The MIND Foundation Resources consist of three main segments: Psychedelic Compendium, Multimedia Trove, and the Berlin Registry.

The Resources section was created to give an up-to-date overview of German and international journalistic coverage, high-quality research publications, as well as further media on psychedelic research topics. 

Enjoy our documentation of growing academic interest in psychedelic experience, and its applications in the medical field as well as self-development processes. 

Our Resources for you: 

The Psychedelic Compendium comprises carefully curated and annotated readings on key topics in psychedelic research and implementation. Among these are four categories:

  • Lists for Researchers,
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  • and Lists for Press & Journalists,
  • and Lists for Patients. 

The first two categories summarize scientific publications. Reading Lists for Press & Journalists comprise high-quality journalistic publications from the German and international context. The category of Lists for Patients includes a mix of educational literature.

The Multimedia Trove presents a selection of recommended non-fiction literature, biographies and fiction, podcasts, feature films, and documentaries related to psychedelic research, society, and cultural history. 

The Berlin Registry is a regularly updated overview of companies that are involved in the psychedelic industry worldwide. The interactive map provides an insight into currently active companies and their ongoing projects. 

Enjoy browsing our resources!

Psychedelic Compendium

Further Resources

Research Instruments

Presented here are a variety of tools that assist scientific inquiry, such as questionnaires. Some of these research instruments have been created by those in the MIND family, while some are shared by our collaborators.

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BERLIN REGISTRY

The Berlin Registry is an interactive and regularly updated overview of companies that are involved in the psychedelic industry worldwide. Our interactive map provides an insight into currently active companies and their ongoing projects.

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MULTIMEDIA TROVE

The Multimedia Trove presents a selection of recommended non-fiction literature, biographies and fiction, podcasts, feature films, and documentaries related to psychedelic research, society, and cultural history.

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The MIND Foundation’s research projects are geared towards evidence-based practice and high-quality science. For many of these projects, we are working together with universities in and outside of Germany and in collaboration with our Scientific Advisory Board. We invite you to explore our current projects, which are listed below.

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COOPERATION PARTNER IN PSILOCYBIN DEPRESSION STUDY

Principal investigator Prof. Dr. med. Gerhard Gründer has received the final approval for a psilocybin depression study (EPIsoDE) at the Central Institute of Mental Health Mannheim and the Charité Universitätsmedizin Berlin.  The MIND Foundation is a cooperation partner in the EPIsoDE study.

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UNIMIND

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In recognition of outstanding contributions to the psychedelic research and therapy field, we award young and established academics prizes of various kinds. Usually at the INSIGHT conference.

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     social interoception filtered  social interoception filtered

    Social Interoception

    The case for treating mental illnesses through the body, in a social setting
    • Blog
    • Science
    • Essay
    • 10 minutes
    May 1, 2020
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    Journalist, Managing Editor at InformED

    Saga Briggs is managing editor of InformED, a resource that connects teachers and students with cognitive science.

    View full profile ››

    The growing field of social interoception—which examines how social emotions arise from subjective appraisal of bodily states—calls for a rebranding of mental health issues as “social health issues” and builds the case for new forms of embodied social treatment, including psychedelic-assisted therapy. I spoke with researchers at UC San Diego, the University of Utah’s Social Development Lab, and the University of Zurich to find out more.

    It was by studying a part of the brain called the insula that neuroscientist John Allmann first realized self-awareness and social awareness are part of the same functioning1. Tucked deep within the Sylvian fissure, a connectivity hub disguised as an island unto itself, the insula is one of the main brain structures responsible for translating body states into social emotions. It starts doing this for us the moment we are born, recasting intimate touch into feelings of pleasure or a harsh tone from a parent into feelings of shame. If we do not receive appropriate care as children, the way the insula encodes the relationship between our bodies and social emotions can cement in a maladaptive way, leading to a propensity for mental health issues later in life2. Mounting evidence shows that it may be possible to change this relationship, since the insula also plays a role in therapeutic practices like mindfulness meditation, body trusting, and psychedelic-assisted therapy. Taken together, these findings suggest that the link between body, self, and social emotions plays a bigger part in mental health than we might think, highlighting a need for more forms of therapy which directly target social emotions through the body.

    The Bodily Self

    The insula’s main function—helping us recognize what we are experiencing based on what we sense—is called interoception. It allows us to interpret an “empty stomach” as physical hunger or “butterflies” as excitement or fear. As mentioned above, social emotions arise from this process. Despite the connection between interoception and social emotions, little scientific attention has been given to the social origins of interoception.

    At the University of Utah’s Social Development Lab, Kristina Oldroyd’s pioneering work suggests that early social experiences significantly impact areas of the brain responsible for interoception by influencing the development of the bodily self. Oldroyd’s research team has found that insensitive caregiving—which includes responding inconsistently to a child’s needs or rejecting distress altogether—can impair a child’s ability to form accurate representations of bodily sensations3. For example, when a child who is learning to walk falls down and feels physical pain, a sensitive response from a parent might be, “That must have hurt,” whereas an insensitive response would be, “You’re fine, that didn’t hurt, get back up.” For the child to become comfortable detecting, acknowledging, and expressing bodily cues, the parent must notice what the child is experiencing, draw joint attention to it, and label it3:

    “To the extent that caregivers recognize, honor, and respect their children’s bodily experiences, the child will develop more accurate interoception,” Olroyd explains. “To the extent that a child’s bodily experiences are denied, devalued, ignored, or punished by parents, the child will find ways to avoid feeling them, and develop a distorted sense of interoception.”3

    Oldroyd maintains that the way we learn to regulate physical pain is no different from the way we learn to regulate emotional pain—in both cases, we are socialized through our bodily experience. Neuroscientific studies support her theory, showing that children who are classified as having anxious or avoidant attachment styles have markedly lower insular volume than securely attached children4. If the bodily self remains unchanged throughout those children’s adult lives, when relationships become more complex and social-emotional regulation increasingly important, Oldroyd believes it is poor interoception itself which may lead to disorders like anxiety, depression, and addiction. It may also lead some of us farther away from social connection when, ironically, that may be what we need the most.

    Interoception and Social Health

    “One idea I’m working with,” says Andy Arnold, a psychologist and interoception expert at the University of California San Diego and Visiting Professor at Knox College, “is that interoception might be a critical mechanism for evaluating needed resources in our lives. If interoceptive understanding is turned down, then one might not be able to accurately sense the lack of needed resources [like] social connection and act accordingly.” For example, addiction could be a misevaluation of resources where you “overevaluate the drug but underevaluate other stimuli in your life,” Arnold told me, adding that the insula probably plays a critical role in this process.

    It also works the other way around: substance abuse disrupts interoception and damages the insula. Brain images of people with alcohol use disorder show significantly reduced grey matter in the insula, marked by a profound loss of von Economo neurons (or “empathy cells”)5, a relatively recent evolutionary specialization in humans thought to be crucial for interoceptive sensitivity and prosocial behavior6. Paradoxically, in certain cases, damage to the insula actually reverses addictive behaviors. In a 2015 study on addiction, researchers at the University of Southern California observed: “On the one hand, alcohol dependence damages the insula. On the other hand, damage done to the insula reduces cravings for alcohol.”7

    But this is not a contradiction if you view addiction as social health issue. The insula might normally motivate us to seek social reward, but if we cannot understand our social-emotional needs based on what we are feeling, we might turn to substances to resolve this uncertainty. Heavy substance use may be like putting the wrong type of fuel in the tank: when the brain and body crave social connection, giving it something else harms the engine over time although it appears to run fine. In this case, perhaps the habitual relationship with the drug outlasts the original motivation to use it. On the other hand, damaging the insula outright may destroy its record of the substance as a substitute for social reward, and therefore immediately reduce one’s craving for it.

    The insula shows us just how misguided we may be in labeling disorders like addiction, anxiety, depression, and substance abuse as “mental health” issues. If interoception initially develops in the context of interpersonal relationships, then so do many of our afflictions—and so, too, should our treatments.

    Connecting Through the Body

    In November 2019, Arnold and his colleague, neuroscientist Karen Dobkins, published the first academic discussion of what they call “social interoception,” arguing that interoceptive ability facilitates social connection8. To understand how interoception might work in a social situation, imagine an encounter that raises one’s heart rate—a response meant to enhance alertness and prepare one for “fight or flight.” Dobkins and Arnold believe it may not be one’s physiological response per se that causes social stress, but rather one’s subjective interpretation of it. They reference a series of studies by researchers in Munich who used social stress tests designed around impromptu public speaking9 and social exclusion10 in a game setting to measure interoception. The researchers found that people with higher interoceptive accuracy reported fewer negative emotions after the challenging social situation, despite their heart rate and skin conductance being similar to participants with lower interoceptive accuracy. In other words, two people can have the same internal body state but experience completely different levels of social discomfort.

    “This leads to the interesting idea that perhaps greater interoceptive accuracy allows one to identify the physiological response as resulting from an objective, external ‘social situation’ rather than an attribute of oneself,” Dobkins and Arnold say. “This could reflect better emotional regulation in social situations.” Oldroyd echoes these ideas in her own work: “It is the bias to interpret bodily signals in a negative manner, rather than the noticing of bodily signals, that contributes to both the cognitive and behavioral symptoms of anxiety.”

    There is an important subtext to these statements: Maybe we are not born with our various social neuroses. Maybe we are born with a bias towards positive social signals, towards bonding with others. Poor interoception, often developed in the context of an adverse childhood, may be what shifts the bias towards negative signals. The way to shift it back, Dobkins says, would be to start listening to and trusting your body before your mind jumps to conclusions. In their own work on loneliness, Dobkins and Arnold found that one measure of interoception in particular—body trusting—predicted variations of subjective loneliness amongst university students at UCLA11, suggesting that connecting with your body allows you to connect with others, whether that means making more friends or different friends. The more you trust your own body, the better you become not only at reading yourself but at reading and connecting with other people.

    “You know the feeling when you and another are ‘on the same page’?” Dobkins says. “Well, that’s not what I am talking about. That’s the mind reporting back and saying that, ‘the other person and I believe or want the same thing.’ Connection is body-based. It’s a knowing in the body. Which means you need to know your body.”

    The growing field of social interoception may help us better understand and treat not only loneliness but anxiety, addiction, eating disorders, depression, and other conditions traditionally associated with thought patterns rather than body signals. In fact, social interoception may be a key piece in the puzzle of explaining how psychedelic-assisted therapy functions.

    Psychedelic Drugs and Interoception

    As part of the Salience Network, one of the main functions of the insula is to orchestrate activity between other networks, including the Default Mode Network and the Central Executive Network. In 2017, Robin Carhart-Harris and his research team at Imperial College London found hypo-connectivity of the insula to be “a neurobiological signature of the MDMA experience,” correlating it with reduced anxiety, altered bodily sensations, and changes in interoception12. “Further understanding of how MDMA affects the insula,” Carhart-Harris writes, “might be crucial to elucidating the neurobiological underpinnings of re-emerging interest in MDMA as a therapeutic adjunct to psychotherapy in the treatment of anxiety disorders including PTSD.” Other teams have found similar results, linking insula hypo-connectivity to the LSD experience13.

    Research on the neural correlates of different types of mindfulness meditation points to the insula and the body as well. Commenting on a study on Loving Kindness, Focused Attention, Open Monitoring, and Mantra Recitation, Carhart-Harris notes that although these four meditation styles are clearly dissociated by their neural correlates, there are “a few recurrent patterns of activity modulation, in particular in the insula, an important multisensory area heavily involved in interoceptive awareness”14. He suggests that involvement of the insula in all four styles of meditation points towards “the central role of the attentional control of bodily awareness, and awareness of breathing in particular, during various contemplative practices.” As we’ve seen, body awareness is closely linked to social emotion, which may help explain the benefits of both mindfulness meditation and psychedelic therapy.

    Psychedelics and Connectedness

    At the University of Zurich, Katrin Preller studies the social health benefits of psychedelics. Her work in this area confirms Allmann’s notion that how we see ourselves is inextricably intertwined with social perception. For example, psilocybin and LSD have been found to reduce social pain specifically through alterations in self-processing15, which include experiences of unity and connectedness.

    “One of the main aspects of the psychedelic experience is the sense of connectedness – with the universe, nature, but importantly also with the social environment,” Preller told me. “Furthermore, we see an increase in emotional empathy which may be an important factor contributing to the feeling of connectedness. In clinical trials, we are currently testing the hypothesis that this experience contributes to the efficacy of psychedelic-assisted therapy.”

    In a successful series of Johns Hopkins studies targeting psilocybin and nicotine addiction, participants “identified social factors, i.e., smoking as a way of connecting with other people, that contributed to their addiction.” 16 They reported psilocybin-induced feelings of love and connection with their environment and other people, independent of smoking as a social factor, as important for quitting smoking17. “Psilocybin may have re-instated social reward processing, helping patients to overcome their addiction,” Preller speculates. “My hope is that therapy will focus more on social cognition and the social environment of patients. For example, social trainings may aim at re-instating social reward processing in addicted patients, helping them to re-connect with their social environment.”

    Research on the insula and social interoception suggest that the body is the main channel through which these changes must occur. Feelings of love and connection are exactly that—feelings. It seems we must feel the social reward, hold it in our bodies, to stop needing its replacement. In doing so, maybe we restore some kind of default setting. For all we know, “connectedness” may not be an additive feeling at all. On the contrary, it may be the stripped-down, primordial sensation that the self is socially constructed. And while it may be a new feeling to the psyche, Oldroyd’s work suggests it is not a new feeling to the body. Perhaps this is why psychedelic experiences can feel so profound to some: deep in their bodies, they’ve always known.

    From Global Connectivity to Local Plasticity

    In April 2019, researchers at Johns Hopkins University published an animal study showing that MDMA reopens a “critical period” when the mouse brain is sensitive to learning the reward value of social behaviors18. Although it is a neurobiological study, attributing the reopening  to heightened, oxytocin-induced brain plasticity, the behavioral mechanism sounds very much like Oldroyd’s childhood theory of interoception: Critical periods were first described in snow geese in the 1930s when goslings were found to bond with an object if their mother disappeared 24 hours after they hatched, but not 48 hours after they hatched. You can imagine which goslings would be best able to socialize their bodily cues going into adulthood, assuming geese are self-aware enough to do so. In the Hopkins study, adult mice who were given MDMA showed prosocial behavior in a way normally seen only in juveniles, forming positive associations between companionship and a certain type of bedding in their enclosure. Neuroscientist Gül Dölen and her team found that this happened only if the drug was given to mice when they were with other mice, not if it was given to mice while they are alone. “This suggests that reopening the critical period using MDMA may depend on whether the animals are in a social setting,” Dölen says.

    Embodied Therapy in Social Settings

    Although Dölen suggests this kind of treatment may work in humans by strengthening the psychotherapist-patient bond, I would argue it is also a case for a different type of therapy altogether—something along the lines of social embodied therapy, or group bodywork led by psychotherapists. Social reward learning occurs through the body, in a social setting, in large part because we are socialized through our bodies early in our lives. If the therapeutic aim is adaptive social connection, then why not place a greater emphasis on connection as therapy?

    Indeed, it seems questionable that any of us should heal as isolated subjects, when we are born to bond, and when the rest of our lives are built around connection. No matter how great your relationship is with your therapist, the dynamic is often that of an object being scrutinized under a microscope. Modern therapy still whiffs of stigmatization and quarantine—our problems so private that they must be kept a secret. Even Somatic Experiencing therapy, which at least reveals these problems to us through the body, largely treats each person in isolation. We do not necessarily have to share our problems to heal. In fact, some PTSD patients become asymptomatic after psychedelic assisted therapy sessions where no words are exchanged19. But it may be the case that we can only re-open the doorways of social learning—and heal from social illnesses—through the body, through each other, and through the part of the brain that so ironically appears to stand alone.

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    References

    1. Chen, I (2009). Brain Cells for Socializing. Smithsonian Magazine.

    2. Khalsa S et al (2018). Interoception and mental health: a roadmap. Biological Psychiatry. 10:004. doi: https://doi.org/10.1016/j.bpsc.2017.12.004

    3. Oldroyd K, Pasupathi M and Wainryb C (2019). Social Antecedents to the Development of Interoception: Attachment Related Processes Are Associated With Interoception. Psychol. 10:712. doi: 10.3389/fpsyg.2019.00712

    4. Lim L, Radua J, Rubia K (2014). Gray matter abnormalities in childhood maltreatment: a voxel-wise meta-analysis. J. Psychiatry 171 854–863. 10.1176/appi.ajp.2014.13101427

    5. Senatorov V-V, Damadzic R, Mann C-L, Schwandt M-L, George D-T, Hommer D-W, Heilig M, Momenan R (2015). Reduced anterior insula, enlarged amygdala in alcoholism and associated depleted von Economo neurons. Brain, 10:305. doi: https://doi.org/10.1093/brain/awu305

    6. Yang L, Yang Y, Yuan J, Sun Y, Dai J, Su B (2019). Transcriptomic Landscape of von Economo Neurons in Human Anterior Cingulate Cortex Revealed by Microdissected-Cell RNA Sequencing. Cerebral Cortex. 29, 2, 838–851. doi: https://doi.org/10.1093/cercor/bhy286.

    7. Droutman V, Read S-J, Bechara A (2015). Revisiting the role of the insula in addiction. Trends in Cognitive Neuroscience. 10:005. doi: https://doi.org/10.1016/j.tics.2015.05.005

    8. Arnold AJ, Winkielman P and Dobkins K (2019). Interoception and Social Connection. Psychol. 10:2589. doi: 10.3389/fpsyg.2019.02589

    9. Werner N. S., Duschek S., Mattern M., Schandry R. (2009). Interoceptive sensitivity modulates anxiety during public speaking. Psychophysiol. 23 85–94. 10.1027/0269-8803.23.2.85

    10. Werner N. S., Kerschreiter R., Kindermann N. K., Duschek S. (2013). Interoceptive awareness as a moderator of affective responses to social exclusion. Psychophysiol. 27 39–50. 10.1027/0269-8803/a000086

    11. Arnold AJ, Dobkins K (2019). Trust Some Body: Loneliness is Associated with Altered Interoceptive Sensibility [Abstract and Poster]. Emotion Preconference for Society for Personality & Social Psychology, Portland, Oregon.

    12. Walpola, I, Nest T, Roseman L, et al (2017). Altered Insula Connectivity under MDMA. 422152–2162. doi: 10.1038/npp.2017.35

    13. Preller et al (2019). Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. doi: 10.7554/eLife.35082

    14. Millière R, Carhart-Harris RL, Roseman L, Trautwein F-M and Berkovich-Ohana A (2018). Psychedelics, Meditation, and Self-Consciousness. Psychol. 9:1475. doi: 10.3389/fpsyg.2018.01475

    15. Preller KH, Schilbach L, Pokorny T, Flemming J, Seifritz E and Vollenweider FX (2018). Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study. Journal of Neuroscience. 38 (14) 3603-3611. doi: 1523/JNEUROSCI.1939-17.2018

    16. Noorani T, Garcia-Romeu A, Swift TC, Griffiths RR, Johnson MW (2018). Psychedelic therapy for smoking cessation: qualitative analysis of participant accounts. J Psychopharmacol. 32:756–69. doi: 10.1177/0269881118780612

    17. Preller KH and Vollenweider FX (2019) Modulation of Social Cognition via Hallucinogens and “Entactogens”. Psychiatry 10:881. doi: 10.3389/fpsyt.2019.00881https://doi.org/10.1038/s41586-019-1075-9

    18. Nardou R, Lewis EM, Rothhaas R. et al. (2019). Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature 569, 116–120.

    19. The Tim Ferriss Show Transcripts: Marcela Ot’alora—How to Become a Psychedelic Therapist (#396): https://tim.blog/2019/11/25/marcela-otalora-transcript/

    Over the course of six weeks, you will reconnect deeply with one of your psychedelic experiences in order to identify and embody the insights you have gained in sustainable ways. To support you in unfolding both the challenging and the beneficial aspects you may have uncovered, you will be guided through the integration process in six structured steps. Each week will cover one specific aspect and the modules will build on each other, progressing from intention to transformation.

    The live webinars will happen once a week for six consecutive weeks, starting on April 12th, 7pm.

    The peer group meetings are intended to take place on Sundays from 6pm to 7.30pm (CET) as a follow up to the live webinar sessions. However, the dates for the peer group meetings can be changed, according to the needs of the participants.

    You can join from everywhere in the world!

     

    Get your ticket here: Footsteps on MIND Academy Online
    The ticket price includes the whole course with all six live sessions and access to all recordings, course resources, additional material and access to the course platform.

    Over the course of six weeks, you will reconnect deeply with one of your psychedelic experiences in order to identify and embody the insights you have gained in sustainable ways. To support you in unfolding both the challenging and the beneficial aspects you may have uncovered, you will be guided through the integration process in six structured steps. Each week will cover one specific aspect and the modules will build on each other, progressing from intention to transformation.

    The live webinars will happen once a week for six consecutive weeks, starting on June 1st, 8pm.

    The peer group meetings are intended to take place on Sundays from 6pm to 7.30pm (CET) as a follow up to the live webinar sessions. However, the dates for the peer group meetings can be changed, according to the needs of the participants.

    You can join from everywhere in the world!

     

    Get your ticket here: Footsteps on MIND Academy Online
    The ticket price includes the whole course with all six live sessions and access to all recordings, course resources, additional material and access to the course platform.

    About

    In the MIND Foundation, we distinguish between two general kinds of partnerships which we may develop further into different sub-types. Cooperations are a type of partnership where actual resources flow in via money, personnel, or materials. In this case, an entire corresponding contract is necessary for tax reasons and clarifying characteristics like a partner’s non-profit or for-profit status. In cooperation projects, it is also important to specify, for example, the publication rights. For cooperation contracts, we usually use templates available by the European or German Research Council and adapt them. The second type of partnerships are resource-free collaborations (there is no flow of material resources, but of course time itself is a very important resource) and are usually about the joint implementation of a project or mutual provided services like media cooperations. Here, a contract is not mandatory, but can always be useful to build clarity and avoid controversies – as these here and there occur e.g. in joint publications.

    Cooperations

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    The aim of this section is to act as a platform for individuals interested in the interplay between coaching & psychedelics as to exchange ideas and experiences, share thoughts, concerns, resources and generally explore how coaching and psychedelics may work together to create positive change for people.

    This is a supportive space for professional coaches to discuss their coaching practice in relation to the preparation and integration of psychedelics experiences as a form of peer supervision.

     

     

     PROJECTS

    These are some potential projects that the whole section or individual working groups within the section will work on:

    • The formulation of a professional framework/definition for coaching in the context of psychedelics”.
    • The development of a possible integration coaching methodology (e.g. development of a semi-structured methodology or defined framework for integration and/or preparation coaching).

     

    • An academic white paper to argue the case for the potential coaching & psychedelics to work together and to lay the foundations for future research.”
    • A short online course or document on “what we feel you should know if you are a coach and consider to work with clients around their psychedelic experience”.
    • Creating a professional body.
    • Presenting case studies from professional coaches (possibly culminating in a book of coaching & psychedelics case studies).

     

     

    INSIGHT 2021

    Pre-conference workshop

    The Coaching & Psychedelics Section will present how coaching and psychedelics can go hand in hand. As the therapeutic benefits of psychedelics crystallize, we also see that psychedelics can help those without mental health disorders. This workshop will present our current understanding of that other side of the psychedelic coin. You will learn about our psychedelic coaching framework and receive a sneak preview of our whitepaper on this topic.

    Learn more

     

    Get to know our work environment

    The section has already set-up Google Drive and Zoom infrastructure. Zoom provides a secure video platform for our meetings.

    Google Drive will provide access to shared documents, resources, meeting minutes, member list, bylaws and other relevant information for the section and is accessible to all members.

     

     

     

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    Magic Yeasts and How to Make Them Produce Psilocybin

    An ASC Study Monitor interview with Nick Milne, PhD, CSO of Octarine
    • Blog
    • Science
    • Interview
    • 12 minutes
    January 15, 2021
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    CSO of Octarine

    Nick Milne, PhD, is a Co-founder and the Chief Scientific Officer (CSO) of Octarine, a synthetic biology company developing cannabinoid and psychedelic therapeutics.

    View full profile ››

    Research & Knowledge Exchange Associate, Resources Manager

    Jagoda contributes to the Drug Science Program and the Resources section.

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    Publication Discussed in this ASC Study Monitor interview:
    Milne, N., Thomsen, P., Mølgaard Knudsen, N., Rubaszka, P., Kristensen, M., and Borodina, I. (2020) Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives. Metabolic Engineering, 60:25-36

    J: Welcome, Nick. Thank you so much for coming!  In your lab at The Novo Nordisk Foundation Center for Biosustainability, you have mainly worked on projects related to sustainability. What made you interested in psilocybin?

    N: The research center where I worked is the Center for Biosustainability – A core focus of the center is to develop bio-based processes to replace non-renewable synthetic chemistry. I have always been interested in mental health, and particularly how we treat mental health, or rather how badly we treat mental health today. I was also always interested in the potential of psilocybin.

    J: Psilocybin is not a mainstream medication yet; it is actually still quite far from it. At the same time, your research topic sounded like a great idea; was it really so easy to pursue?

    N: At the time, it was undoubtedly a bit of a risk, and the first time I pitched the idea, I got laughed at! Eventually, what swayed people was showing them the clinical data. About two years ago, there was a lot of excellent clinical data starting to come out that showed the potential of these molecules, and I think that was what really swayed the people at the center to kind of say: ‘Okay, let’s give this a go.’ Thankfully, it has spun out into a company, and now, a year later, the psychedelics industry is becoming a promising one.

    Interested in learning more the psychedelics industry and the current legal context? Check out our INSIGHT 2021 conference in September, which includes presentations by Charles Raison, M.D., on an open science approach to drug development, and a workshop on legal and ethical considerations in psychedelic research by Dr. Fabian Wenner.

    J: And just a little bit over one year later, you have already published your results! That went pretty quickly.

    N: It was indeed fast! Even by our standards, it did go very quickly, and the time it took to go from idea to proof of concept was only about four months. It took a while to put everything into publication form, but the research went surprisingly well. Thankfully there was a bunch of other researchers who helped a lot with this project which made the whole thing go faster.

     

    J: That sounds great! Could you then summarize what you found in your study and how difficult it was to obtain these results?

    N: Our research’s primary goal was to identify how Psilocybe mushrooms produce psilocybin and then figure out how to replicate that process in Saccharomyces cerevisiae, also known as brewer’s yeast. The biosynthetic pathway to produce psilocybin was discovered a couple of years ago, but notably, not all of the genes were found. Since biosynthesis is a process requiring a concerted action of genes involved in synthesis, transport, and regulation it is necessary to classify them all. The main genes identified were the ones that catalyzed the critical reactions, but there was a couple that were left out and still needed to be found. We had to dig a little bit into the genome of Psilocybe cubensis to find the missing genes. We then introduced them into yeast by transferring the genetic material.

    We were able to demonstrate the production of psilocybin, which was a good start, but a lot of the work was focused on figuring out how to produce more psilocybin. Basically, the way that we did that was to work on the native yeast metabolism. Essentially how this works is that the genes that we transferred from Psilocybe cubensis work together with the genes that could transform tryptophan into psilocybin. Tryptophan is an essential amino acid, but it is also an amino acid that yeast produces endogenously, and actually, most species do. The most challenging part of the work was increasing tryptophan production – so playing around with the native yeast metabolism to increase the rate of tryptophan production, which subsequently led to more psilocybin production.

    The last thing we did was to play around with the genetic code of the Psilocybe genes a little bit so that we could divert production towards some of the other intermediates and derivatives of the pathway. For example, we showed that we could make a small tweak and produce aeruginascin instead of psilocybin, and we showed that by introducing entirely foreign genes, we could make molecules that did not yet exist in nature.

    J: Other studies, however, successfully demonstrated the production of psilocybin in E. coli.1 Could you explain why did you chose brewer’s yeast and what was the advantage of it?

    N: I think, first, it is good to explain why it is a good idea to produce psilocybin in living cells in the first place. Today, apart from our method, there are two main ways of getting psilocybin – either you have to grow the mushroom, or you have to synthesize it chemically. When it comes to the mushroom, if you have seen what a mushroom looks like, it is not that easy to grow, and the psilocybin accumulates in tiny quantities in the mushroom.

    J: Psilocybin is also found not evenly distributed across the different parts of the mushroom, so I imagine that extracting psilocybin from large quantities of Psilocybe cubensis must be tricky.

    N: Exactly! If we are thinking about commercial applications, we would need massive amounts of mushroom biomass. It would be challenging to extract, and the complexity of this process makes it very difficult for pharmaceutical applications. If we want to use psilocybin in humans, it needs to be very pure, and the production needs to be very consistent. On top of that, most pharmaceutical drugs are derived from non-renewable resources, including psilocybin. Synthetic psilocybin is derived from benzene, which is a fossil fuel.  It is also very environmentally hazardous and the chemical synthesis methods generate toxic waste, so there is undoubtedly an urgent need to develop a more sustainable way, which leads us to production in microorganisms.

    And why yeast instead of E. coli? That’s an excellent question; in my mind, there are two reasons – the first is that yeast is  the world’s oldest example of domestication. A thousand years ago, humans started domesticating yeast to produce beer, and fast forward to today; we have this organism bred essentially to thrive in an industrial environment – it does exceptionally well in beer fermentation and ethanol production. That is because it has evolved over all these years to tolerate the very extreme conditions of industrial-scale fermentation.

    Still, importantly for psilocybin, the other main reason is that yeast is a very close relative of Psilocybe mushrooms from an evolutionary point of view. They are both from the same kingdom – they are both fungi, so this makes a crucial difference if you want to express foreign genes in an organism; it helps if they are already closely related, and for Psilocybe this is very important. Hydroxylation, which is the key enzymatic step, does not work in bacteria such as E. coli. E. coli is actually missing an organelle – an essential piece of machinery that would allow this enzyme to work. Hence, reconstruction of the entire pathway is virtually impossible in bacteria. Other reports have successfully produced psilocybin in E. coli, but essentially, they had to circumvent this problem by feeding their strain a synthetic compound. From a cost point of view and from an environmental point of view, it is not really feasible. Our study has used sugar as a starting substrate, so it is very sustainable, and we can achieve a much lower cost of production, and our process is almost CO2 neutral.

     

    J: The sustainability of the process is definitely a significant advantage over other methods. You have also fine-tuned the yeast metabolic pathway, but it is probably not optimized yet for large scale production. What exactly would you have to improve to make it optimal for production on an industrial scale?

    N:  The main challenge is to increase the amount of sugar that gets converted into psilocybin. Beyond that, to reach commercial-scale production satisfactory enough to be used for human clinical trials, we need to scale the process from one liter to thousands of liters. The fermentation development is critical, and of course, the other issue that we need to look into is how to efficiently purify psilocybin from the fermentation broth.

    J: How far is the work, do you think, from achieving a production protocol available to be used industrially? 

    N: This work is what we are doing at Octarine right now. It is already feasible to produce small amounts of psilocybin, but to produce the quantities needed for human clinical trials and eventually commercial applications, there is still a little way to go.  Still, the biggest hurdle is the regulatory approval, so we can have a production process ready considerably faster than the regulatory bodies will give the authorization to use it.

    J: You have used the method of introducing foreign pieces of DNA into the yeast genome. This has been done already with gene-editing techniques like CRISPR all over the world, and it is not a new thing to do, but there is always a risk involved in the process of playing around with genomes of living organisms, which may produce some unwanted effects. Have you observed any of these?

    N: Indeed, it can be a big issue. Not only expressing foreign genes in heterologous hosts [an organism naturally lacking the gene of interest] but also just producing molecules which the organism has not encountered before. In our case, thankfully, we did not see any of these issues. That is another good reason for using yeast – it tolerates foreign gene expression very well and it typically does well when faced with a foreign metabolite. The natural host often produces these molecules for a very good reason, so there has to be a reason why mushrooms produce psilocybin. Often the produced compound acts as a deterrent, which means it is a toxin to microorganisms. This is the case with, for example, cannabinoids, which we also work with. Cannabis produces cannabinoids primarily as an antimicrobial, so if you are trying to produce it in a microorganism, you are going to come across toxicity effects. Thankfully we have not seen any issues so far in the psychedelics we are working with.

    J: Right. You have also achieved a stable transformation of the cells, which means that the foreign genetic material is integrated forever.

    N: Exactly! This is another excellent reason for using yeast. It is very easy to integrate straight into the genome and integrate stably, so essentially the genes are in there without any selection pressure or anything to force them to stay there.

    J: Usually antibiotic resistance genes are transferred together with genes of interest, so that when an antibiotic is introduced into the growth medium the cells are continuously forced to express the foreign genes. You have managed to integrate your genes of interest without any antibiotic selection?

    N: Yes, and that is important for large scale production, you do not want to have antibiotics or any sort of selection pressure, both from a cost point of view – antibiotics are expensive – but also from a human safety point of view – you do not want antibiotics in your mixture, and you also do not want any activation of the antibiotic resistance genes.

     

    J: Next to all those impressive achievements, you have managed to do another thing – to synthesize a novel molecule that has not existed in nature before, N-acetyl-4-hydroxytryptamine. Could you tell us about this compound and if you are going to investigate it in more detail in the future?

    N: We are not only interested in producing psilocybin; we are also interested in the range of other molecules that Psilocybe mushrooms produce. We were inspired by the fascinating findings in the research on cannabinoids, which shows that some of the minor cannabinoids have new or improved functions. For example, CBD seems to be very effective at treating epilepsy, but one of the minor cannabinoids, CBDv, potentially could be even better. The amount of evidence is growing, and it suggests that the same could be true for Psilocybe mushrooms, so we are, of course, very interested in all of the derivatives and all the intermediates that the Psilocybe mushroom produces.

    Going beyond that, one of the things that we are very interested in, especially at Octarine, is how we can use biological machinery to create molecules that do not exist in nature. At least in theory, enzymes should be vastly superior to synthetic chemistry. They should be able to catalyze reactions that synthetic chemistry cannot do, do it much more efficiently, and under much more favorable conditions. The trick here is figuring out how you can ‘convince’ an enzyme to catalyze a reaction it does not normally do. That is a part of the core technology that we are developing at Octarine, but in this paper, we just wanted to demonstrate the potential of natural enzymes to be coaxed into catalyzing reactions, which they do not normally do.  That was an example with this molecule N-acetyl-4-hydroxytryptamine, which is essentially half psilocybin and half melatonin. In general, we are very interested in investigating the properties not only of novel molecules that are produced in our platform but also the properties of some of the minor tryptamines that Psilocybe mushrooms and other psychedelic organisms produce.

    J: Melatonin is a sleep hormone found in the human brain and psilocybin acts on serotonin receptors. Do you think this new type of tryptamine could also have some psychoactive effects in humans?

    N: I would say it is too early to speculate. This work is more about a production proof of concept, but what I can say is that, in general, the idea is that we are creating new molecules in the hope of creating a better version of psilocybin or a molecule that has a different therapeutic effect. This is essentially the work that is going on right now – we try to figure out what these molecules do and whether they could be interesting from a therapeutic point of view.

    J: It seems like there is a whole new generation of compounds waiting to be discovered, which is very exciting! Now, imagine somebody gives you an unlimited grant for Octarine, for any research project. What would it be?

    N: This is a very good question and what comes to my mind is that in nature, there are thousands and thousands of interesting molecules that have interesting therapeutic effects, and we have been exploiting these natural sources since, well, forever.

    J: That is true in the indigenous context, but in Western medicine they have been relatively neglected.

    N: Exactly, and I think part of the reason is that there is a big gap that exists between understanding what these molecules do and figuring out how we can produce them. There are plenty of examples of molecules that we know exist in nature, and we even know that they have remarkable therapeutic properties, but we do not have the tools yet to produce them in quantities suitable for pharmaceutical application.  For a very long time we had no idea how the natural organism produced them. It was only in the last few years that we actually figured out how cannabis makes cannabinoids and how Psilocybe mushrooms make psilocybin. However, for the thousands of other molecules, we have little idea how they are produced, and we have no idea which enzymes and which genes are responsible. I think this is a bottleneck in developing natural molecules for therapeutic applications.

     

    J: What exactly would be the first big step to improve this situation?

    N: In my opinion, the main problem is speed – we have methods in place for elucidating biosynthetic pathways, but they are incredibly laborious and time-consuming. There have been considerable advances in obtaining increasingly large data sets on cellular processes. Perhaps using things like machine learning or artificial intelligence to take some of the guesswork out of the interpretation of this data could be a significant improvement. We make some good guesses about what we think is going on, but then we spend a very long time testing it, and far too often… we are wrong.

    J: So, computer modeling could definitely speed up the process.

    N: I think so. Taking the human aspect out of it and improving our methods of figuring things out would definitely improve our best guesses on which genes are involved. It would be a giant leap in the field, I think.

    J: I will keep my fingers crossed for the developments in Octarine. My last question relates to what you said before about the first time you pitched your idea to others and it was met with… not the most fertile ground. Do you have any hints for researchers and students about how to push for this kind of research?

    N: I think that, at least in the research community, the stigma around these molecules is rapidly decreasing.  In my opinion, it is because we can look at the clinical data and it is fairly black and white that these molecules hold a lot of promise, so it is not the research community that needs to worry about stigma; it is the public perception which I think is a more significant issue. In general, a part of how I got into the field was looking at the clinical data and being convinced that there is something interesting there. I always think that a good place to start is to dive deep into the data and see for yourself the potential of these molecules.

    One of the great things about this field, as well as with cannabinoids, is that it brings together people from entirely different backgrounds. I could never imagine that I would be working with all different kinds of researchers, but that just shows how promising these industries are and that it requires collaboration from so many different backgrounds. In my case, the background is yeast and microbiology. I have spent my career making biofuels and trying to decrease fossil fuel emissions, so it is fascinating how different experiences can be relevant. The field is developing thanks to people applying the skills they have picked up in one area and figuring out how it can be applied to the psychedelics industry. I think that would be my advice – look at the skills you have and try to see how they can be applied to this new industry because I really believe that there is so much opportunity for development in the ecosystem.

    J: Thank you so much for this advice! One piece of good news that I could share with you is that the Central Institute of Mental Health (ZI) Mannheim have just recently announced the start of a psilocybin-depression study lead by Prof. Dr. Gerhard Gründer. The MIND Foundation participates in this research and our clinical partner OVID supports with therapists at the second study center in Berlin – and both are thus providing additional financial resources for the study. It is the first study of this kind with the prospect of being funded by German governmental funds.

    N: I think that in the world, the momentum is very rapidly building, and I read about this the other day. It is a huge moment, since public funding is being used for psychedelic research. One thing that was really encouraging for us is that one of our investors is the Danish government.

    J: That is amazing!

    N: The Danish government has a venture fund and they are one of our biggest investors. For us, that is a hugely positive sign for industry in terms of overcoming the stigma – the fact that public institutions and even governments are getting behind this kind of research. Even the FDA has a lot of positive things to say about psychedelics and they are very pragmatic about this, so indeed, times are changing and I have no doubt that five years from now, this will not be an issue anymore and it will become clear that psychedelics can be used for therapeutic benefit.

    J: As soon as the pharmaceutical industry recognizes the benefits?

    N: Essentially, that is what we have seen with cannabinoids.

    J: That is true; the therapeutic use of cannabinoids became mainstream so quickly.

    N: It is essentially mainstream by now, right? The majority of people agree that cannabis is therapeutic and it is a pharmaceutical drug now, so seeing how that has changed in such a short amount of time makes me really think that psychedelics will closely follow.

    J: It makes me optimistic as well, so fingers crossed for that and thank you so much for the talk!

    N: Thanks, I appreciated the time.

    For more on this and many other issues in psychedelic research, be sure to check out our INSIGHT 2021 conference program and pre-conference workshops.

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    References

     

    1. Adams, A. M., Kaplan, N. A., Wei, Z., Brinton, J. D., Monnier, C. S., Enacopol, A. L., Ramelot, T. A., & Jones, J. A. (2019). In vivo production of psilocybin in E. coli. Metabolic engineering, 56:111–119.

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        Melina Mitsotaki, M.Phil., RKE Associate & uniMIND Project Coordinator
        Greece

        “I am passionate about the ways in which psychedelics not only open the gates to, but intently ring the bells for interconnectedness and systems thinking. Be it in the context of interpersonal relationships or mainstream science, to me it’s high time that our interconnectedness is embraced, so we can create a thriving world around us and tackle the systemic problems of our time. Looking at psychedelic research from such a lens reveals not a disparate outlier in the tree of science, but a central metabolic pathway that really strengthens the communication between all other branches of science.”

        Vlad Nicolescu, M.Sc., RKE, MIND Academy, and Communications Associate
        Romania

        “As many scientists and therapists have pointed out in the past decades, psychedelics have a great potential as tool to understand, transform and heal the human consciousness. Where I come from, these matters are rarely, if ever, discussed, and the consequence is that people suffer silently from mental illness and its stigmatization. The authoritarian political regime of the past century left a deep mark in our psyche, which is especially visible if you look at mental health and social inequality issues, both of which are addressed with a certain fear and misunderstanding. I hope that eventually psychedelic-assisted therapy will be able to alleviate some of these issues by providing a way to understand, accept and transform oneself and one’s social context.”

        Alejandra Díaz, M.B.A., Members Manager
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        Jagoda Mackowiak, M.Sc., Resources and ASC Study Monitor Coordinator, RKE Associate
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        “As cliché as it sounds, I do believe that psychedelics can change the world. Although neglected in the modern history, psychedelic substances have been present in indigenous medicinal practices for centuries. It is an enormous loss for society that, instead of exploring their therapeutic potential and focusing on harm reduction, we have put them on the shelf. Since today we observe a revival of psychedelic science, I would like to be a part of the reversal of the bad fame of psychedelics and contribute to the improvement of global mental health.”

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