How Psilocybin Can Rewire Our Brain, Its Therapeutic Benefits & Its Risks | Huberman Lab Podcast

Podcast Host: Dr. Andrew Huberman (Stanford Associate Professor - brain development, brain plasticity, and neural regeneration and repair fields).

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Key takeaways

Psilocybin is a controversial psychedelic compound, which is illegal in the United States, except for Oregon (Segment 1).
Psilocybin is converted into psilocin in the gut, which then acts on serotonin, leading to altered states of consciousness (Segment 2).
The Serotonin 2A receptor is a key player in the therapeutic potential of psilocybin (Segment 3).
Psilocybin can trigger profound visual hallucinations, even when the eyes are closed (Segment 4).
The person taking the psilocybin may experience a range of emotions and may need help processing the experience (Segment 7).
Music is an essential component of the psilocybin journey (Segment 8).
By modulating activity in brain networks, psilocybin may facilitate a shift in perspective and increased emotional processing (Segment 10).
Psilocybin promotes neuroplasticity which is the reason for its therapeutic potential in depression (Segment 12).
Not all psychedelic experiences are positive, and some individuals may have challenging experiences ( (Segment 14).
Neurobiological changes, specifically enhanced neuroplasticity underlie psychedelics' therapeutic effects (Segment 16).
Combining psilocybin therapy and talk therapy for the treatment of depression is promising (Segment 18).

Overview and Purpose:

Oftentimes in conversation, podcast hosts/guests will reference a given study but aren't able to provide the entire context or citation link for listeners. To help underscore the impact of science podcasts, such as this one, we construct the posts to reference all studies discussed in their conversation as well as provide some more background/information on topics that we think the listeners may be interested in. If there are changes, you'd like to see to the format of these posts or any other feedback you'd like to provide - please let us know in the Discussion section below this post.

Note: In the ethos of Open Science and transparent publication, this is a living document that will undergo continuous improvement. If you have suggestions, expansions, or corrections please feel free to comment in this thread and we will adjust the document as well as award some RSC for your help.

Discussion and Publications by Section:

(1): 00:00:00 Psilocybin, Legal Considerations

Psilocybin is a psychedelic compound that modifies the psyche, changing one's level of consciousness and perception of the world, thoughts, feelings, and memories, not just while under its influence but also afterward, for a long period of time. Psilocybin mimics serotonin and activates a subset of serotonin receptors, leading to neuroplasticity at the level of the neural circuits in the brain[1]. Psilocybin is being researched for its potential therapeutic application in treating mental health issues such as depression, alcohol and drug abuse, OCD, and eating disorders. Proper psilocybin therapeutic approaches take place after the session in which one experiences the typical effects of hallucinations and changes in thought patterns [2]. The conditions inside of a psilocybin journey, including eyes closed or open, alternating between the two, the type of music played, and the dosage level, make up a larger neuroplasticity trigger of which psilocybin is a critical but variable part.

Legal Considerations

Psilocybin is a Schedule 1 drug, which is illegal in the United States, except for Oregon, where it has been approved for use in particular therapeutic settings for depression and addiction. Access to psilocybin worldwide has been largely restricted since the 1960’s [2]. Richard Nixon’s “war on drugs” combined with tighter regulation of pharmaceutical research is largely responsible for the halting of psychedelic research and subsequent restricted access for therapeutic purposes in North America. Despite support for the safety and efficacy of psilocybin and other psychedelics, research and exploration of psilocybin as a therapeutic has not re-emerged until recently. Some other areas in the country have decriminalized psilocybin. May 2023 is still a schedule one drug it is considered illegal in the United States it’s perhaps just one exception to that maybe a few others but the main exception is in the state of Oregon so psilocybin has been approved in particular therapeutic settings for use in particular conditions only depression and some forms of addiction. So in Oregon it’s more or less in the domain of decriminalized as opposed to actually legal prayers of the country including Oakland CA there are some areas in which it has been decriminalized and perhaps there are a few others that I’m not aware of but in general, are still considered and other psychedelics are still considered illegal this is very important not just saying this protect me I’m saying this to protect you possessing or certainly selling psilocybin such as clinical studies [3].

Figure 1. Psilocybe semilanceata, commonly known as the liberty cap.

References

Plotnik, L., G. Gibbs, and T.J.I.J.o.M.M. Graham, Psilocybin conspectus: status, production methods, and considerations. 2022. 24(1).
Mithoefer, M.C., C.S. Grob, and T.D.J.T.L.P. Brewerton, Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. 2016. 3(5): p. 481-488.
Meyers, C., The Question, in Drug Legalization: A Philosophical Analysis. 2022, Springer. p. 3-24.

(2): 00:12:00 Psilocybin Becomes Psilocin in the Gut, Serotonin

Psilocybin, a tryptamine that is closely related to serotonin, is a neuromodulator that is naturally produced in the brain and body. Serotonin is involved in a wide variety of functions, including mood regulation, pleasure, motivation, and appetite, among others. The similarity between psilocybin and serotonin leads to the question of why psilocybin, when ingested in the form of magic mushrooms or other psilocybin-containing substances, leads to specific experiences such as hallucinations, changes in thought patterns, and improvements in mood and various compulsive disorders[1]. When psilocybin is consumed, it is rapidly metabolized by the body into psilocin, which is the active compound that produces the psychoactive effects of psilocybin mushrooms. This process occurs primarily in the liver and gastrointestinal tract, where enzymes break down psilocybin into psilocin.

Tryptamine, a chemical compound that closely resembles serotonin, is a naturally occurring neuromodulator that changes the activity of other neurons and neural circuits in the brain and body. Tryptamines include not only psilocybin but also other psychedelics such as DMT and 5-MO-DMT. Psilocybin and its active derivative, psilocin, are structurally similar to serotonin, which means that they can bind to serotonin receptors and activate them, leading to a wide range of effects [4]. Serotonin is involved in many different functions, including mood regulation, pleasure, motivation, and appetite, among others. It works in concert with other neuromodulators such as dopamine, epinephrine, and norepinephrine to produce a complex array of effects on the brain and body. There are many different serotonin receptors, each of which can cause different effects when activated by serotonin or similar compounds.

The fact that psilocybin closely resembles serotonin raises the question of why it produces such specific effects when ingested. In the case of magic mushrooms or other psilocybin-containing substances, the effects can include visual and auditory hallucinations, changes in thought patterns, and improvements in mood and various compulsive disorders. The answer to this question is complex and multifaceted, but it likely involves the activation of specific serotonin receptors in the brain and the modulation of neural circuits that are involved in mood regulation and other functions. In the clinical setting, psilocybin has shown promise as a treatment for depression, anxiety, and other mental health disorders. Its ability to produce neuroplasticity, or the ability of the brain to reorganize and form new connections, may play a role in its therapeutic effects. However, much more research is needed to fully understand the mechanisms underlying the effects of psilocybin and other psychedelics [5].

Figure 2. The metabolic profile of psilocybin.

References

4. Winkelman, M.J.C.d.a.r., Psychedelics as medicines for substance abuse rehabilitation: evaluating treatments with LSD, Peyote, Ibogaine and Ayahuasca. 2014. 7(2): p. 101-116.

5. Wiltshire, P.E., et al., Light microscopy can reveal the consumption of a mixture of psychotropic plant and fungal material in suspicious death. 2015. 34: p. 73-80.

6. Jann, M. W. (2021). Psilocybin Revisited: The Science behind the Drug and Its Surprising Therapeutic Potential. Psychiatric Times, 38(3), 39-43.

(3): 00:17:00 The Serotonin 2A Receptor, Therapeutic Outcomes SSRIs vs. Psilocybin

Serotonin is a neurotransmitter that is naturally released in the brain and is responsible for regulating mood, appetite, and sleep. When serotonin is released, it binds to several different serotonin receptors throughout the brain, each with its function. Selective serotonin reuptake inhibitors (SSRIs) are a type of antidepressant medication that increases the availability of serotonin in the brain by blocking its reuptake, allowing it to remain active for longer periods.

The serotonin 2A receptor is a type of serotonin receptor that is expressed in specific areas of the brain and on particular areas of neurons, allowing for very specific changes in neural circuitry to take place. Psilocybin mainly binds to and activates the serotonin 2A receptor, which is responsible for triggering all the changes in neural circuitry that lead to improvements in mood and relief from compulsive disorders (7).

Clinical trials for psilocybin have shown that two psilocybin journeys, done with particular dosages of psilocybin, lead to maximal binding or occupancy of serotonin 2A receptors in ways that lead to significant and unprecedented relief for major depression (8). The results of these trials have outperformed standard therapy and various other antidepressants in terms of providing depression relief in ways that are frankly staggering. SSRI medications, such as Prozac and Zoloft, are selective serotonin reuptake inhibitors. While there is controversy surrounding the use of SSRIs, they are still commonly prescribed and can be beneficial for conditions such as obsessive-compulsive disorder. In terms of therapeutic outcomes, psilocybin and SSRIs may have different effects. Psilocybin's selective binding to the serotonin 2A receptor can lead to profound changes in neural circuitry that may provide more rapid and lasting relief from depression and other mood disorders. In contrast, SSRIs work by increasing the availability of serotonin in the brain, leading to a slower and more gradual improvement in symptoms.

Overall, the serotonin 2A receptor is a key player in the therapeutic potential of psilocybin, and its selectivity for this receptor is what sets it apart from other medications. While SSRIs and psilocybin may have different effects and benefits for different individuals, the potential of psilocybin as a therapeutic tool is promising and continues to be the subject of ongoing research.

Figure 3. The 2A receptors of Serotonin (9).

References

7. Stenbæk, D. S., Madsen, M. K., Ozenne, B., Kristiansen, S., Burmester, D., Erritzoe, D., ... & Fisher, P. M. (2021). Brain serotonin 2A receptor binding predicts subjective temporal and mystical effects of psilocybin in healthy humans. Journal of Psychopharmacology, 35(4), 459-468.

8. Kargbo, R. B. (2020). Psilocybin therapeutic research: the present and future paradigm. ACS medicinal chemistry letters, 11(4), 399-402.

9. An Introduction to Serotonin/https://www.spiritpharmacist.com/blog/serotoninintro (Access: 10/05/2023)

(4): 00:21:40 Serotonin Receptor Expression; Visual Hallucinations & Eyes Closed

Serotonin is a neurotransmitter that plays an important role in regulating mood, appetite, sleep, and other physiological functions. It acts on various serotonin receptors, which are proteins found on the surface of neurons and other cells in the body. When serotonin is released in the brain, it can bind to a variety of different serotonin receptors, including the 5-HT2A receptor. This receptor is highly expressed in the neocortex, which is the outer layer of the brain that is involved in complex cognitive processes such as perception, thinking, and decision-making. In particular, the visual cortex, which is responsible for processing visual information from the eyes, has a very high concentration of 5-HT2A receptors.

When someone takes psilocybin, a compound found in certain species of mushrooms, it selectively and strongly activates the 5-HT2A receptor. This leads to a cascade of downstream effects, including altered sensory perception, changes in mood, and visual hallucinations. These effects can occur even when someone's eyes are closed, as the visual cortex is still active and processing information from the brain.

Visual Hallucinations & Eyes Closed

Psilocybin's effects on visual perception can be highly varied and individualized, but they often involve geometric patterns, distortions, and morphing of objects and faces. These effects can be highly appealing to some people who are seeking a novel and unique experience, but they can also be overwhelming or distressing for others. It's worth noting that psilocybin's effects are not limited to the visual cortex or the 5-HT2A receptor (10). The compound has also been shown to affect other brain regions and neurotransmitter systems, such as the default mode network and dopamine signaling. These effects may contribute to psilocybin's therapeutic potential for conditions such as depression, anxiety, and addiction.

Overall, the relationship between serotonin receptor expressions, visual hallucinations, and closed eyes is complex and multifaceted. While psilocybin's effects on the 5-HT2A receptor and visual perception are well-documented, further research is needed to fully understand the mechanism of action and therapeutic potential of this compound. In addition, the visual cortex, which is responsible for processing visual information, has a very high expression of serotonin 2A receptors (11). This is why psilocybin can trigger profound visual hallucinations, even when the eyes are closed. The hallucinations may appear as geometric shapes, melting objects, or morphing faces, among other effects.

Figure 4. Serotonin system involvement in depression and anxiety (12).

References

10. Manford, M., & Andermann, F. (1998). Complex visual hallucinations. Clinical and neurobiological insights. Brain: a journal of neurology, 121(10), 1819-1840.

11. Pizzi, S. D., Chiacchiaretta, P., Sestieri, C., Ferretti, A., Onofrj, M., Della Penna, S., ... & Sensi, S. L. (2023). Spatial correspondence of LSD-induced variations of brain functioning at rest with serotonin receptor expression. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.

12. Deo, N., & Redpath, G. (2022). Serotonin Receptor and Transporter Endocytosis Is an Important Factor in the Cellular Basis of Depression and Anxiety. Frontiers in Cellular Neuroscience, 15, 804592.

(5): 00:27:21 Safety & Cautions for Specific Patient Populations

It is important to note that psilocybin use is not recommended for everyone and there are certain safety precautions that need to be taken. Psilocybin can have powerful effects on perception, cognition, and mood, and may not be appropriate or safe for everyone to use (13). There are certain patient populations for whom psilocybin use should be approached with caution or avoided altogether Psilocybin may trigger psychotic episodes or bipolar episodes, especially in individuals who have a predisposition or a family history of these conditions. In clinical studies, individuals with these conditions are typically excluded for fear of triggering these episodes.

Furthermore, it is important to note that most of the studies involving psilocybin have focused on adults ranging from 25 to 70 years of age, and not on individuals younger than 25 years of age (13). This is because the brain's basic wiring and rewiring, known as developmental neuroplasticity, is typically completed by the age of 25. It is also important to note that psilocybin is still illegal in many parts of the world, and its use should only be considered in a clinical or research setting (14). Even in these settings, caution needs to be taken to ensure that the experience is safe and therapeutic. Therefore, while psilocybin has shown promising results in treating certain conditions, it should not be taken lightly and should only be used under the guidance of a trained professional in a controlled setting. It is not a recreational drug and its effects can have long-standing changes after the effects of psilocybin wear off. Safety precautions need to be taken, and individuals with a history of mental illness or psychiatric disorders should consult with their healthcare provider before considering psilocybin. If you are interested to learn more about Psychedelics and depression in detail from on the Link.

References

13. Hodge, A. T., Sukpraprut-Braaten, S., Narlesky, M., & Strayhan, R. C. (2023). The use of psilocybin in the treatment of psychiatric disorders with attention to relative safety profile: a systematic review. Journal of psychoactive drugs, 55(1), 40-50.

14. Johnson, M. W., Garcia-Romeu, A., & Griffiths, R. R. (2017). Long-term follow-up of psilocybin-facilitated smoking cessation. The American journal of drug and alcohol abuse, 43(1), 55-60.

(6): 00:30:28 Psilocybin, “Magic Mushrooms” Dosing, Micro-Dosing, “Heroic Doses”

Psilocybin is a naturally occurring psychedelic compound found in certain species of mushrooms, commonly referred to as "magic mushrooms." Dosing of psilocybin can range from microdosing, which is a repeated low dose over some time, to macrodosing, which is a single high dose. In clinical studies, the typical dosage of psilocybin used ranges from 1 milligram per day for micro-dosing, up to 25-30 milligrams for a single macro dose session (15). These doses are usually given orally or through intravenous injection, and the effects can last for several hours.

Dosing, Micro-Dosing

Microdosing psilocybin involves taking a low dose of the compound regularly, typically 1-3 milligrams per day over some time (16). This approach is gaining popularity among people who believe it can enhance creativity, focus, and overall well-being without producing the intense hallucinogenic effects associated with larger doses.

On the other hand, macro dosing involves taking a high dose of psilocybin, typically 10 milligrams or more in a single session (16). This can produce profound psychedelic experiences that can last several hours and is often used in clinical studies to treat conditions such as depression, anxiety, and addiction. The so-called "heroic dose" is a term often used in the non-clinical, psychedelic community to refer to a particularly high dose of psilocybin, typically around 50 milligrams (equivalent to approximately 5 grams of mushrooms) (17). This dose is thought to produce an intense, transformative experience, but should be approached with caution due to the potential for adverse effects and psychological distress. It's important to note that the concentration of psilocybin can vary greatly between different strains of mushrooms and batches, so precise dosing can be difficult to achieve without laboratory analysis. Additionally, the effects of psilocybin can vary greatly depending on individual factors such as age, weight, and mental state, so it's crucial to approach the use of psilocybin with caution and under the guidance of a trained professional or medical practitioner.

Figure 5. Categories of micro-dosing benefits and challenges. Values indicate percentage endorsement of outcomes (17).

References

15. Hewitt, K. (2019). Psychedelic Feminism: A Radical Interpretation of Psychedelic Consciousness?. Journal for the Study of Radicalism, 13(1), 75-120.

16. Forward, R. S., & Brandenburg, B. Full Scope 33. Hallucinogenic Psilocybin Mushrooms.

17. Anderson, T., Petranker, R., Christopher, A., Rosenbaum, D., Weissman, C., Dinh-Williams, L. A., ... & Hapke, E. (2019). Psychedelic microdosing benefits and challenges: an empirical codebook. Harm reduction journal, 16(1), 1-10.

(7): 00:36:21 Psychedelic Journey: Set, Setting & Support

A psychedelic journey, whether it's through the use of substances like LSD, psilocybin, or DMT or through non-chemical means such as meditation or breathwork, can be a profound and potentially transformative experience. The key factors to consider when embarking on a psychedelic journey are set, setting, and support.

Set refers to your mindset or mental state going into the experience.
Setting refers to the physical and social environment in which the experience takes place.
Support refers to the people who will be with you during the experience (18).

The structure of a safe and effective psilocybin journey involves the concepts of set, setting, and support. Set refers to the mindset of the person taking the psychedelic, and setting refers to the physical and social environment in which the person is taking it (18). It is important to have a safe and controlled environment with responsible individuals who are not under the influence of psychedelics present to ensure the person taking the psilocybin is not going to harm themselves or others. It is also important for the person taking the psilocybin to be seated or lying down and has their eyes covered or wear an eye mask so that they can combine any spontaneous visual hallucinations that occur with the various thought processes that are occurring while under the influence of psychedelics. Additionally, support is essential, and this can involve a trained therapist or facilitator to guide the journey and provide emotional support (19). The person taking the psilocybin should also have a trusted friend or family member to be available for them after the journey, as they may experience a range of emotions and may need help processing the experience. Ultimately, the goal of the psilocybin journey is to create a safe and supportive environment in which the person can explore their inner thoughts and feelings and potentially achieve lasting changes in their mood, behavior, and brain chemistry. Research has shown that approaching psychedelic experiences with intention, in a safe and supportive environment, can lead to more positive outcomes and lasting benefits. However, it is important to note that the use of psychedelics is not without risks and should be approached with caution and proper guidance.

Figure 6. Key factors to consider when embarking on a psychedelic journey.

References

18. Hartogsohn, I. (2020). American trip: set, setting, and the psychedelic experience in the twentieth century. MIT Press.

19. Strickland, J. C., Garcia-Romeu, A., & Johnson, M. W. (2020). Set and setting: a randomized study of different musical genres in supporting psychedelic therapy. ACS Pharmacology & Translational Science, 4(2), 472-478.

20. Kelly, J. R., Gillan, C. M., Prenderville, J., Kelly, C., Harkin, A., Clarke, G., & O'Keane, V. (2021). Psychedelic therapy's transdiagnostic effects: a research domain criteria (RDoC) perspective. Frontiers in Psychiatry, 2295.

(8): 00:43:43 Music & the Psilocybin Journey; Duration of Effects

Music can play a significant role in the psilocybin journey. It has the ability to enhance the experience, facilitate emotional processing, and induce a range of profound states of consciousness. However, the effects of music on the psilocybin journey can vary depending on various factors, including the type of music, the volume, and the duration of the experience. Psilocybin is a powerful psychedelic compound found in certain species of mushrooms. When ingested, it can induce a profound and transformative experience known as a psilocybin journey. The experience is heavily influenced by the "set and setting," which includes the physical environment, the psychological state of the person, and other factors such as the presence of music (21). According to research conducted by pioneers in the study of psychedelics, music is not just a peripheral aspect of the psilocybin journey, but one of its major drivers. Music can impact the emotional and cognitive experiences of individuals during a psilocybin journey. In fact, the use of music has been described as one of the most important and profound positive experiences a person can have in their life.

Description of the Study

The typical duration of a psilocybin journey is around 4-6 hours, depending on various factors such as dose, metabolism, and food intake (21). In most clinical studies, participants are advised not to eat for at least 4 hours prior to ingestion, as food can impact the effectiveness of the compound (22). During the psilocybin journey, there is a peak component that lasts for several hours, during which individuals may experience intense emotions and anxiety. This anxiety is part of the process of ego dissolution, which can be a transformative experience. As the journey progresses, the anxiety usually subsides, and individuals gradually come back to their normal state (21). In clinical studies, individuals undergoing a psilocybin journey are typically lying down, wearing an eye mask, and accompanied by guides who are not taking the compound but are there to provide support and ensure safety. Music is also an integral part of the setting, and its effects are carefully curated to match the contours of the journey.

Volume of Music

The volume of the music is also an important consideration. Music played at a moderate volume can help to create a supportive and immersive environment without overwhelming the senses. However, excessively loud music can be disruptive and overwhelming, leading to feelings of anxiety or discomfort.

Duration of Psilocybin

The duration of the psilocybin experience can also affect the role of music. A shorter experience, lasting a few hours, may benefit from a carefully curated playlist that corresponds to the specific intentions and needs of the individual. A longer experience, lasting six to eight hours or more, may require a broader range of music to maintain engagement and interest throughout the journey. At the beginning of the session, low-volume music is played, typically classical music without vocalizations. This helps to calm and relax the individual. As the journey progresses and the individual approaches, the peak component, the music transitions to higher volume, more intense music, often percussion-based with drums. This intense music is played for about 45 minutes to 90 minutes, depending on the study (23). As the peak component subsides, the music transitions back to softer, more melodic music, often with female vocals. Finally, the music transitions to nature sounds, which mimic the outside world and help the individual reorient themselves as the journey comes to an end. In conclusion, music is an essential component of the psilocybin journey. It can impact the emotional and cognitive experiences of individuals and is carefully curated to match the contours of the journey. The use of music in clinical studies is one of the most important and profound positive experiences a person can have in their life.

Figure 7. Psilocybin facilitator students sit with eye masks on while listening to music during an experiential activity at a training session near Damascus, Ore., Dec. 2, 2022.

References

21. Messell, C., Summer, L., Bonde, L. O., Beck, B. D., & Stenbæk, D. S. (2022). Music programming for psilocybin-assisted therapy: guided imagery and music-informed perspectives. Frontiers in Psychology, 13, 6664.

22. Tomlinson, G. (1994). Music in Renaissance magic: Toward a historiography of others. University of Chicago Press.

23. Fachner, J. (2011). Time is the key–music and altered states of consciousness. Altering consciousness: A multidisciplinary perspective, 1, 355-376.

(9): 00:48:58 Psilocybin & the Brain: Subjective Experiences, Perception

Psilocybin is a psychedelic compound found in certain species of mushrooms, and it has been shown to cause a range of subjective experiences and perceptual changes in people who take it. It has profound effects on the brain and subjective experiences of individuals. Psilocybin affects the brain by binding to serotonin receptors, particularly the 5-HT2A receptors, which are involved in a wide range of cognitive and perceptual processes (24). Some of these changes include perceptual blending or synesthesia, where different senses become merged or blended together, and changes in the intensity or movement of visual hallucinations that may be linked to the music that a person is listening to. Under the influence of psilocybin, people may also report that their breathing becomes linked to the perceptions of things that they are hearing or seeing or feeling and that they have some sense of control over their perceptions and emotions in a way that is very unordinary.

These subjective experiences can be explained by understanding the way psilocybin interacts with serotonin 2A receptors in the brain (24). Serotonin 2A receptors are predominantly activated by psilocybin, and they are found in many places throughout the brain, including on the apical dendrites of pyramidal neurons. When psilocybin binds to these receptors, it increases lateral communication across brain areas, effectively reducing the modularity of the separateness of function in the brain and increasing the integration of communication (25). In addition to these effects, psilocybin also causes a reduction in the hierarchical organization of the brain, meaning that sensory information no longer comes in from the outside environment in a bottom-up fashion, but rather in a more integrated and holistic way. Overall, these effects result in the subjective experiences and perceptual changes that people report when taking psilocybin.

Figure 8. Whole brain cerebral blood flow map vs one map after therapy.

References

24. Turton, S., Nutt, D. J., & Carhart-Harris, R. L. (2014). A qualitative report on the subjective experience of intravenous psilocybin administered in an FMRI environment. Current Drug Abuse Reviews, 7(2), 117-127.

25. Hirschfeld, T., & Schmidt, T. T. (2021). Dose–response relationships of psilocybin-induced subjective experiences in humans. Journal of Psychopharmacology, 35(4), 384-397.

26. https://www.eurekalert.org/news-releases/600194

(10): 00:59:48 Brain Networks & Therapeutic Outcomes

The emerging novel therapeutic psilocybin produces psychedelic effects via the engagement of cerebral serotonergic targets by psilocin (active metabolite). The serotonin 2A receptor critically mediates these effects by altering distributed neural processes that manifest as increased entropy, reduced functional connectivity (FC) within discrete brain networks (i.e., reduced integrity), and increased FC between networks (i.e., reduced segregation) (27). Reduced integrity of the default mode network (DMN) is proposed to play a particularly prominent role in psychedelic phenomenology.

DMN is one of the brain networks that has been studied about psilocybin and its therapeutic effects. The DMN is involved in self-referential and introspective processes and has been implicated in various psychological disorders such as depression and anxiety. One theory about the therapeutic effects of psilocybin suggests that it works by reducing activity in the DMN, leading to a decrease in self-referential thought and an increase in the experience of a sense of interconnectedness with others and the environment (28). This effect has been linked to the therapeutic potential of psilocybin, particularly in the treatment of depression and anxiety. Other brain networks that have been implicated in the therapeutic effects of psilocybin include the salience network (SN) and the executive control network (ECN). The SN is involved in the processing of emotionally relevant information, and psilocybin has been shown to increase activity in this network, leading to a heightened sensitivity to emotional cues and an increased ability to process and integrate emotional experiences. The ECN, on the other hand, is involved in cognitive control and attention, and psilocybin has been shown to increase activity in this network as well, leading to improvements in cognitive flexibility and creativity (29).

Overall, the effects of psilocybin on brain networks provide insight into the mechanisms underlying its therapeutic potential. By modulating activity in key brain networks, psilocybin may facilitate a shift in perspective and increased emotional processing, leading to profound and long-lasting changes in behavior and thought patterns.

Figure 9. The default mode network (DMN). Strong overlap in the DMN representation based on anti-correlations and positive correlations in resting state data.

References

27. Johnson, M. W., & Griffiths, R. R. (2017). Potential therapeutic effects of psilocybin. Neurotherapeutics, 14, 734-740.

28. Madsen, M. K., Stenbæk, D. S., Arvidsson, A., Armand, S., Marstrand-Joergensen, M. R., Johansen, S. S., ... & Fisher, P. M. (2021). Psilocybin-induced changes in brain network integrity and segregation correlate with plasma psilocin level and psychedelic experience. European Neuropsychopharmacology, 50, 121-132.

29. Johnson, M. W., Hendricks, P. S., Barrett, F. S., & Griffiths, R. R. (2019). Classic psychedelics: An integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology & therapeutics, 197, 83-102.

(11): 01:05:23 Creativity; Music, Emotionality & Psychedelic Journeys

The use of psychotropic compounds for medicinal, spiritual, and recreational purposes has ancient origins in a diverse set of human cultures, and likely stretches back into pre-history. Psilocybin has been reported by some users to increase creativity and enhance the experience of life. Some users have reported feeling more open and receptive to new ideas, and more able to think outside of their usual patterns of thought. Pleasurable emotional reactions to music seem to be related to the reward system of the brain, which comprises the ventral striatum and ventromedial prefrontal cortex (vmPFC) (30). Modern and historical psychedelic therapies both incorporate music, which is important for its calming effects at different stages of the healing process as well as its ability to work in concert with the drug to elicit autobiographical memories and guide emotional experiences.

Research conducted by Wall 2023 reveals that by comparing music-listening and resting-state brain scans, the researchers found that there was a significantly greater amplitude of low-frequency fluctuations (ALFF) in certain regions of the brain following psilocybin treatment (31). Specifically, they found greater ALFF in the bilateral superior temporal cortex for the music scan, and in the right ventral occipital lobe for the resting-state scan. This suggests that psilocybin treatment may have altered the neural activity in these brain regions, potentially leading to enhanced experiences of music and altered visual perception during the resting state. Regarding music, psilocybin has been reported to enhance the experience of listening to music and can result in a more profound and emotionally charged experience. Users have described feeling a greater sense of connectedness to the music and may experience a heightened appreciation for the complexity and beauty of the music they are listening to. However, it is important to note that the effects of psilocybin can vary widely from person to person, and some users may not experience these effects at all.

Psilocybin can also cause a wide range of emotional experiences, including sensations of exhilaration, wonder, and awe. It is crucial to remember that certain users could also feel adverse emotional effects, such as anxiety or paranoia, particularly if they use the drug in a dangerous setting or in high amounts (31).

Figure 10. Comparison of pre-and post-therapy effects (after > before) for each scan individually (A = music; B = resting). The red-yellow color scale denotes increased responses post-therapy and the blue-green color scale denotes decreased responses post-therapy (32).

References

30. Koelsch, S. (2020). A coordinate-based meta-analysis of music-evoked emotions. NeuroImage, 223, 117350.

31. Wall, M. B., Lam, C., Ertl, N., Kaelen, M., Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2023). Increased low-frequency brain responses to music after psilocybin therapy for depression. Journal of Affective Disorders.

32. Watts, R., Day, C., Krzanowski, J., Nutt, D., & Carhart-Harris, R. (2017). Patients’ accounts of increased “connectedness” and “acceptance” after psilocybin for treatment-resistant depression. Journal of humanistic psychology, 57(5), 520-564.

(12): 01:12:39 Depression & Psychedelics as Neuroplasticity “Wedge”

There is growing evidence to suggest that psilocybin may have therapeutic potential in depression, but the exact mechanisms underlying its effects are still not fully understood. The hypothesis that psilocybin promotes neuroplasticity in the brain is one possible explanation for its therapeutic potential in depression. Several studies have shown that psilocybin can promote the growth of new neurons and synapses in the brain, and can also increase the strength of existing neural connections. For example, one study found that psilocybin increased the density of dendritic spines on neurons in the prefrontal cortex of rats (33). Another study found that psilocybin increased the functional connectivity between brain regions involved in emotional processing (34). These findings suggest that psilocybin may be able to promote neuroplasticity in the brain, which could be beneficial in the treatment of depression. Depression is characterized by decreased neuroplasticity, which may contribute to the persistence of negative thought patterns and emotions (33). By promoting neuroplasticity, psilocybin may be able to counteract this effect and facilitate the formation of new neural connections that are more adaptive and flexible. However, it is important to note that the evidence for psilocybin's effects on neuroplasticity is still limited, and more research is needed to fully understand the underlying mechanisms. In addition, the therapeutic potential of psilocybin in depression is still a topic of debate, and there are concerns about the safety and long-term effects of its use (35).

It is also worth noting that the hypothesis that psychedelics promote neuroplasticity is not universally accepted. Some researchers have suggested that the effects of psychedelics on the brain may be more related to changes in the balance between excitation and inhibition, rather than to neuroplasticity.

References

33. LaBua, R. S. (2021). The Effect of Psilocybin on Personality (Doctoral dissertation, City University of New York).

34. Jones, N. (2019). A Traditional Medicine’s Deep Time History and Rethinking Depression.

35. Duman, R. S., & Aghajanian, G. K. (2012). Synaptic dysfunction in depression: potential therapeutic targets. science, 338(6103), 68-72.

(13): 01:16:53 Positive Psychedelic Journeys, Unity, “Oceanic Boundlessness”

Positive psychedelic journeys can be characterized by a wide range of experiences, including mystical and transcendental experiences. One common theme that emerges from these experiences is a sense of unity and interconnectedness with the universe, often described as a feeling of "oceanic boundlessness." The term "oceanic boundlessness" describes a feeling of limitless unity and oneness with the universe that he observed in some of his patients (36). This concept has since been explored in the context of psychedelic experiences, with many individuals reporting similar feelings of interconnectedness and transcendence during their psychedelic journeys. Research has suggested that these experiences may be mediated by changes in brain function and connectivity, particularly in the default mode network, which is responsible for self-referential thinking and awareness. Psilocybin, for example, has been shown to decrease activity in this network, leading to a dissolution of the boundaries between the self and the external world (37). These experiences of unity and interconnectedness can have a profound impact on individuals, leading to increased feelings of compassion, empathy, and interconnectedness with others and the environment. They may also provide individuals with a sense of meaning and purpose, as well as a greater sense of well-being and contentment.

Roseman researched twenty patients with treatment-resistant depression who underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin) (38). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health (38). Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety.

It is important to note, however, that not all psychedelic experiences are positive, and some individuals may experience negative or challenging experiences that can be difficult to integrate into their lives. Therefore, it is important for individuals to approach psychedelic experiences with caution and to seek support from trained professionals when necessary.

Figure 11. ASC (11 dimensions) of responders and non-responders at 5 weeks. Error Bars = Standard Error (38).

References

36. Artinian, T. (2022). Transpersonal Gratitude and Psychedelic Altered States of Consciousness. Philosophy and Psychedelics: Frameworks for Exceptional Experience, 13.

37. Aday, J. S., Davis, A. K., Mitzkovitz, C. M., Bloesch, E. K., & Davoli, C. C. (2021). Predicting reactions to psychedelic drugs: A systematic review of states and traits related to acute drug effects. ACS Pharmacology & Translational Science, 4(2), 424-435.

38. Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2018). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Frontiers in pharmacology, 8, 974.

(14): 01:25:23 “Bad Trips”, Anxiety & Physiological Sighs

Many people report positive experiences during psychedelic trips, there is also a "bad trip," which can be characterized by feelings of anxiety, fear, and paranoia. These negative experiences can be overwhelming and distressing, and may even lead to physiological symptoms such as increased heart rate and blood pressure. Physiologically, bad trips may be associated with changes in neurotransmitter levels and activity in the brain (39). For example, elevated levels of cortisol, a stress hormone, have been observed in individuals who experience bad trips. In addition, changes in the activity of the default mode network, which is involved in self-referential thinking, may also play a role in the development of anxiety and fear during a psychedelic experience. Roseman reported that the Dread of ego-dissolution is considered to probe negative, aversive experiences in which anxiety is a central aspect. Visionary restructuralization measures altered perception and meaning including visual hallucinations and synesthesia (38). The DED sub-dimensions are impaired control or cognition, and Anxiety. The VRS sub-dimensions are complex imagery, elementary imagery, audio/visual synaesthesia, and changed the meaning of percepts.

People should approach psychedelic experiences cautiously and take precautions to reduce the likelihood of a disastrous trip. This can entail getting emotionally and mentally ready for the experience, selecting a welcoming and familiar setting, and having a reliable friend or professional on hand to offer support if necessary. Additionally, people who have a history of anxiety or mental health problems should exercise caution when thinking about using psychedelics. (40). They may benefit from collaborating with a trained expert to prepare for the experience and manage any negative side effects that may emerge. In conclusion, unpleasant trips during psychedelic experiences can be characterized by emotions like worry and terror and may be linked to alterations in the brain's neurotransmitter activity and levels. People should take precautions to reduce the likelihood of a disastrous trip, and when required, seek professional assistance to manage any adverse symptoms that may develop.

References

39. Johnson, M. W., Richards, W. A., & Griffiths, R. R. (2008). Human hallucinogen research: guidelines for safety. Journal of psychopharmacology, 22(6), 603-620.

40. MacLean, K. A., Leoutsakos, J. M. S., Johnson, M. W., & Griffiths, R. R. (2012). Factor analysis of the mystical experience questionnaire: A study of experiences occasioned by the hallucinogen psilocybin. Journal for the scientific study of religion, 51(4), 721-737.

(15): 01:32:57 Therapeutic Use of Psilocybin

The interest in psilocybin as a therapeutic approach has grown exponentially in recent years. Despite increasing access, there remains a lack of practical guidance on the topic for healthcare professionals. This is particularly concerning given the medical complexity and vulnerable nature of patients for whom psilocybin-assisted psychotherapy may be considered. One area of interest is the use of psilocybin in the treatment of depression and anxiety. Studies have shown that psilocybin can have profound effects on mood and outlook, with some individuals reporting long-lasting positive changes in their mental health (41). Psilocybin has also shown promise in the treatment of addiction, particularly in its ability to help individuals break free from entrenched patterns of thought and behavior (42).

While the therapeutic potential of psilocybin is promising, it is important to approach its use with caution and under the guidance of trained professionals. Psychedelic experiences can be unpredictable and intense, and may not be suitable for all individuals (43). However, with proper preparation and support, psilocybin and other psychedelics may offer a new avenue for the treatment of mental health disorders and other conditions. Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine (44). The proposed route is by inducing brain neuroplasticity. In summary, psilocybin has shown promise in the treatment of depression, anxiety, addiction, and other conditions. Its therapeutic effects may be related to changes in brain activity and connectivity and may offer new insights and perspectives for individuals seeking healing and growth.

Figure 12. Therapeutic uses of Psilocybin for various disorders (45).

References

41. MacCallum, C. A., Lo, L. A., Pistawka, C. A., & Deol, J. K. (2022). Therapeutic use of psilocybin: Practical considerations for dosing and administration. Frontiers in Psychiatry, 13, 2699.

42. Kargbo, R. B. (2020). Psilocybin therapeutic research: the present and future paradigm. ACS medicinal chemistry letters, 11(4), 399-402.

43. Lowe, H., Toyang, N., Steele, B., Valentine, H., Grant, J., Ali, A., ... & Gordon, L. (2021). The therapeutic potential of psilocybin. Molecules, 26(10), 2948.

44. De Vos, C. M., Mason, N. L., & Kuypers, K. P. (2021). Psychedelics and neuroplasticity: a systematic review unraveling the biological underpinnings of psychedelics. Frontiers in psychiatry, 12, 724606.

45. https://www.hopkinsmedicine.org/news/articles/tapping-into-psilocybins-potential

(16): 01:36:11 Neuroplasticity, Structural Brain Changes & Psilocybin

Neuroplasticity refers to the brain's ability to change and adapt throughout an individual's lifespan in response to environmental, behavioral, and neural factors. Recent research has suggested that the use of psilocybin, a psychedelic compound found in certain species of mushrooms, may facilitate neuroplasticity and lead to structural changes in the brain (46). Studies have shown that psilocybin can increase the growth of new neural connections and dendritic spines, which are the small protrusions on the branches of neurons that facilitate communication between them. Psilocybin has also been shown to increase the thickness of the prefrontal cortex, a brain region associated with higher cognitive functions such as decision-making and problem-solving (47). At a molecular level, neuroplastic changes occur via signaling pathways, that is, cascades of intracellular proteins transmitting signals from receptors to the DNA. Signaling pathways are activated by Ca2+ influx through depolarization or N-methyl-D-aspartate receptor (NMDAR) activation. To summarize, it is hypothesized that neurobiological changes, specifically enhanced neuroplasticity, underlie psychedelics' therapeutic effects (44). The techniques mentioned above can be used to assess changes in plasticity after the administration of psychedelics compared to a baseline, a placebo, or a control group. Understanding the biological pathways of psychedelics' acute and persisting effects is essential to grasp these compounds' full therapeutic potential (48). Although psychedelics do not have an established therapeutic use in psychiatry yet, promising preliminary findings of their therapeutic potential support further investigation and give insight into psychiatric disorders' biological underpinnings.

Structural Brain Changes

These structural changes in the brain may be related to the therapeutic effects of psilocybin. For example, increased dendritic spine growth and neural connectivity may facilitate the formation of new neural pathways and help individuals break free from entrenched patterns of thought and behavior. The thickening of the prefrontal cortex may also improve cognitive flexibility and enhance an individual's ability.

Figure 13. Evaluation of psychedelics' influence on cellular and molecular neuroplasticity in preclinical and clinical studies.

References

46. Davoudian, P. A., Shao, L. X., & Kwan, A. C. (2023). Shared and distinct brain regions targeted for immediate early gene expression by ketamine and psilocybin. ACS Chemical Neuroscience, 14(3), 468-480.

47. Du, Y., Li, Y., Zhao, X., Yao, Y., Wang, B., Zhang, L., & Wang, G. (2023). Psilocybin facilitates fear extinction in mice by promoting hippocampal neuroplasticity. Chinese Medical Journal, 10-1097.

48. Artin, H., Zisook, S., & Ramanathan, D. (2021). How do serotonergic psychedelics treat depression: the potential role of neuroplasticity. World Journal of Psychiatry, 11(6), 201.

(17): 01:48:08 Psychedelics: Therapeutic Breakthroughs & Depression

Psychedelic therapy is showing promise for a broad range of mental health conditions, indicative of a transdiagnostic action. Several small-scale clinical trials have reported positive outcomes, with patients experiencing reductions in symptoms of depression, anxiety, and existential distress (49). However, it is important to remain critical and cautious when evaluating these findings. One major limitation of these studies is the small sample sizes, which make it difficult to generalize the results to a larger population. Additionally, many of these studies are open-label, meaning that both the researchers and the participants are aware that they are receiving psilocybin, which may introduce bias and placebo effects. Future randomized, double-blind, placebo-controlled trials are needed to better understand the effectiveness of psilocybin for depression. The endgame for many scientists in this area is to decriminalize psychedelics (both synthetic and natural) and establish safe protocols that will allow doctors and psychotherapists to harness the “magic” in these compounds for medical purposes (50). The goal is to achieve a lasting recovery in patients.

Another concern is the potential for adverse reactions and negative experiences, commonly referred to as "bad trips." While most participants in clinical trials have reported positive experiences, a significant minority have reported distressing and sometimes traumatic experiences (50). The lack of reliable predictors of who may have a negative experience highlights the importance of careful screening and preparation before administering psilocybin. Additionally, the long-term effects of psilocybin use on mental health and well-being are not yet fully understood. It is possible that the benefits seen in short-term clinical trials may not be sustained over time, or that there may be unforeseen negative consequences. More research is needed to investigate the potential risks and benefits of long-term psilocybin use.

References

49. Spriggs, M. J., Kettner, H., & Carhart-Harris, R. L. (2021). Positive effects of psychedelics on depression and wellbeing scores in individuals reporting an eating disorder. Eating and Weight Disorders-Studies on Anorexia, Bulimia and Obesity, 26, 1265-1270.

50. Hickie, I. B., & Rogers, N. L. (2011). Novel melatonin-based therapies: potential advances in the treatment of major depression. The Lancet, 378(9791), 621-631.

(18): 01:56:37 Combining Psilocybin Therapy & Talk Therapy, Antidepressant Effects

The idea of combining psilocybin therapy and talk therapy for the treatment of depression is promising, as both approaches have individually shown efficacy in treating depression. However, the research in this area is still in its early stages, and there are several limitations and concerns to consider. This approach is based on the idea that psilocybin can facilitate emotional breakthroughs and insight, while talk therapy can help patients integrate these experiences into their lives and develop new coping skills (51). In a recent small-scale clinical trial, patients with treatment-resistant depression received two doses of psilocybin, two weeks apart, along with weekly psychotherapy sessions. The study found that this combination led to significant reductions in symptoms of depression and anxiety, with some patients experiencing remission of their depression. The authors suggest that the combination of psilocybin therapy and talk therapy may help to address the root causes of depression, rather than simply treating the symptoms. Firstly, the studies conducted on this combination therapy have been small and open-label, meaning that both the researchers and the participants were aware of the treatment being given. This introduces the possibility of bias and placebo effects, making it difficult to generalize the results to a larger population (52). Additionally, the studies have lacked a control group, making it difficult to determine the specific effects of psilocybin and talk therapy.

Another concern is the safety of combining psilocybin with other forms of therapy, such as antidepressant medication (53). There is currently little research on the potential risks and benefits of combining psilocybin with other medications, and it is unclear whether this combination could lead to adverse reactions or interactions. While these results are promising, it is important to note that this was a small-scale, open-label study, and further research is needed to confirm these findings. Additionally, the potential risks and benefits of combining psilocybin with other forms of therapy, such as antidepressant medication, are not yet fully understood.

Figure 14. Combining Psilocybin therapy and talk therapy in patients.

References

51. Greenway, K. T., Garel, N., Jerome, L., & Feduccia, A. A. (2020). Integrating psychotherapy and psychopharmacology: psychedelic-assisted psychotherapy and other combined treatments. Expert Review of Clinical Pharmacology, 13(6), 655-670.

52. Earleywine, M., & De Leo, J. (2020). Psychedelic-assisted psychotherapy for depression: How dire is the need? How could we do it?. Journal of Psychedelic Studies, 4(2), 88-92.

53. Kočárová, R., Horáček, J., & Carhart-Harris, R. (2021). Does psychedelic therapy have a transdiagnostic action and prophylactic potential?. Frontiers in Psychiatry, 1068.

(19): 02:03:11 Psilocybin Experience & Mental Health

Psilocybin, a classic hallucinogen, is a chemical produced by more than 100 species of mushrooms worldwide. It has a high affinity for several serotonin receptors, including 5-HT1A, 5-HT2A, and 5-HT2C, located in numerous areas of the brain, including the cerebral cortex and thalamus. With legislation introduced in 1992, more work is being done to further understand the implications of psilocybin use in several disease states (54). Certain mental health disease states and symptoms have been studied, including depressed mood, anxiety disorders, obsessive-compulsive disorder, alcohol use disorder, and tobacco use disorder.

Many of the studies conducted on psilocybin and mental health have been small and have lacked a control group, making it difficult to generalize the results to larger populations. Additionally, many of the studies have relied on self-reported measures of mental health outcomes, which can be subject to bias and placebo effects (55). Another concern is the potential risks associated with psilocybin use, particularly for individuals with a history of mental health conditions or other medical issues. Psilocybin has been shown to increase heart rate and blood pressure, and there is a risk of adverse psychological effects such as anxiety, paranoia, and depersonalization. Moreno and his colleagues conducted a study involving 9 patients with OCD as defined by the DSM-IV and at least 1 treatment failure (adequate treatment of at least 12 weeks with a serotonin reuptake inhibitor) (56). In conclusion, while psilocybin may hold promise as a therapeutic tool for mental health conditions, several limitations and concerns must be taken into account.

References

54. Sayalı, C., & Barrett, F. S. (2023). The costs and benefits of psychedelics on cognition and mood. Neuron.

55. Daniel, J., & Haberman, M. (2017). Clinical potential of psilocybin as a treatment for mental health conditions. Mental Health Clinician, 7(1), 24-28.

56. Moreno, F. A., Wiegand, C. B., Taitano, E. K., & Delgado, P. L. (2006). Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder. Journal of clinical Psychiatry, 67(11), 1735-1740.

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