Dr. Robin Carhart-Harris: The Science of Psychedelics for Mental Health | 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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Podcast Guest: Dr. Robin Carhart-Harris ( Professor, Neurology at the University of California, San Francisco)

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Key takeaways

Psychedelics interact with serotonin receptors, influencing perception and cognition in significant ways (Segment 02).
Psychedelics in psychotherapy reveal repressed material and facilitate therapeutic processes through heightened awareness (Segment 03).
Psilocybin shows promise in treating depression, but further research is needed for conclusive evidence (Segment 05).
LSD affects emotional processing, social behavior, and empathy, but individual responses vary (Segment 08).
Psychedelics enhance brain communication, involving intermodular connectivity and the potential integration of subjective experiences (Segment 09).
Psilocybin therapy shows promise in reducing depression and enhancing brain connectivity for therapeutic outcomes (Segment 11).
Psychedelic therapy shows potential as a treatment for eating disorders, requiring further investigation (Segment 12).
Psilocybin administration in middle-aged individuals showed positive effects on cognition and brain connectivity (Segment 14).
The efficacy of micro-dosing psychedelics remains uncertain, while psychedelic therapy shows potential benefits (Segment 17).
Psychedelic decriminalization efforts are underway, signaling potential shifts in legal landscapes worldwide (Segment 21).
Psychedelic-assisted therapy shows promise in addressing mental health disorders, necessitating safeguards and paradigm shifts (Segment 24).

Summary

The present podcast features Robin Carhart-Harris, Ph.D., who holds the esteemed position of professor in the fields of neurology and psychiatry at the University of California, San Francisco. The individual in question is a prominent scholar in the field of investigating the effects of psychedelic substances, including psilocybin, LSD, and DMT, on the human brain. This research has yielded promising results in the treatment of a variety of mental health conditions, including but not limited to major depression, anorexia, obsessive-compulsive disorder, and addiction. The author elucidates how psilocybin elicits persistent alterations in the adaptive neural circuitry and cognitive processes. The article presents a discussion by Dr. Andrew Huberman and Dr. Robin Carhart-Harris on the fundamental elements of secure and efficient psychedelic experiences. The discourse covers the significance of hallucinations, and the utilization of eye masks to facilitate introspection and music. Additionally, the authors delve into the components of adequate therapist support, both pre and post-session, commonly referred to as integration. The authors additionally deliberate upon the comparative merits of micro-dosing and macro-dosing, as well as the methodologies employed by researchers to mitigate the influence of placebo effects in psychedelic research. Additionally, the authors delve into an analysis of the present legal framework concerning psychedelic treatments. Psychedelic therapies are rapidly gaining recognition as potent treatments for medical health conditions that are likely to become mainstream in the near future. However, they are not devoid of potential risks. Therefore, this particular episode is likely to benefit individuals who possess an interest in brain plasticity, mental health, psychology, or neuroscience.

(01): 00:00:00 Dr. Robin Carhart-Harris

One of the top researchers on the subject of psychedelics and how they alter the neuronal circuitry in the brain is Dr. Robin Carhart-Harris, a distinguished professor of neurology and psychiatry at the University of California. The knowledge of how psilocybin, commonly referred to as a magic mushroom, alters neuronal circuitry in the brain comes from his laboratory. such that fresh concepts and new leadership styles emerge. His lab is also in charge of conducting numerous clinical trials, some of which have shown that using the right dosage of psilocybin can treat serious depression in more than 67% of users. This does not mean that everyone should take psilocybin, though. In today's session, he will cover both clinical therapy and the reasons why using psychedelics to treat depression can be effective in certain situations but not others. Additionally, Dr. Harris is an authority on N, N-Dimethyltryptamine (DMT), Lysergic Acid Diethylamide (LSD), and psilocybin [1].

References

1. Robin Carhart-Harris, PhD. Available from: https://profiles.ucsf.edu/robin.carhart-harris.

(02): 00:06:31 Origin of the Word: “Psychedelics”; Pharmacology

The term "psychedelics" comes from the Greek terms "psyche," which means "soul," and "deloun," which means "to manifest." Hence, "mind manifesting". The term was initially introduced by Humphry Osmond, a psychiatrist from the United Kingdom, in the year 1957. Although the term has gained popularity among the general public over the course of several decades, its usage has been generally disapproved by the scientific community due to its connotation of the substances possessing beneficial properties. During the late 1960s, it was deemed appropriate within scientific communities to exclusively label these substances as 'psychotomimetics', indicating that these drugs facilitated a psychological condition akin to psychosis. Subsequently, it was discerned that these compounds were not viable representations of psychosis or other mental disorders. Consequently, the term 'hallucinogens' gained greater prevalence in usage. However, the aforementioned term carries unfavorable implications as it suggests that these substances primarily induce hallucinatory experiences. In actuality, the majority of users do not encounter hallucinations at typical dosages. Despite its historical origins, this nomenclature continues to be extensively employed in contemporary times and persists as the favored appellation for these compounds in academic literature [2].

The substances known as classical serotonergic hallucinogens primarily function as agonists or partial agonists on the 5-hydroxytryptamine (5-HT) 2A receptors in the brain, as illustrated in Figure 1. These compounds are widely recognized as psychedelics. The 5-HT2A receptors, also known as serotonin receptors, are categorized as G protein-coupled receptors and ligand-gated ion channels. These receptors are present in both the central and peripheral nervous systems. These entities have the ability to modulate the facilitation and inhibition of neurotransmitter transmission. Furthermore, the aforementioned receptors play a crucial role in modulating the secretion of diverse neurotransmitters, such as dopamine, epinephrine, and acetylcholine. The serotonin 5-HT2A receptors have a significant impact on a range of biological and neurological functions, including but not limited to aggression, anxiety, appetite, mood, and memory. Regarding psychedelics, these substances exhibit an affinity for serotonin 5-HT2A receptors, which regulate crucial neural pathways in the brain, specifically those associated with sensory perception and cognitive processes [3].

Figure 01. shows the amino acids in the 5-HT2A serotonin receptor complex, which is linked to a psychedelic substance (magnified on the right in pink) [2].

References

2. Gunn, S. Psychedelics: A new kind of trip. 2021; Available from:https://frontlinegenomics.com/psychedelics-a-new-kind-of trip/#:~:text=The%20term%20'psychedelic'%20is%20derived,psychiatrist%220in%20.

3. Erkizia-Santamaría, I., et al., Serotonin 5-HT2A, 5-HT2c and 5-HT1A receptor involvement in the acute effects of psilocybin in mice. In vitro pharmacological profile and modulation of thermoregulation and head-twitch response. Biomedicine & Pharmacotherapy, 2022. 154: p. 113612.

(03): 00:12:05 Psychedelics & Revealing the Unconscious Mind, Psychotherapy

The phenomenon of blindsight has attracted considerable scholarly interest. It is noteworthy that blindsight is distinct from non-conscious processing, which could potentially encompass implicit processing. This pertains to the cognitive mechanisms implicated in subliminal perception, which exert a significant impact. The topic at hand, despite its correlation, is separate from the subconscious mind as proposed in depth psychology, psychoanalysis, and psychodynamic ideologies, which have been advocated by notable personalities such as Sigmund Freud and Carl Jung. The unconscious component of the human psyche is primarily preoccupied with fundamental aspects of human nature. The construct in question pertains to the personal unconscious, which comprises suppressed recollections, specifically those linked to distressing occurrences or intricate interpersonal connections. The condition under investigation has the potential to entail intricate trauma, rather than a solitary incident of trauma. Furthermore, the notion of the collective unconscious proposed by Carl Jung constitutes a noteworthy contribution to the discipline of psychology. The transpersonal quality of the unconscious psyche encompasses facets of human experience that surpass the individual level. The aforementioned aspects, which pertain to the oral cavity, cognitive processes, and mental state, surpass the limits of conscious perception but may manifest in particular circumstances. The discipline of psychoanalysis has extensively explored the significance of dreaming as a means of accessing the information stored in the subconscious mind [4].

The effects of psychedelics, such as LSD and psilocybin found in magic mushrooms, have been observed in psychotherapy. These substances have been found to bring forth repressed material that holds therapeutic value. The heightened awareness and insight gained from these experiences seem to facilitate the therapeutic process, often resulting in the release of strong emotions. These cathartic experiences and insights may be personal or transpersonal in nature [5].

Figure 02: Improving cognitive functioning with psychedelics [4].

References

4. Magaraggia, I., Z. Kuiperes, and R. Schreiber, Improving cognitive functioning in major depressive disorder with psychedelics: A dimensional approach. Neurobiology of Learning and Memory, 2021. 183: p. 107467.

5. Sanacora, G., B.M. Kitay, and S.T. Wilkinson, Chapter 35 - The Search for Rapid Acting Antidepressants: Research Synthesis and Perspectives, in Neurobiology of Depression, J. Quevedo, A.F. Carvalho, and C.A. Zarate, Editors. 2019, Academic Press. p. 401-413.

(04): 00:17:32 Microdosing

A microdose can be defined as a dose of a conventional psychedelic substance, such as LSD or psilocybin, that elicits a sub-threshold psychedelic effect, thereby precluding the occurrence of a discernible altered state of consciousness that is characteristic of a full-blown psychedelic experience. Based on the administered dose of LSD, it appears that the threshold level was observed to be approximately 10, 11, or 12 micrograms. A dose of 10 micrograms of LSD is considered to be the threshold dose, which is capable of eliciting a perceptible response in individuals who are sensitive to it. However, it is noteworthy that the majority of individuals are unlikely to experience visual hallucinations at this dose level. Conversing with micro-dosing specialists may suggest that semi-regular ingestion of an LSD dose within this range is deemed as a microdose. Various protocols exist for this type of activity, typically involving a regimen of alternating periods of one day on and one day off or one day on and two days off. The underlying premise posits that a genuine microdose is capable of inducing a discernible alteration at the trait level, as opposed to the state level, potentially manifesting in behavioral changes, and ultimately leading to an enhancement of overall well-being. An alternative perspective regarding micro-dosing is that it has the potential to enhance specific cognitive functions, particularly those associated with cognitive reasoning. Researchers are currently anticipating conclusive evidence, however, no such evidence has been presented thus far. It's difficult to conduct a study using micro-dosing because you need to have permission to give participants a microdose that they could reasonably take home. Otherwise, it would be necessary to mandate their attendance at the laboratory thrice weekly for a specified duration to fulfill the prerequisites of a micro-dosing curriculum, which may entail a frequency of two to three times per week over the course of a month. It is premature to exhibit excessive enthusiasm regarding notable positive discoveries pertaining to alterations in the mood [6].

The study in question can be classified as a citizen science initiative, wherein participants were provided with LSD tabs to be self-administered. The tabs were subsequently divided and encapsulated in opaque gel capsules, with a separate set of empty capsules serving as the placebo. The capsules were then labeled with a unique barcode. Dr. Robin Carhart-Harris and his team employed an innovative study design whereby participants were instructed to self-administer a placebo-controlled blinding protocol during micro-dosing. They also tried mushrooms, which had the drawback of making people burp or belch and leaving them with a mushroom flavor. As a result, he told them to buy some non-psychoactive mushrooms instead, making the study considerably more difficult. The short version of the tale is that the micro-dosing did not significantly outperform the placebo, therefore the results are noteworthy. Because they were questioned, they also controlled for anticipation. People had favorable expectations, which are in a sense the means by which the placebo response is delivered. This is the mechanism by which a placebo may elicit a therapeutic effect. In order to understand how those who received a placebo but believed they were receiving a microdose performed as well as those who received a microdose and believed they were receiving one, one of his lab researchers measured that before the trial and then utilized it to sort of compensate for the reaction. Therefore, even if there was a larger effect, the majority of it came from believing you had just received a microdose. It was a success for the placebo effect in that sense, but it also stirred up a lot of debate because many people don't want to accept that kind of evidence. However, that is the beauty of science: it is not about what you want to believe [7].

Figure 03: Psychedelic mushroom microdoses improve mood and mental wellness [8].

References

6. Anderson, T., et al., Psychedelic micro dosing benefits and challenges: an empirical codebook. Harm Reduction Journal, 2019. 16(1): p. 43.

7. Murphy, R.J., et al., MDLSD: study protocol for a randomized, double-masked, placebo-controlled trial of repeated microdoses of LSD in healthy volunteers. Trials, 2021. 22(1): p. 302.

8. Psychedelic mushroom microdoses can improve mood and mental health. 2022; Available from: https://news.ok.ubc.ca/2022/07/11/psychedelic-mushroom-microdoses-can-improve-mood-mental-health/.

(05): 00:26:08 Psilocybin vs. Magic Mushroom Doses

According to a research inquiry, psilocybin exhibited comparable efficacy to escitalopram in alleviating depressive symptoms. Nevertheless, the difference in the changes in mean scores between the two groups did not achieve statistical significance. Psilocybin demonstrated higher response and remission rates when compared to escitalopram. It is crucial to consider that the analyses were not subjected to adjustment for multiple comparisons, which may have implications for the interpretation of the secondary outcomes. Further research with larger sample sizes and rigorous methodology is required to validate these findings and determine the relative efficacy and safety of psilocybin compared to escitalopram in treating the specified condition. A perceptible dose of psilocybin is 25 milligrams, which is presumed to induce hallucinations. The percentage of psilocybin present within the mushroom mass is accompanied by psilocin, a metabolite of psilocybin, which is present at a concentration of approximately one percent. A single gram of magic mushroom or 1000 milligrams of magic mushroom would comprise approximately 10 milligrams of psilocybin [9].

Figure 04: Magic Mushroom [10].

References

9. Carhart-Harris, R., et al., Trial of Psilocybin versus Escitalopram for Depression. 2021. 384(15): p. 1402-1411.

10. The psychedelic escape from depression. Available from: https://www.nature.com/articles/d41586-022-02872-9.

(06): 00:28:28 “Psychedelic-Therapy”, Music

Several autonomous research groups and investigations have discovered that the intensity of specific encounters, as evaluated by subjective rating instruments, exhibits a robust and consistent correlation with the effectiveness of therapeutic interventions. This discovery is presently informing our comprehension of these phenomena. Although there is a possibility that these experiences may be attributed to a central brain action, it is noteworthy to acknowledge that all experiences could be regarded as epiphenomena based on this principle. However, these experiences continue to be of interest to us. The cognitive ability to recognize and comprehend the influence of one's environment on social interactions is a fundamental element of human consciousness. Hence, in the context of psilocybin therapy, the physiological impact of the drug, including the initiation of paresthesia, assumes considerable significance for the recipient of the intervention. Initially, the participants undergo a state of anxiety, which is followed by the observation of patterns and colors in their mental imagery. The complexity and dynamism of these patterns may increase, exhibiting an intriguing organic quality. According to Dr. Harris' statement, the participants of the study employed an eye mask during the experiment, leading to the closure of their eyes [11].

A fundamental differentiation between psychedelic therapy and recreational psychedelic consumption lies in the application of the imagination, rather than reliance on extrinsic visual cues. In the context of psychedelic therapy, it is common for individuals to engage in the practice of closing their eyes as a means of directing their attention toward their internal experiences. Psychedelic therapy differs significantly from the recreational use of psychedelics, such as at a rave. The former pertains to a meticulously regulated and organized setting, wherein the patient's state is closely observed and music is frequently utilized as a supplementary component to the curative procedure. The empirical investigations conducted on these ailments have revealed negligible divergence among diverse research locations. In general, it is customary for a pair of individuals, ideally possessing expertise in mental health, with one of them being a psychiatrist, clinical psychologist, or psychotherapist, to oversee the administration of drugs to the subject. Throughout the session, music is played in a continuous manner, commencing with instrumental pieces and gradually intensifying to encompass ambient sounds, such as remote tribal percussions or avian vocalizations. The objective is to establish a uniform and unvarying outcome. As the potency of drugs increases, the music is intentionally crafted to evoke emotional responses through the strategic utilization of instruments, including strings. Conducting an experiment to examine whether the emotional intensity of the psychedelic experience during therapy would persist in the absence of music would be a captivating endeavor. The utilization of music constitutes a fundamental constituent of psychedelic therapy, as substantiated by a plethora of published research studies that have exerted a noteworthy influence on the discipline of psychiatry and its associated domains. The adequacy of testing the assumption that music is a necessary component of psychedelic therapy is a notable aspect that requires further examination. From a critical standpoint, one could contend that the incorporation of music in psychedelic therapy merits acknowledgment as a variant of music therapy. Hence, the overemphasis on the significance of psychedelics in these experiments could be considered unwarranted, considering the noteworthy and favorable influence of music in similar circumstances. The aforementioned statement implies that music could potentially have a pivotal function in the therapeutic effects witnessed in psychedelic therapy [12].

Figure 05: Music for Psychedelic Therapy [13].

References

11. Strickland, J.C., A. Garcia-Romeu, and M.W. Johnson, Set and Setting: A Randomized Study of Different Musical Genres in Supporting Psychedelic Therapy. ACS Pharmacol Transl Sci, 2021. 4(2): p. 472-478.

12. Kaelen, M., et al., The hidden therapist: evidence for a central role of music in psychedelic therapy. Psychopharmacology (Berl), 2018. 235(2): p. 505-519.

13. Music for Psychedelic Therapy Available from: https://wavepaths.com/blog/music-for-as-psychedelic-therapy-a-four-part-online-workshop-series.

(07): 00:36:26 Psychedelic Journey: “Trust, Let Go, Be Open”

The expression "Trust, Let Go, Be Open" is commonly embraced by individuals who partake in psychedelic encounters. This specific cognitive framework prioritizes the importance of instilling confidence in the methodology and the sagacity of psychedelic therapeutics. The process entails letting go of emotional and mental connections and anticipations while sustaining a receptive attitude toward innovative occurrences and perceptions. The principle mentioned above serves as a navigational aid for efficiently managing the diverse sensations and perceptions that arise during psychedelic experiences. The utilization of psychedelic substances has the capacity to evoke significant and enduring impacts on an individual's psyche. Nevertheless, it is crucial to exercise caution and embark on such expeditions within a safe and supportive environment. It is imperative to engage with qualified experts and conduct thorough investigations in order to fully comprehend the potential risks and benefits associated with psychedelic substances [14].

The phenomenon of the unconscious material becoming conscious or the emergence of the unconscious into consciousness is commonly referred to as the mind revealing itself to itself. The challenge at hand is indeed remarkable in its enormity, yet it is one that must be embraced. The act of letting go is a crucial element in the approach of various teams towards this task, as it fosters a disposition that is open to change. The initial foray into depression research involving psychedelics was a pioneering effort, as it marked the first instance of such a trial being conducted on a formally diagnosed population suffering from depression. The phrase "trust, let go, be open" was emphasized as a mantra to encourage individuals to engage in therapeutic practices. Trust was highlighted as a key component in this process. The concept of therapeutic rapport has been formally measured by researchers, indicating that it extends beyond mere intuition. Please report on this matter once again. Even a solitary item, such as a visual analog scale, can be utilized as a subjective rating scale item during the pre-dose assessment, and it has been observed to be a statistically significant predictor of the quality of the psychedelic therapy experience. Furthermore, this pre-dose assessment has been linked to therapeutic outcomes that manifest weeks or months after the therapy session. The aforementioned predictive components form a potent chain that places significant emphasis on trust, not solely relying on intuition but also on data. It is noteworthy that the readiness to surrender, let go, and not resist is a crucial factor that Dr. Harris measures and finds to be predictive of response. Additionally, being open entails a willingness to confront and be inquisitive, which can be a daunting task despite being easier said than done. One is aware when they are working with a highly vulnerable demographic. It is common for individuals undergoing psychedelic therapy to have experienced significant adversity or trauma in their lives. The message of being open and willing to confront these experiences is a powerful one and often leads to struggles and difficult emotions. Despite the challenges, the therapy can be effective, particularly with the use of high doses. Patients may express a desire to avoid their emotions, but ultimately, facing them can be a transformative experience. A remarkable project is currently underway within Dr. Harris' Ph.D. program, which aims to characterize the various phases of the psychedelic experience. The initial stages of this experience are often characterized by negative emotions and anxiety, while the latter stages present a different narrative altogether [15].

Figure 06: Psychedelic drugs induce consciousness.

References

14. Tersavich, C. Why the "Trust, Let Go, Be Open" Mantra is Important in Psychedelic Healing. 2022; Available from: https://www.mindbloom.com/blog/exploring-the-trust-let-go-be-open-tlo-mantra.

15. Ko, K., et al., Psychedelics, Mystical Experience, and Therapeutic Efficacy: A Systematic Review. Front Psychiatry, 2022. 13: p. 917199.

(08): 00:43:01 Negative Emotions, Fear & Psychedelics

The present study aimed to examine the immediate impact of LSD on emotional processing, social behavior, and empathy through the administration of multiple assessments. The findings indicated that the administration of LSD elicited emotions of euphoria, reliance, and interpersonal proximity. The intervention yielded an augmentation in both explicit and implicit emotional empathy, a rise in participants' inclination to engage in social interactions, and facilitation of prosocial conduct. Nevertheless, the administration of LSD resulted in a decline in the ability to identify sad and fearful facial expressions. The results indicate that LSD has the capacity to impact emotional processing and social behavior, potentially offering advantages in the realm of LSD-facilitated psychotherapeutic interventions [16].

It is noteworthy that the impact of psychedelics on emotions and fear is subject to variability contingent on factors such as dosage, set and setting, and individual traits. The subjective nature of psychedelic-induced experiences can result in significant variations in individual responses. It is noteworthy to mention that the modifications in affect and emotion perception that are observed with psychedelic substances may potentially stem from adjustments in the regulation of emotion via top-down mechanisms. The aforementioned proposition posits that psychedelics may exert an impact on the management and interpretation of affective states by means of alterations in cognitive and neural processes [17].

Figure 07: Psychedelics and Mental Health [18].

References

16. Dolder, P.C., et al., LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality. Neuropsychopharmacology, 2016. 41(11): p. 2638-2646.

17. Barrett, F.S., et al., Emotions and brain function are altered up to one month after a single high dose of psilocybin. Scientific Reports, 2020. 10(1): p. 2214.

18. Gregorio, D.D., et al., Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine. 2021. 41(5): p. 891-900.

(09): 00:46:21 Global Functional Connectivity, Serotonin 2A Receptor; Subjective Experiences

Dr. Robin Carhart-Harris has recently conducted research that suggests that the effects of psychedelics on the brain may persist even after the psychedelic experience has ended. This phenomenon may be attributed to the maintenance of communication between various brain regions. A visual representation that may be familiar to some individuals is that of two interconnected circles. Typically, communication within the visual system occurs primarily within the visual system, similar to other regions of the visual system. The quality of communication in the brain exhibits a certain degree of cliquishness or modularity. However, the noteworthy discovery with psilocybin is that the communication transcends these modules and becomes more intermodular, spanning across various modalities. This phenomenon is positively correlated with the subjective effect's magnitude. The same effect was replicated using different methods with LSD, and a new paper is soon to be published demonstrating similar effects with DMT. There is ongoing discourse regarding the regions that are predominantly involved, however, the overall consequences of the augmentation in global functional connectivity are commonly referred to as global communication in the brain. This phenomenon is subject to examination by administering brain scans to individuals under the influence of drugs. It is noteworthy that undergoing such scans can be a rather unique experience, given the confined space of the scanning apparatus. However, it is not always necessary to circumvent, or at least not exclusively through the use of psychedelics. It is imperative to maintain composure despite the presence of a loud scanner noise, which can be anticipated due to its regularity, thus minimizing unexpected occurrences. The level of tolerance towards the aforementioned setting is unexpectedly high, with a majority of individuals exhibiting a notable degree of tolerance towards it. Furthermore, it is observed that there is an increase in inter-system communication within the brain, which suggests a potential integration of subjective experiences from various modalities. This phenomenon may be indicative of an intuitive process [19].

It is hypothesized that the activation of the serotonin 2A receptor is accountable for facilitating intercommunication among brain regions that would not typically communicate under normal circumstances. There exist several rationales for the efficacy of computational modeling in the identification of the 2A receptor and its impact on neural activity. By replicating the observed effects of scanning data, computational modeling can effectively simulate the fundamental effects of the receptor on neural activity. This is achieved by manipulating the known actions of psychedelics through the identification of key receptors. There are two distinct possibilities that merit differentiation. The first possibility is that the activation of the serotonin 2A receptor results in heightened connectivity, which in turn gives rise to auditory and visual hallucinations, altered patterns of thinking, and other related phenomena. An additional possibility is that the observed increase in connectivity may represent a distinct phenomenon that is superimposed upon other effects of psychedelic drugs that impact access to unconscious hallucinations. These two phenomena may occur concurrently and exhibit a degree of correspondence, but further investigation is warranted [20].

Figure 07: Psychedelic and its effect on Brain [21].

References

19. Castelhano, J., et al., The Effects of Tryptamine Psychedelics in the Brain: A Meta-Analysis of Functional and Review of Molecular Imaging Studies. 2021. 12.

20. Zhang, G. and R.W. Stackman, The role of serotonin 5-HT2A receptors in memory and cognition. 2015. 6.

21. Mapping the Psychedelic Brain. Available from: https://www.science.org/content/article/mapping-psychedelic-brain.

(10): 00:52:33 Pharmacology: Therapeutics without Psychedelic Effects; SSRIs

In the scientific community that investigates psychedelics, there is now some interest in creating medications that treat many depression symptoms without producing hallucinations or significant alterations in subjective experience. Some scientists have altered psychoactive substances so they can be used therapeutically to treat depression but have no hallucinatory effects. It would be a wonderful strategy if these medications were to be effective.

Delix Therapeutics:

Delix Therapeutics is using a novel strategy by creating psychoplastogens, or analogs of psychedelic substances. These analogs seek to mimic the psychedelics' effects on neuronal activity while avoiding their frequently severe side effects. Delix Therapeutics seeks to maximize the beneficial effects of psychedelic chemicals while limiting their negative effects by concentrating on psychoplastogens [22].

David E. Nichols and Eleusis:

Eleusis is a corporation that specializes in drug development, and David E. Nichols is an emeritus professor of pharmacology at Purdue University. Their controversial method aims to reverse the hallucinogenic effects of psychedelic substances. However, this illustration shows that efforts are still being made by companies and researchers to determine how to distinguish between the medicinal benefits of psychedelic medicines and their hallucinogenic side effects [23].

Psychedelic-like molecules with therapeutic potential:

Scientists are investigating the therapeutic potential of psychedelic-like molecules that don't have the head-tripping side effects of psychedelics. The goal of this line of inquiry is to find substances that can mimic the therapeutic benefits of psychedelics in the treatment of ailments like depression while reducing or eliminating psychedelic experiences. In conclusion, businesses and researchers are putting a lot of effort into developing medications without hallucinatory side effects. These techniques include developing psychoplastogens, removing psychedelic side effects, and researching substances that have therapeutic potential but seem similar to psychedelics. It will be possible to find novel drugs and treatment modalities that have the required therapeutic effects while minimizing or eliminating psychedelic experiences with more research and scientific investigation in this field [24].

Animal studies have shown that 5-HT1A and 5-HT2C receptor stimulation may counteract the effects of 5-HT2A receptor activation. The activation of 5-HT2A receptors may also be negatively influenced by 5-HT1B/1D/5/7 receptors and other 5-HT receptors. The combination of highly selective 5-HT2A antagonists with highly effective 5-HT2A receptor and 5-HT transporter inhibition in a single drug may offer promise for therapeutic breakthroughs in a variety of neuropsychiatric illnesses, according to these clinical and preclinical studies [25].

Figure 08. Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor [26].

References

22. Garber, K. Delix Therapeutics: psychedelics without the trip. 2022; Available from: https://www.nature.com/articles/d41587-022-00006-0.

23. Halford, B. Drug companies are investing big in psychedelics, but can they engineer out the trip? 2022; Available from: https://cen.acs.org/pharmaceuticals/drug-development/Drug-companies-investing-big-psychedelics/100/i9.

24. Cameron, L.P., et al., A non-hallucinogenic psychedelic analog with therapeutic potential. Nature, 2021. 589(7842): p. 474-479.

25. Marek, G.J., et al., Synergistic Action of 5-HT2A Antagonists and Selective Serotonin Reuptake Inhibitors in Neuropsychiatric Disorders. Neuropsychopharmacology, 2003. 28(2): p. 402-412.

26. Kim, K., et al., Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 2020. 182(6): p. 1574-1588.e19.

(11):00:58:45 Psilocybin & Depression; Long-Term Effects: Connectivity & Neuroplasticity

Psilocybin treatment for depression has exhibited promising outcomes in various clinical trials. According to a study carried out by scholars at Johns Hopkins Medicine, the utilization of psilocybin as a treatment method resulted in noteworthy reductions in depression among the subjects. Furthermore, the intensity of depression persisted at a low level even after one year of the treatment. A recent investigation revealed that the administration of psilocybin therapy was associated with a noteworthy decrease in indications of anxiety and depression among cancer patients receiving medical treatment [27].

According to Dr. Robin Carhart Harris, their research findings suggest the presence of functional plasticity, which refers to the presumed functional modifications characterized by heightened global connectivity functional connectivity, and increased communication across the system. The aforementioned impacts have been noted both in the course of and subsequent to the journey, evincing a robust association with the potent pharmacological outcomes encountered during the trip. The aforementioned phenomenon was witnessed in two discrete cohorts of individuals diagnosed with depression, who received psilocybin therapy as a treatment modality for their ailment. In a specific research investigation, a residual impact was noted on the subsequent day that bore a resemblance to the acute impact. A subsequent investigation revealed the persistence of the residual effect after a duration of three weeks. The decrease in modularity, as observed in two separate datasets, can be interpreted as a rise in functional connectivity or global connectivity. The study was conducted on a sample of healthy volunteers, and the analysis was performed at a correlational level rather than measuring absolute changes. It is imperative to underscore the correlation between the aforementioned variable and a psychological outcome, specifically within the framework of investigations pertaining to depression. The study found a correlation between the degree of alteration, specifically the decrease in modularity or increase in global connectivity, and the improvement in symptom severity [28].

A strong correlation has been identified between enhanced intercommunication among distinct brain modules and favorable therapeutic results. The correlation between physical activity and cognitive performance can be elucidated by various factors, including peripheral factors induced by exercise, the modular organization of the brain, and the involvement of extracellular vesicles in intercommunication between the brain and the periphery. Improving the understanding and advancement of efficient communication and coordination between distinct cognitive modules can have noteworthy ramifications for therapeutic interventions aimed at addressing diverse neurological and psychiatric disorders [29].

Figure 09: Psilocybin to treat depression [27].

References

27. Cherry, K. What to Know About Using Psilocybin for Depression. 2022; Available from: https://www.verywellmind.com/psilocybin-for-depression-what-you-need-to-know-5088261.

28. Galli, S.J., N. Borregaard, and T.A. Wynn, Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nature Immunology, 2011. 12(11): p. 1035-1044.

29. Calder, A.E. and G. Hasler, Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology, 2023. 48(1): p. 104-112.

(12):01:10:26 Psilocybin Therapy & Anorexia

The potential of psychedelic therapy is being demonstrated in a wide spectrum of mental health disorders, suggesting a transdiagnostic effect. Although the effectiveness of treatments that target symptoms of eating disorders (EDs) is restricted, it is believed that enhanced mental health and psychological well-being can enhance treatment results. The aforementioned results furnish corroborative substantiation for the favorable psychological consequences ensuing from a psychedelic encounter, which hold pertinence for the management of eating disorders. The expectation is that this will stimulate additional investigation and reinforce endeavors to scrutinize the safety and effectiveness of psychedelic-assisted therapy as a remedy for eating disorders in forthcoming clinical trials [30].

A further investigation was conducted with the objective of comprehending the viewpoints of persons afflicted with eating disorders regarding supplementary therapies and psychedelic research and therapy. The study comprised a sample of 200 individuals who responded to an online questionnaire. Seventy percent of the participants reported utilizing complementary therapies as a means of managing their eating disorder. The participants conveyed a moderate degree of apprehension, yet maintained a belief in the potential value of psychedelic research. The study participants proposed potential remedies, including educational initiatives on the subject of psychedelics and their impact, their application in the realm of psychiatry, and validation from experts within the discipline. The significance of a secure and supervised setting, along with a robust patient-therapist alliance, was underscored by the proponents of psychedelic therapy. In general, the results offer valuable perspectives for forthcoming studies investigating the potential of psychedelics as a viable therapeutic intervention for eating disorders [31].

Figure 10. Therapeutic Strategies for Anorexia Nervosa [32].

References

30. Spriggs, M.J., H. Kettner, and R.L. Carhart-Harris, Positive effects of psychedelics on depression and wellbeing scores in individuals reporting an eating disorder. Eat Weight Disord, 2021. 26(4): p. 1265-1270.

31. Harding, F., et al., Perspectives on psychedelic treatment and research in eating disorders: a web-based questionnaire study of people with eating disorders. J Integr Neurosci, 2021. 20(3): p. 551-560.

32. Foldi, C.J., et al., Rethinking Therapeutic Strategies for Anorexia Nervosa: Insights From Psychedelic Medicine and Animal Models. 2020. 14.

(13):01:12:56 Integration Phase & Psychedelic-Therapy; Meditation

The utilization of MDMA-assisted psychotherapy has demonstrated efficacy in the treatment of individuals diagnosed with post-traumatic stress disorder (PTSD), while also maintaining a justifiable level of safety. It is imperative to ensure that the administration of therapy is executed in a regulated and controlled manner, as the utilization of unregulated MDMA or an insufficient psychotherapeutic milieu may present significant hazards [33]. The phase of integration holds significant importance in the context of psychedelic therapy. Following the psychedelic encounter, the integration stage entails a joint effort between the therapist and the client to comprehend and assimilate the perceptions and occurrences acquired throughout the psychedelic session. This stage is centered on the assimilation and practical application of the significance and insights gained from the psychedelic encounter towards the individual's everyday existence and holistic welfare [34].

Psychedelic therapy is a therapeutic approach that involves the administration of psychedelic substances, including but not limited to psilocybin, ketamine, MDMA, ayahuasca, and DMT, within a clinical context to address various mental disorders. The aforementioned substances have been the focus of clinical trials aimed at treating diverse mental health conditions. The results of these studies have demonstrated noteworthy effect sizes in ameliorating symptoms [35]. The integration phase is a pivotal component of psychedelic therapy, as it facilitates the assimilation and processing of the insights and experiences acquired during the psychedelic session into the individual's daily life. The process entails collaborating with a therapist to comprehend the significance of one's experiences, recognize recurring themes or revelations, and convert them into practical measures for individual development and recuperation. The process of integration may transpire over a protracted duration, as individuals persist in contemplating and assimilating their experiences into their routine existence. In general, the phase of integration holds significant importance in the context of psychedelic therapy, as it allows individuals to effectively assimilate and implement the knowledge and understanding acquired during the psychedelic experience in their routine existence. The process entails working in tandem with a therapist to promote the assimilation of the psychedelic encounter and foster individual development and recuperation [36].

Figure 11. Mediation therapy

References

33. Smith, K.W., et al., MDMA-Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review With Meta-Analysis. J Clin Pharmacol, 2022. 62(4): p. 463-471.

34. Psychedelic Therapy Is Having a Moment — Here’s What You Need to Know. Available from: https://www.healthline.com/health/mental-health/psychedelic-therapy.

35. Bathje, G.J., E. Majeski, and M. Kudowor, Psychedelic integration: An analysis of the concept and its practice. 2022. 13.

36. Frymann, T., et al., The Psychedelic Integration Scales: Tools for Measuring Psychedelic Integration Behaviors and Experiences. 2022. 13.

(14):01:19:50 First-Time Psychedelic Use, “Entropic Brain Effect”, Neuroplasticity, Cognition

A study was conducted by Dr. Robin Carhart-Harris on a sample of middle-aged healthy volunteers, with an average age of 40 and an equal distribution of males and females. Notably, all staff members involved in the study were female. The study employed a repeated measure design, wherein participants were assessed at multiple time points. Baseline data was collected prior to administering a placebo and conducting a brain scan. The study aims to administer psychedelics to a group of middle-aged individuals who have never previously consumed such substances and who are in good health. The intention is to provide these participants with their inaugural experience of psychedelics. The study employs a repeated measures design in which participants are initially administered a placebo. This allows for the implementation of all procedures, therapies, and music-listening activities without the administration of a substantial dose of psilocybin. A placebo dose of psilocybin is administered at a dosage of one milligram. Additionally, the participants donned EG headsets throughout the duration of the experience in order to capture and record their brain activity. In addition, MRI scanning is conducted both pre-and post-treatment to provide a more comprehensive analysis of the brain, including an examination of functional connectivity. The observed psychological and neurobiological changes were documented upon administration of a 25-milligram dose. The occurrence transpired as a result of a substantial and significant dosage. Furthermore, there are notable enhancements in individuals' psychological well-being. The researchers also observed an improvement in the entropic brain effects and the informational complexity of the ongoing brain activity recorded on the electroencephalogram (EEG) with the administration of psilocybin. The most captivating findings of their study were likely the MRI and the in-depth exploration of the brain. Functional brain changes have been observed alongside anatomical brain changes through the utilization of diffusion tensor imaging, a technique that examines the white matter tracts of the brain. Alterations in prominent neural pathways were observed, with a focus on fibers of substantial diameter. The identified fibers that exhibited changes were those that traversed the prefrontal cortex, thalamus, and striatum [17].

The study reveals that two prefrontal tracks underwent changes characterized by a decrease in axial diffusivity, which may signify an improvement in tracked integrity. Specifically, a decrease in axial diffusivity is indicative of an increase in track integrity. The phenomenon of axial diffusivity is observed in the maturation of the brain, wherein a decrease in axial diffusivity is noted from infancy to adulthood. Conversely, in the context of aging and age-related pathologies, an increase in axial diffusivity is observed. The reduction in axial diffusivity is indicative of an enhanced accuracy in the transmission of information between the prefrontal cortex, thalamus, and striatum. As individuals progress from infancy to adulthood, their proficiency in certain tasks tends to improve while their aptitude in other areas may decline. The observed alterations are anatomical in nature and do not have an impact on functionality. The aforementioned research methodology involves the examination of communication within the brain, by analyzing the temporal fluctuations in activity and assessing the synchronicity of such fluctuations across different regions. The presence of synchronous activity between regions indicates functional connectivity. The researchers have inferred that the communication between the subjects is taking place due to their synchronous vertical movements. However, it should be noted that the anatomical aspects being discussed are purely static in nature. The researcher is observing alterations in the fibers and their corresponding properties. The researchers also assessed the cognitive abilities of the participants through the utilization of a cognitive flexibility paradigm. This paradigm evaluates an individual's capacity to detect a modification in a rule and subsequently adjust their behavior accordingly. The results indicated that the participants demonstrated an improvement in cognitive flexibility subsequent to the administration of a 25-milligram dose, whereas no significant improvement was observed following the administration of a placebo [37]. No correlation was found between the change in cabling and psychological outcomes. The observed phenomenon entails a reversal in the direction of brain anatomy changes, which is contrary to the typical pattern observed in aging or age-related pathologies. Rather, it is consistent with the normative neurodevelopmental trajectory of a healthy brain transitioning from adolescence to adulthood [38].

Figure 12. LSD-induced brain entropy [39].

References

17. Barrett, F.S., et al., Emotions and brain function are altered up to one month after a single high dose of psilocybin. Scientific Reports, 2020. 10(1): p. 2214.

37. Daws, R.E., et al., Increased global integration in the brain after psilocybin therapy for depression. Nature Medicine, 2022. 28(4): p. 844-851.

38. Collins, A. and A. Muñoz-Solomando, The transition from child and adolescent to adult mental health services with a focus on diagnosis progression. BJPsych Bull, 2018. 42(5): p. 188-192.

39. Lebedev, A.V., et al., LSD-induced entropic brain activity predicts subsequent personality change. 2016. 37(9): p. 3203-3213.

(15):01:30:16 Fibromyalgia & Psychedelic Treatment; MDMA Therapy & “Inner Healer”

Fibromyalgia is a medical condition that is distinguished by diffuse musculoskeletal pain in conjunction with symptoms such as fatigue, sleep disturbances, cognitive impairment, and mood alterations. According to scholarly research, fibromyalgia is thought to enhance the perception of painful stimuli by modulating the processing of both nociceptive and non-nociceptive signals within the central nervous system, specifically the brain and spinal cord. The onset of symptoms is frequently observed subsequent to an occurrence, such as bodily injury, medical operation, contagion, or notable psychological strain. In certain instances, indications progressively amass over a period of time without any singular inciting incident. Fibromyalgia is a condition that exhibits a higher prevalence among women as compared to men. A significant proportion of individuals diagnosed with fibromyalgia concurrently exhibit comorbidities such as tension headaches, temporomandibular joint (TMJ) disorders, irritable bowel syndrome, as well as anxiety and depression. Although fibromyalgia has no known cure, a range of pharmaceuticals can assist in managing its symptoms. Incorporating physical activity, relaxation techniques, and stress-reduction strategies may also prove beneficial [40].

The conventional therapeutic interventions for fibromyalgia frequently encompass a blend of pharmacotherapy, physiotherapy, and cognitive-behavioral therapy. Recently, there has been an increasing inclination towards investigating alternative therapeutic approaches, such as the utilization of psychedelic substances in combination with psychotherapeutic interventions. The therapeutic approach for fibromyalgia utilizing psychedelic treatment entails the controlled administration of substances such as psilocybin or LSD, in conjunction with psychotherapy sessions. The objective is to address pain by means of neuroplasticity, a process that entails the modification and restructuring of neural networks within the brain [41]. There exist multiple conceivable biological pathways through which conventional psychedelic substances may alleviate persistent pain. The aforementioned compounds exhibit an affinity for serotonin 5-HT2A receptors, which are implicated in the modulation of nociceptive processing within the central nervous system. The activation of said receptors has the potential to alleviate pain, however, additional research is required to comprehensively comprehend this correlation. The potential of psychedelics in the treatment of chronic pain, particularly fibromyalgia, is currently under investigation. Researchers have posited that these substances may have the capacity to mitigate the concomitant symptoms of depression and substance use disorders, which frequently co-occur with chronic pain conditions. The implementation of this measure has the potential to enhance the overall quality of life for individuals who suffer from chronic pain [42].

Dr. Robin Carhart-Harris conducted research on the use of psychedelics as a potential treatment for fibromyalgia. The study involved administering a single dose of the substance to the participants. The study is highly mechanistic in nature, as the patients are required to wear an EG cap during the sessions, similar to the protocol followed in the healthy volunteer study. The patients are not being instructed to contemplate their pain. A therapeutic framework exists that centers on the concept of embracing and acknowledging one's pain. Similar to certain approaches used in treating PTSD, the individual is not prompted to concentrate on the traumatic experience and subsequently process and assimilate it. The distinction between traditional psychedelic therapy and 3,4-Methylenedioxymethamphetamine or MDMA therapy is evident. MDMA therapy bears some resemblance to conventional talk therapy, as it involves a greater degree of dialogue. During the MDMA trials, participants are provided with eye masks and are able to converse while under the influence of the substance [43].

Figure 13. MDMA therapy [44].

References

40. Fibromyalgia. Available from: https://www.mayoclinic.org/diseases-conditions/fibromyalgia/symptoms-causes/syc-20354780.

41. Can Psychedelics Be Used to Treat Fibromyalgia? ; Available from: https://www.painnewsnetwork.org/stories/2021/7/21/can-psychedelics-be-used-to-treat-fibromyalgia.

42. Watson, C. The psychedelic remedy for chronic pain. 2022; Available from: https://www.nature.com/articles/d41586-022-02878-3.

43. Mitchell, J.M., et al., MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 2021. 27(6): p. 1025-1033.

44. MDMA, Or Ecstasy, Shows Promise As A PTSD Treatment. Available from: https://www.npr.org/sections/health-shots/2019/08/14/746614170/mdma-aka-ecstasy-shows-promise-as-a-ptsd-treatment.

(16):01:38:55 Placebo Response & Psychedelic Therapy

Dr. Harris assessed pre-trial expectancy for both conditions in the psilocybin therapy versus the escitalopram trial. What are the anticipated improvements in the trial's outcome with the administration of Lexapro (escitalopram) and in the psilocybin arm with two high doses of psilocybin? The presence of sample bias was identified, leading to a tendency for individuals to hold higher expectations on average for psilocybin in terms of its efficacy and effectiveness, as compared to the SSRI, Lexapro. However, upon examining the correlation or the predictive association between pre-trial expectancy and response. The researchers observed that the pre-trial expectancy for escitalopram was significantly associated with the response to escitalopram across a wide range of measures, including those related to depression, anxiety, and overall well-being. None of the approximately 12 mental health rating scales exhibited a correlation with pre-trial expectancy, despite its high level. The pre-trial expectancy failed to predict the response to psilocybin therapy. The available evidence suggests that the therapeutic effects of classic psychedelics may be attributed to a placebo response [9].

References

9. Carhart-Harris, R., et al., Trial of Psilocybin versus Escitalopram for Depression. 2021. 384(15): p. 1402-1411.

(17):01:41:39 LSD & Psychedelic Therapy, Micro-Dose

Microdosing is a prevalent phenomenon that involves the consumption of a small amount, usually between 5 to 10 percent of a standard dose, of a psychedelic substance, such as LSD or psilocybin, which is the primary psychoactive component found in magic mushrooms. As per the assertions of select proponents of micro-dosing, there exists a potential for it to confer benefits pertaining to psychological wellness. However, the scientific community is presently encountering difficulties in validating the claims associated with micro-dosing. The intricate nature of the variables implicated renders it arduous to carry out an empirical investigation on the claims posited by microdoses. A plausible approach to investigate micro-dosing is to conduct placebo-controlled trials, in which a subgroup of subjects is administered a minimal amount of a psychedelic substance while others receive a placebo. The present research outcomes have not demonstrated positive results up to this point. A double-blind and controlled study was carried out to examine the impacts of micro-dosing LSD. The results of this investigation were not deemed satisfactory. The research utilized a unique methodology that involved recruiting pre-existing micro doses who self-supplied their own substances for the purpose of experimentation. The main aim of this methodology was to accelerate the pace of placebo-controlled clinical trials. Whilst the outcomes of this particular research may be discouraging, the methodology employed has the capacity to serve as a beneficial model for future inquiries. The existing literature on micro-dosing psychedelics, specifically LSD, indicates a shift away from previously proposed benefits. The overall effectiveness of micro-dosing has been subject to skepticism among researchers due to negative results obtained from several laboratories [45].

It is noteworthy that ongoing discussions and investigations persist in this field, and a conclusive determination regarding the efficacy of micro-dosing remains pending. Psychedelic therapy generally entails the administration of a controlled therapeutic dose of a psychedelic substance, such as LSD, within a supervised therapeutic environment, overseen by trained professionals. Psychedelic therapy is frequently complemented by psychotherapy sessions and endeavors to facilitate profound psychological investigation and recuperation. This distinguishes it from micro-dosing, which entails the administration of periodic, sub-perceptual quantities of psychedelic substances with the aim of potentially improving mental well-being [46].

A recent study has revealed the benefits and challenges related to the act of micro-dosing psychedelic substances. The research involved a group of 278 participants who provided self-reported narratives of their experiences with micro-dosing LSD and psilocybin, the psychoactive component of magic mushrooms. The study utilized a grounded theory approach to analyze the qualitative narratives presented by the research subjects. The study's findings revealed a range of perceived benefits and limitations associated with the practice of micro-dosing psychedelics. The benefits that were frequently cited included improvements in effect, cognitive focus, creativity, and energy. The participants of the study reported improvements in multiple dimensions of their overall well-being, such as reduced levels of anxiety, increased involvement in meditative practices, higher levels of physical activity, healthier dietary habits, and improved quality of sleep. The literature indicates that prevalent concerns related to psychedelic compounds include their unlawful nature, imprecise dosing, deficient concentration, and anxiousness. These obstacles have been reported in the literature [6].

Figure 14. LSD Microdosing [47].

References

45. Plackett, B. Psychedelic micro dosing hits a rough patch in clinical trials. 2022; Available from: https://www.nature.com/articles/d41586-022-02876-5.

46. More People Are Microdosing for Mental Health. But Does It Work?; Available from: https://www.nytimes.com/2022/02/28/well/mind/microdosing-psychedelics.html.

47. Does LSD make you smarter? New study suggests it promotes learning and memory. Available from: https://www.zmescience.com/medicine/does-lsd-make-you-smarter-new-study-suggests-it-promotes-learning-and-memory/.

(18):01:48:19 Combination Psilocybin-MDMA Therapy

Psilocybin and MDMA have been proposed as potential alternative treatment options for mental health disorders [48]. The aforementioned discourse has provided extant evidence that may support the utilization of psilocybin-assisted psychotherapy as a viable intervention for symptoms related to trauma, and MDMA-assisted psychotherapy as a potential remedy for symptoms of depression. Depression is a complex psychosocial condition that can arise from a variety of triggers. Nevertheless, there is significant empirical evidence suggesting that it could originate from traumatic experiences, particularly during the developmental phases of an individual's life. When post-traumatic stress disorder (PTSD) co-occurs with other conditions, it is imperative to adopt a comprehensive treatment approach. The amalgamation of psychotherapy and pharmacology, as demonstrated in drug-assisted psychotherapy paradigms, presents a hopeful approach to tackle depression and PTSD, especially in patients who have not manifested favorable outcomes to current treatments. The sporadic persistence of depressive symptoms following the administration of MDMA could potentially serve as either an artifact or a crucial mechanism in the cognitive processing of traumatic memories. A plausible therapeutic strategy entails the utilization of MDMA-assisted psychotherapy as an initial intervention, succeeded by the administration of psilocybin-assisted psychotherapy for individuals who persist in manifesting depressive symptoms. As per the findings of Krediet et al, the present course has the potential to aid patients in adapting to the increased arousal linked with psilocybin by providing exposure to altered states of consciousness induced by MDMA that are more "present" in nature. The capacity of MDMA to augment trust has the potential to be advantageous in strengthening the therapeutic alliance at the outset, thereby promoting a more profound acute psilocybin experience subsequently. Proof of concept studies is required to explore the potential transdiagnostic uses of psilocybin- and MDMA-assisted psychotherapy for individuals with PTSD and depression, both with and without comorbidities [49].

Figure 15. Psilocybin-MDMA Therapy for PSTD [50].

References

48. Gill, H., et al., The emerging role of psilocybin and MDMA in the treatment of mental illness. 2020. 20(12): p. 1263-1273.

49. Bird, C.I.V., N.L. Modlin, and J.J.H. Rucker, Psilocybin and MDMA for the treatment of trauma-related psychopathology. International Review of Psychiatry, 2021. 33(3): p. 229-249.

50. Ecstasy as a Remedy for PTSD? You Probably Have Some Questions.; Available from: https://www.nytimes.com/2018/05/01/us/ecstasy-molly-ptsd-mdma.html.

(19):01:56:06 DMT “Rocketship” & Serotonin 2A Receptors; Ibogaine

The metaphorical usage of the term "rocketship" is employed to depict the expeditious and intense onset of the DMT encounter. It is noteworthy that the effects of psychedelics can exhibit substantial variability across different individuals. DMT is a potent hallucinogen that has the ability to elicit profound and transformative experiences in individuals. This substance occurs naturally in specific botanical species and can also be artificially produced. DMT is recognized for its swift onset and brief duration of effect, frequently characterized as an "explosive" or "breakthrough" encounter. During the DMT experience, individuals may experience a perceived sense of acceleration or propulsion, which can be metaphorically linked to a "rocketship" [51].

DMT is classified as a classic psychedelic due to its interaction with the serotonin 2A receptor. This substance acts as a direct agonist by stimulating the serotonin 2A receptor. The potency of the substance in question is comparatively lower than that of psilocybin. However, it is important to note that potency is a complex concept that is contingent upon the dosage administered. This implies that the intensity of the experience with DMT is not necessarily inferior to that of psilocybin, but rather that a higher dosage of the former is required. However, this property is counterbalanced by its high affinity for the serotonin receptor, a fundamental principle in the field of psychedelic research that was first identified in the 1980s. The potency of a psychedelic substance is closely linked to its affinity, stickiness, or binding potential for the 2A receptor, specifically the serotonin 2A receptor. The stickier the drug, the more potent it tends to be. For instance, LSD exhibits a high degree of stickiness, which contributes to its exceptional potency. Merely minuscule microgram quantities are required. DMT exhibits a slightly lower potency in terms of its affinity, however, its effects are remarkably intense when administered at a standard dose. It is noteworthy that DMT is accompanied by another compound, namely 5 methoxy DMT, which exhibits distinct pharmacological and subjective differences. It exhibits comparable kinetics to that of another spacecraft. Both compounds found in the wilderness are frequently consumed through smoking, and presently, individuals are also utilizing vaping as a method of consumption. Individuals frequently opt for 5-Methoxy-N, N-Dimethyltryptamine (5-MEO-DMT) due to its perceived dependability in inducing ego dissolution, as well as its comparatively reduced emphasis on visual effects and greater inclination towards a comprehensive immersion in the broader context, resulting in a loss of self-identity and complete immersion in the surrounding environment [52].

Figure 16. Distribution of the serotonin receptor in the brain [53].

References

51. Dr. Robin Carhart-Harris: The Science of Psychedelics for Mental Health. Available from: https://hubermanlab.com/dr-robin-carhart-harris-the-science-of-psychedelics-for-mental-health/.

52. Smith, R.L., et al., Agonist properties of N, N-dimethyltryptamine at serotonin 5-HT2A and 5-HT2C receptors. Pharmacol Biochem Behav, 1998. 61(3): p. 323-30.

53. Saulin, A., M. Savli, and R. Lanzenberger, Serotonin and molecular neuroimaging in humans using PET. Amino acids, 2011. 42: p. 2039-57.

(20):02:01:04 “Ego Dissolution”, Cocaine vs. Psychedelics; Relapses

Ego dissolution is a state of consciousness characterized by a significant reduction or dissolution of one's sense of self or ego boundaries. This altered state of consciousness is profound in nature. The utilization of psychedelic substances, namely LSD, mescaline, psilocybin, and DMT, is frequently linked to this phenomenon. Ego dissolution is a phenomenon that can result in an individual experiencing a loss of personal identity, a merging with their surroundings or the universe, and a sense of interconnectedness with everything. The serotonin 2A (5-HT2A) receptors are known to have a substantial impact on the effects of psychedelic substances and are hypothesized to be a fundamental mechanism involved in the dissolution of the ego. Psychedelics, which encompass serotonin 2A receptor agonists, have the ability to attach to and stimulate these receptors located in the brain. Activation of 5-HT2A receptors induces alterations in the operational dynamics of diverse cerebral regions, with a particular emphasis on the default mode network (DMN) [54].

The Default Mode Network (DMN) comprises a set of cerebral areas that participate in cognitive processes related to self-referential cognition, introspection, and the formation of an individual's self-concept or ego. The function of this cognitive process involves the processing of information pertaining to personal identity, autobiographical memories, and social cognition. The binding of psychedelics to 5-HT2A receptors results in the disturbance of the typical operation of the default mode network (DMN), which consequently causes a reduction in the activity and connectivity of this network. It is believed that the decrease in activity and connectivity of the default mode network (DMN) plays a role in the phenomenon of ego dissolution. Psychedelics have the ability to disrupt the typical patterns of self-referential and self-reflective thought processes by reducing the influence of the DMN. This results in a temporary dissolution of the ego and an altered state of consciousness, as reported in previous studies. It is noteworthy that the mechanisms that underlie ego dissolution are currently being investigated and comprehended. The occurrence of ego dissolution is thought to implicate serotonin 2A receptor activation, however, it is probable that intricate interplays among various brain regions and neurotransmitter systems are also at play. Additional investigation is required to comprehensively explicate the neural mechanisms underlying ego dissolution and its correlation with serotonin 2A receptors [55].

Studies have reported that Coccine induces a higher dopamine release in comparison to serotonin, while MDMA has been found to act as an enhancer of the ego. Individuals may cultivate a hyper-linear and hyper-linked attachment to their personal desires and aspirations, which can result in an obsessive preoccupation with future outcomes. The analyzed work exhibits similarities to the literary archetype of the American psycho, while also integrating common tropes and archetypes of the cocaine culture that was prevalent during the 1980s. A study was conducted by Dr. Harris to investigate the correlation between ego inflation and ego dissolution in a dose-dependent manner. The findings suggest a notable distinction between the effects of cocaine and psychedelics, as evidenced by the pronounced elevation of ego inflation observed with cocaine use. The process of dissolution is not implicated, whereas psychedelics demonstrate an opposing effect. Multiple hypotheses propose that the serotonin receptor, which is the focus of classic psychedelics, is significantly expressed in the neocortex. This region is commonly known as the "recent brain" due to its evolutionary novelty in the human species. The assertion is substantiated by the cortical expansion mapping conducted from chimpanzees to humans, which demonstrates a higher prevalence of cortex in humans than in all other species. The aforementioned map delineates the precise placement of the 2A receptor, which functions as the primary site of action for classical psychedelics. It is feasible to correlate this receptor with the ego-centric brain. The administration of classical psychedelics has been observed to disrupt entropic brain activity, resulting in a breakdown of boundaries and a spread of entropic action throughout the entire system. The mechanism in question does not bring about a complete cessation of the function, but instead causes its dispersion. In the context of a psychedelic experience, it is possible for the ego to undergo a transient dissolution, which can result in significant insights pertaining to the interconnectedness of molecules and the universal genesis of life. Upon regaining sobriety, the ego invariably resurfaces, frequently following a prolonged duration. Empirical evidence suggests that there is a notable prevalence of relapse among individuals who suffer from chronic depression, especially in cases of treatment-resistant depression that persist for a duration of three months or longer. While a state of remission may be attained, it is frequently transitory and lacks longevity [56].

Figure 17: Dissolution on Classical Psychedelics [57].

References

54. Tagliazucchi, E., et al., Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution. Curr Biol, 2016. 26(8): p. 1043-50.

55. Letheby, C. and P. Gerrans, Self unbound: ego dissolution in psychedelic experience. Neuroscience of Consciousness, 2017. 2017(1).

56. Georgieva, E., et al., Oxidative Stress and Cocaine Intoxication as Start Points in the Pathology of Cocaine-Induced Cardiotoxicity. 2021. 9(12): p. 317.

57. Correlates of Ego Dissolution on Classical Psychedelics (5HT2A Agonists). Available from: https://unlimitedsciences.org/correlates-of-ego-dissolution-on-classical-psychedelics-5ht2a-agonists/.

(21):02:12:26 Psychedelics & Legal Landscape; Decriminalization

In recent times, there has been a significant development in the legal structure concerning psychedelics. Despite the fact that federal and state legislation in the United States generally prohibits the growth, dissemination, ownership, and ingestion of plant and fungal psychedelics or entheogens, certain regions have undergone notable progressions and alterations. The summary is derived from the search results that were presented. Psychoactive substances derived from plants and fungi, commonly known as psychedelics, are considered illegal under federal law in the United States [58]. Moreover, a significant number of states have implemented laws that replicate federal statutes, which forbid the possession, usage, and distribution of psychedelics as a criminal act. It is worth noting that the legality of psychedelic substances may depend on the specific compound and the governing jurisdiction. Notwithstanding the general prohibition, specific states have implemented actions aimed at decriminalizing or modifying the legal standing of psychedelics. As indicated by source [59], Oregon and Colorado have taken steps towards the decriminalization of specific psychedelics and the establishment of regulatory structures to facilitate their therapeutic application. The aforementioned initiatives aim to optimize research processes and potentially create a new field focused on the use of psychedelic substances to enhance therapeutic outcomes. The ongoing discourse surrounding the legal status of psychedelics is a matter of frequent discussion among legal professionals and proponents. Legal professionals who have expertise in the field of psychedelics are facing the challenge of striking a balance between managing risks, addressing liability concerns, and fulfilling the need for genuine and significant access to psychedelics, both at the individual and collective levels. As the understanding of psychedelics progresses, it is probable that alterations to the legal framework will persist [60].

Also, Oakland, California is currently considering the legalization of the distribution and sale of psychedelic drugs, such as psilocybin mushrooms and ayahuasca. If approved, this would mark a significant milestone in the United States, as Oakland would be the first city to adopt such a policy. This move would be reminiscent of the city's pioneering efforts in the normalization of commercial medical marijuana sales [61].

Figure 18. Decriminalizing psychedelic drugs [62].

References

58. The Legal Landscape of

Psychedelics. Available from: https://psychedelics.berkeley.edu/wp-content/uploads/2022/07/BCSP_Fact-Sheet_Legal-Landscape.pdf.

59. Leaders Forecast the 2023 Legal Landscape for Psychedelics. Available from: https://alpharoot.com/insights/leaders-forecast-the-2023-legal-landscape-for-psychedelics/.

60. The Legal Landscape of the Psychedelic Ecosystem. https://maps.org/news/bulletin/the-legal-landscape-of-the-psychedelic-ecosystem/

61. Oakland Officials Decriminalize Psychedelics And Say They’ll Work To Legalize Sales Next. Available from: https://www.marijuanamoment.net/oakland-officials-decriminalize-psychedelics-and-say-theyll-work-to-legalize-sales-next/#:~:text=Oakland%2C%20California%20may%20become%20the,normalize%20commercial%20medical%20marijuana%20sales.

62. California moves closer to decriminalizing psychedelic drugs. Available from: https://www.nbcnews.com/news/us-news/california-moves-closer-decriminalizing-psychedelic-drugs-n1279509.

(22):02:17:54 MDMA, Trauma & Clinical Trials; Future Regulatory (FDA) Approval?

The compound 3,4-methylenedioxymethamphetamine, commonly referred to as MDMA, has been the focus of clinical investigations aimed at examining its potential therapeutic applications for trauma-induced disorders, specifically post-traumatic stress disorder (PTSD). Based on the search results provided, the following is a summary. A phase 3 clinical trial (NCT03537014) was carried out to assess the effectiveness and safety of MDMA-assisted therapy for patients with severe PTSD, including those with common comorbidities such as dissociation and depression. The purpose of this study was to evaluate the potential therapeutic advantages of MDMA as a supplementary treatment to psychotherapy for individuals with PTSD, utilizing a randomized, double-blind, placebo-controlled, and multi-site trial design. Regrettably, the search results furnished did not provide access to the precise findings and consequences of this experiment [63]. According to preliminary findings from a study, the utilization of MDMA-assisted psychotherapy has the potential to serve as a new and innovative method for addressing anxiety in individuals who are experiencing life-threatening illnesses (LTI). While the investigation did not specifically Centre on anxiety related to trauma, it offers valuable perspectives on the wider implications of utilizing MDMA-assisted therapy [64].

The pivotal juncture lies in the FDA's approval and subsequent authorization of psychedelic substances as medicinal agents, thereby enabling their lawful prescription and distribution throughout the United States and other regions. Additionally, it is worth noting that clinical trials are typically conducted in multiple phases, with phase three being of particular significance. The authorization of a pharmaceutical product by the FDA indicates that the Centre for Drug Evaluation and Research (CDER) has conducted a thorough evaluation of the drug's data and effects. The process of approval adheres to a systematic framework that entails a meticulous examination of the intended outcome, a comprehensive analysis of clinical data to determine potential benefits and limitations, and the implementation of measures to alleviate risks. The decision made by the FDA is grounded in a methodology that conforms to scientific principles and employs the latest scientific and technological data that is presently available. In specific cases, the FDA may employ the Accelerated Approval pathway as a means to hasten the process of granting approval. This specific pathway holds significance in the context of therapeutic interventions aimed at treating severe or life-threatening conditions and demonstrating therapeutic benefits that surpass those of existing treatments. The Accelerated Approval pathway allows for the approval of pharmaceutical products based on surrogate or preliminary clinical endpoints, which may not exhibit the same degree of robustness as traditional endpoints. However, it is essential to carry out clinical trials after the drug has been marketed in order to verify and clarify its therapeutic benefits. If the clinical trials fail to confirm the expected clinical benefit, the FDA retains the authority to withdraw its approval. The Food and Drug Administration (FDA) utilizes drug development designations as a strategy to provide motivation for the progression of particular pharmaceuticals. The Fast Track designation expedites the drug development and evaluation process for medications that target crucial diseases and meet unmet medical needs. The Breakthrough Therapy designation is granted to pharmaceuticals that demonstrate potential for substantial improvement over existing therapies for serious medical conditions. The purpose of the Priority Review designation is to expedite the assessment of pharmaceuticals that significantly enhance the treatment, diagnosis, or prevention of serious medical conditions. It is crucial to recognize that the information provided is based on established beliefs regarding FDA drug approval protocols and may not necessarily represent the latest advancements or specific cases [65].

Figure 19. FDA Approval of Psychedelics.

References

63. Mitchell, J.M., et al., MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study. Nat Med, 2021. 27(6): p. 1025-1033.

64. Wolfson, P.E., et al., MDMA-assisted psychotherapy for the treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study. Scientific Reports, 2020. 10(1): p. 20442.

65. Development & Approval Process | Drugs. Available from: https://www.fda.gov/drugs/development-approval-process-drugs#:~:text=Developed%20and%20Approved.-,FDA%20Approval%3A%20What%20it%20means,risks%20for%20the%20intended%20population.

(23):02:23:25 Psilocybin & Current Clinical Trials

During a virtual Capital Markets Day, COMPASS Pathways, a mental health care company committed to expediting patient access to evidence-based innovation in mental health, revealed the design of the Phase 3 pivotal program for COMP360 psilocybin therapy in treating treatment-resistant depression (TRD). The meeting was attended by executives and influential figures associated with COMPASS Pathways. The agenda included an evaluation of the current treatment options available for TRD, as well as a discussion of COMPASS' clinical care and digital strategy, patient and market access, commercial model, and overall development pipeline. A recording of the session is available for reference. The program developed by COMPASS is set to become the inaugural Phase 3 program for psilocybin therapy worldwide. This follows encouraging outcomes from the Phase 2b study conducted on treatment-resistant depression, which was presented at the annual meeting of the American Psychiatric Association in May 2022. The Phase 3 program comprises a triad of clinical trials, including two pivotal trials and one long-term follow-up. It is anticipated that the program will commence by the conclusion of 2022 [66].

A clinical trial in phase 2 has shown that it is feasible to utilize psilocybin as a monotherapy for a duration of 12 weeks in individuals who suffer from major depression that is resistant to treatment [67]. The objective of this study was to evaluate the safety and potential antidepressant properties of psilocybin within a controlled environment. According to the retrieved information, psilocybin clinical trials are expected to be conducted in 2023, providing participants with advanced treatments and high-quality care [68]. The search results did not furnish the particulars of the aforementioned clinical trials, including their respective locations and objectives. The efficacy of psilocybin in treating Major Depressive Disorder (MDD) has been investigated in three trials, as reported in a review article. The trials conducted encompassed an open-label trial, a randomized controlled trial (RCT) with a waiting-list control, and another RCT that compared the efficacy of psilocybin to that of selective serotonin reuptake inhibitor (SSRI) treatment. Although the search results did not furnish the precise results and deductions of these trials, they underscore the continuing investigation into the potential advantages of psilocybin for Major Depressive Disorder [69].

References

66. First-ever phase 3 program of psilocybin therapy globally is scheduled to begin in 2022. Available from: https://compasspathways.com/compass-pathways-announces-phase-3-pivotal-program-design-for-comp360-in-treatment-resistant-depression-at-capital-markets-day/.

67. Goodwin, G.M., et al., Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. 2022. 387(18): p. 1637-1648.

68. Psilocybin Clinical Trials 2023. Available from: https://www.withpower.com/clinical-trials/psilocybin.

69. von Rotz, R., et al., Single-dose psilocybin-assisted therapy in major depressive disorder: a placebo-controlled, double-blind, randomized clinical trial. eClinicalMedicine, 2023. 56.

(24):02:28:41 Mental Health & Psychedelic Treatment, Safeguards, Paradigm Shift

Psychedelic-Assisted Psychotherapy (PAP) has been posited as a prospective intervention for individuals undergoing a psychiatric emergency. The study investigates the implementation of Psychedelic-Assisted Psychotherapy (PAP) in the context of the triple-axis psychiatric crisis. The PAP model is represented by an icon that is positioned within a triangle, projecting the three axes that are central to the current psychiatric crisis. These axes include therapeutics, diagnosis, and explanation, as documented in reference [70]. The findings suggest that psychedelic medicine has emerged as a new approach to tackling mental health disorders, including but not limited to depression, anxiety, addiction, and post-traumatic stress disorder. Encouraging clinical trials have provided support for the potential approval of psychedelic compounds by medical regulators as a treatment option for mental health disorders that are unresponsive to conventional therapies [71]. The classification of psychedelic compounds in the context of a conventional Psychedelic-Assisted Psychotherapy (PAP) model has both pragmatic and conceptual ramifications, which encompass protective measures. A restricted quantity of therapeutic sessions incorporates the application of specific substances, namely LSD, MDMA, ketamine, psilocybin, and ibogaine. While there may be discrepancies in terms of safety and mode of operation, the PAP framework prioritizes the curative utilization of exceedingly potent psychoactive agents, several of which are categorized as scheduled compounds [72].

Figure 20. Psychotherapy using Psychedelics [73].

References

70. Schenberg, E.E., Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development. Front Pharmacol, 2018. 9: p. 733.

71. Andrews, T. and K. Wright, The frontiers of new psychedelic therapies: A survey of sociological themes and issues. 2022. 16(2): p. e12959.

72. Schenberg, E.E., Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development. 2018. 9.

73. Psychedelic-Assisted Therapy: Applications in Mental Health. Available from: https://www.clinicaladvisor.com/home/topics/psychiatry-information-center/psychedelics-applications-in-mental-health/.

Preprint

Dr. Robin Carhart-Harris: The Science of Psychedelics for Mental Health | Huberman Lab Podcast