers have recently found a

therapeutic effect. Psilocybin also correlates with a decrease in depressive symptoms. Since this

is a new medicine to research, there are lots of new, intriguing studies. It is a medicine that can

be taken and have immediate effects on perspective and decrease symptoms of depression and

anxiety long-term—an essential research topic for the psychology and biology fields.

Psychedelic Induced Improvement in Mood and Social Behavior are Mediated by Changes

in the Ventral-Medial Prefrontal Cortex-Amygdala Axis

Research Proposal

This study aims to research the use of psilocybin to treat depression in a group of

naturalistic settings. The hypothesis is that psychedelics in natural settings improve mood

disorders and that the improvements are mediated by social connection and biologically

mediated by the ventral medial prefrontal cortex changes. The second hypothesis is that

psychedelics in therapy may also mediate mood improvements by enhancing social connections.

The issue is that mood disorders are prevalent and are expensive to treat. Clinical psychedelic

therapy is costly though, it proposes an option to heal, deal with mood, social behavior

substantially, and sustain. This hypothesis asks if psychedelics would make the same or more

significant impact in a naturalistic setting without a therapist. They are also offering a more cost-
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effective way to heal through disorders. There is plenty of research up to this point confirming

the biological and psychological significance of psychedelics in treating mood disorders.

Major Themes Found in the Research of Psilocybin for Depression

This section of the paper is dedicated to the major themes found in the current research of

psilocybin to treat depression. Many of these significant themes overlap, forming an overall view

of the biopsychological theories.

Psilocybin and Reduction of Depressive Symptoms

The most common theme throughout the psilocybin for depression research is that after

the administration of psilocybin, many patients reduce depressive symptoms. Davis et al. (2021),

whose goal was to find the effects of psilocybin on major depressive disorder, came to this

conclusion. Other studies that reported the same finding were Carhart-Harris et al. (2017) and

Carhart-Harris et al. (2021) after administering psilocybin to patients with treatment-resistant

depression and after a comparative study of psilocybin and escitalopram. Davis et al. (2021) and

Carhart-Harris et al. (2021) also found that psilocybin had an immediate and sustained

antidepressant effect.

Psilocybin and Changes in Mood, Behavior, and Overall Well-Being

James, Robertshaw, Hoskins, and Sessa (2020), Ross et al. (2016), and Griffiths et al.

(2016) all explored the theme of mystical-type experiences that arise from the administration of

psilocybin. These mystical experiences gave the participants substantial changes in mood,

behavior, and attitude. The experiences are also related to improved attitudes towards death

found in two different studies done by Ross et al. (2016) and Griffiths et al. (2016) that

administered psilocybin in cancer patients with depression and anxiety. The participants in these

studies also experienced increased quality of life, life meaning, and optimism (Griffiths et al.,
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2016). Griffiths et al. (2016) also had ratings on the patients that showed improved attitudes

about life, self, relationships, and spirituality. Erritzoe (2018) researched the impacts on

personality after administration. He concluded that traits such as neuroticism decrease. He found

that traits such as extroversion, openness, and contentiousness increase.

Psilocybin and the 5HT2A Receptor

A biological theme that scatters throughout these studies was the occupancy in the

5HT2A receptor (also known as the psychedelic receptor) when psilocybin is administered.

Madsen et al. (2019) found that activation in the 2A receptors was up 72% from the baseline

measurement, suggesting that psilocybin leads to significant 2A receptor activation, psilocin, and

plasma levels. The increase was related to the intensity of the experience. Madsen et al. (2019)

were also able to confirm that the 2A receptor is the primary binding site responsible for

psychedelic activity in the brain. Kraehenmann et al. (2015) also mention the 2A receptor when

discussing levels of reactivity in the amygdala after administration of psilocybin.

Psilocybin and the Amygdala

The amygdala is another biological theme, the effects of psilocybin on the amygdala. The

amygdala is found in the medial temporal lobe and inhibits firings (Nichols, 2016). The

amygdala is correlated with decreased symptoms of depression when there is decreased

activation (Nichols, 2016). Carhart-Harris et al. (2017) found decreased levels of cerebral blood

flow in the prefrontal cortex, including in the amygdala. Kraehenmann et al. (2015) reported that

the administration of psilocybin (2A agonist) reduces neural responses to negative stimuli.

Instead, it induces positive states and mood changes as the activity in the amygdala decreases.
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Psilocybin and Other Areas of the Brain

The subsequent biological theme is that the prefrontal cortex is in the default mode

network (where there are many 2A receptors). When 2A receptors are activated, they destabilize

the prefrontal cortex. After the prefrontal cortex is deactivated, the default mode network

destabilizes, including the hippocampus in the medial temporal lobe. Lebedev et al. (2015) found

the association between psilocybin administration and decreased functional connectivity between

the medial temporal lobe and higher-level cortical regions. Ego dissolution during administration

happens this way. Ego dissolution is one of the reasons that patients feel a change in mood or

depressive symptoms. Lebedev et al. (2015) also found that individuals with lower diversity of

network nodes are more likely to experience ego-dissolution.

Overview and Confirmation of Major Themes

Nichols (2016) wrote an article called “Psychedelics.” This article confirms all of the

biological findings or proposed biological assessments of the brain when administered psilocybin

from the studies above. The major themes of the Nichols (2016) journal are that the amygdala is

responsible for emotional behaviors, memories, and fear. Many 5HT2A receptors belong in the

amygdala. Nichols (2016) also confirms all of the information in the sections about 2A receptors

and the brain. He writes that the first experiment that showed the role of the 2A receptors for the

action of medicines such as psilocybin came from a clinical study done by Vollenweider et al.

(1998). They showed that the effects of psilocybin were blocked by the 2A receptors using

antagonists.
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Studies Similar to Proposal Study

The studies provided above create a perfect timeline to discuss the biological,

psychological concepts that have already been discovered regarding psychedelic therapy studies.

Some studies apply a naturalistic setting similar to the proposal.

5-MeO-DMT Used in a Naturalistic Group Setting

Davis, So, Lancelotta, Barsuglia, and Griffiths (2019) studied the distribution of 5-

methoxy-N, N-dimethyltryptamine (5-MeO-DMT) for spiritual and recreational reasons that

connect with a personal improvement of depression and anxiety. Davis, So, Lancelotta,

Barsuglia, and Griffiths (2019) examined self-reported involvement in depression and anxiety

among those who use 5-MeO-DMT in a group setting with structured doses, procedures, and

administration. The respondents also included activities for preparation and support during and

after the experience. All of those procedures are similar to the ones used in the clinical

administration of hallucinogens. Responses indicate whether symptoms increased or decreased.

The responses will also indicate a connection between the conditions of individuals and the

minor effects or beliefs about 5-MeO-DMT. The researchers used 362 respondents to complete

an anonymous web survey. Of those 362 respondents, 41% had reported that they had been

diagnosed with depression and 48% with anxiety. Following 5-MeO-DMT use, they reported

improved symptoms of depression and anxiety. 80% of respondents had improvements in

depression, and 79% had improvements in anxiety. 17% and 19%, respectively, claimed that their

symptoms were unchanged, and 3% and 2% worsened. In conclusion, the improvements relate to

increased spiritual significance or experience ratings and the personal meaning attached to the

experience.
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Social Connectedness Mediates the Mood-Enhancing Effects of Psychedelic Use in Natural

Settings

Forstmann, Vudkin, Prosser, Heller, and Crockett (2020) hypothesized that transformative

experience and social connectedness mediate the mood-enhancing effects of psilocybin and other

psychedelics in a naturalistic setting. Forstmann, Vudkin, Prosser, Heller, and Crockett (2020)

mentioned that the past studies have already shown the effectiveness of these substances on

mood and feelings of connectedness but suggested that these experiences happen in a naturalistic

setting are robust or direct, but not shared enough. This study was conducted over three years

through field studies and included 1,225participants across six multiple-day mass gatherings in

the United States and the U.K. The researchers apply three divisions or categories to their

research: transformative experience, social connectedness, and mood. Field studies included

teams of 5-10 experimenters who recruited attendees. These participants provided informed

consent and completed a questionnaire with several scales and tests. The survey asked if the

individuals took a substance within the past 24 hours or at all during the week. Attendees were

asked if they were under the influence at the time or if they had taken substances belonging to

the psychedelic class for the first time at the gathering. The researchers found that the increased

levels of transformative experiences are not explained by a stronger desire or expectation of

having such experiences. The users considered their transformative experiences to be more

positive and intense. They were more likely to report changes to their moral value as a

consequence of the experience. Transformative experiences and social connectedness statistically

mediated the effects of recent psychedelic use on positive mood. This study was significant

because it shows that the use of psilocybin and other psychedelics in a naturalistic setting is

associated with experiences of personal transformation, increased feelings of social

connectedness, and increased positive mood. The Oxford Central Research Ethics Committee

approved the research protocol. This study is essential for the research of this topic in the future.

LSD Induced Increase in Social Adaptation Are Associated with Stimulation in Serotonin

Receptors

Duerler, Schilbach, Stämpfli, Vollenweider, and Preller (2020) directed their study to

show that adapting one's attitude and behavior to group norms is essential for successful social

integrations and participation in society. LSD alters social processing, allowing the opportunity

to investigate the role of 5HT2A receptors in social influence processing. In this double-blind

random crossover study, 24 volunteers either got a placebo and a placebo, a placebo, and LSD

(100 micrograms), or a 5HT2A receptor antagonist plus LSD (100 micrograms) over three

different occasions. The results of this study were that LSD increased social adaptation but only

if opinions around them were similar to their own. The increases are associated with the

increased activity of the ventral medial prefrontal cortex while receiving social feedback

processing. This is an essential insight into the neuropharmacological basis of social cognitive

behavior. This study, along with the others, is a perfect foundation for the study proposal's

hypothesis.

Ventral Medial Prefrontal Cortex-Amygdala Axis

All of the studies written about are helpful to create the connection made in the

hypothesis of the study proposal. That psychedelic induced improvement in mood and social

behavior are mediated by changes in the ventral medial prefrontal cortex-amygdala axis. From

the information pulled out of the articles of Nichols (2016), Carhart-Harris et al. (2017), and

Kraehenmann et al. (2015), we find more information about the amygdala. When administered

psilocybin, the amygdala is correlated with decreased symptoms of depression and reduces
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neural responses to negative stimuli. These researchers also found that the prefrontal cortex

(included in the default mode network) contains 2A receptors. When these receptors are

activated, the prefrontal cortex is deactivated. Between the deactivated prefrontal cortex and

amygdala, individuals lose fear response to harmful stimuli and increase serotonin, which allows

them to regulate social behavior.

The Research Method

This study will include 15 random participants. The participants will be split into two

groups the active control group and the experimental group. They would be asked questions prior

to the trial, such as their first-time using psilocybin. Then questions asking if they have used

them in a group setting. All individuals will first be put into an fMRI scan to see the initial

connectivity in the brain. The individuals assigned to the active control group will complete a

session of one-on-one clinical psychedelic-assisted therapy with the administration of psilocybin.

The individuals assigned to the experimental group will complete the session in a naturalistic

setting. In a naturalistic setting, the researchers will do a field study and take the participants to a

group setting, and then the group will be administered psilocybin. After the sessions, the patients

will have a questionnaire to evaluate social integration. The questionnaire would include similar

questions as in prior studies, such as "were there any mood or behavior changes?" Other

questions that may be posed to the participants are if they felt open and comfortable during their

session, did the individuals feel a sense of social connectedness. Another interesting question to

ask the participants would be if they felt open themselves or if they felt any fear during their

experience. They would then again have an fMRI scan to determine increased connectivity

between the ventral medial prefrontal cortex and the amygdala. To ensure the validity of the

study will be a randomized study. There will be an active control group for a comparison of
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results after the experiment. Lastly, there will also be a rigorous exclusion criterion. This

criterion will ensure that the results are valid and that the patients are not at risk by participating

in a session. In order to conduct this study ethically, all of the individuals need to provide

consent. They will need the option to opt-out if they so wish. The study will also have to be

approved to be carried out. Lastly, this study will have to follow safety guidelines and criteria

during administration. All information about the study should be available to the participants.

The Rationale for Study Method

The method of this study is designed so that the researchers will know what parts of the

brain show connectivity during a resting state. Then on the flip side, they will find out if there

was increased connectivity in the ventral medial prefrontal cortex- amygdala regions compared

to the initial scan. The scans can then be used to compare a higher amount of connectivity in the

active control group or the experimental group that was involved in a group psychedelic therapy

session. The questionnaire will be used to find out how the subjects felt before and after their

experience. The questionnaires will tell the researchers whether or not the participants felt more

social connectedness during the experience. There need to be two groups to compare the

differences between an ordinary psilocybin therapy session and a naturalistic group setting

version of the therapy session. The rigorous exclusion criterion is to ensure valid results and so

that all participants are safe during the study. Randomization of the study is to ensure valid

results. The study should be the ethics criteria as this is a schedule I drug in the United States and

is still in question in other countries.

Summary of Study Proposal

The next topic to be researched relating to psychedelic therapy is the mechanisms in

which it works biologically. This study proposal aims to determine if the psychedelic-induced
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improvement in mood and social behavior is mediated by changes in the ventral medial

prefrontal cortex- amygdala axis. These two brain areas are less active during psychedelic

experiences than resting because the 5HT2A receptors are primarily in play. Some studies have

concluded that participants reported increased transformative experiences and social

connectedness when taking psychedelics in a group setting. This research proposal would dive

deeper into that issue and potentially validate those results. The study will include 15 participants

either in an active control group, who will be administered psilocybin in a clinical setting with a

therapist, or in the experimental group administered the same dose of psilocybin in a naturalistic

setting with a group. The participants are put through an fMRI scanner both before and after the

session. They will also fill out a questionnaire. The results will be determined by the fMRI scans

that will indicate whether or not the ventral medial prefrontal cortex-amygdala area is the

primary point for increased social connectedness or other beneficial outcomes of administration.

Conclusion

Psilocybin for the treatment of depression is an important research topic and will

continue to be as there are many patients with treatment-resistant depression. The research of all

schedule I drugs will be necessary over the coming years, providing insights into healing and

new information about the brain that are not accessible without the studies of these medicines.

The most significant hurdle will be approving psilocybin and other treatments clinically since

they have had such a bad reputation and the general public sees them as "drugs." A society that

wants individuals to believe this keeps them away from potentially the most important form of

healing to the suffering society has caused. The research on psilocybin implies that the

administration of the compound will give individuals immediate and long-lasting treatment.
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