An interdisciplinary exploration of the structures and processes emerging around psychedelic research

The uniMIND Symposium is the first-ever Symposium organized by and for the MIND Foundation’s extended uniMIND ecosystem. The event aims to bring together emerging and established voices from the growing field of psychedelic research. As such, the uniMIND Symposium welcomes university students, faculty, researchers, and professionals.

The theme for this year’s uniMIND Symposium is Regenerative Structures.

It aims to inspire transdisciplinary discussion on the ways in which psychedelic research and implementation may support the development of a healthier, more connected society. Join us for a day of insightful exchange on the integration of research across disciplines and practice, and explore with us innovative methods to solve some of the complex problems of today.

The event will feature keynote sessions by prominent researcher in the psychedelic research space Dr. Katrin Preller, and PhD candidate and researcher Helena Aicher.

Prof. Dr. Med. Franz Vollenweider, and the MIND Foundation’s Director of Research and Knowledge Exchange, Marvin Däumichen, will also be joining us for a panel discussion.

Find out more about the uniMIND Symposium and the full schedule, and apply to be a speaker at:


Already in the early years of the new millennium, Prof. Evgeny Krupitsky and his team used Ketamine in the treatment of opioid addiction in pioneering clinical studies. In one of these projects, seventy detoxified opioid addicts received either a low, sub-psychedelic dose of Ketamine or a high, psychedelic dose of Ketamine, both supported by accompanying psychotherapy in a randomized trial. Prof. Kupitsky will talk about the implications and results for his groundbreaking work that will inspire other clinicians in the years to come.

Oft sprechen Depressionen nicht auf erste Behandlungsansätze an, woraufhin von einer „therapieresistenten“ Depression gesprochen wird. Der Vortrag zeigt auf, dass es allerdings entgegen der semantischen Bedeutung der „Therapieresistenz“ ein weites Spektrum an weiteren wirksamen Behandlungsoptionen gibt. Diese umfassen medikamentöse, psychotherapeutische und verschiedene somatische Strategien, unter welchen auch dem Ketamin eine neue Bedeutung zukommt.


Dr. Levine will provide an overview of the early translation of research on ketamine for depression to real-world applications in private clinics across the United States, its evolution over the past decade, and implications as a new model of psychiatric care delivery.

Sind LSD, MDMA & Psilocybin neue Substanzen in der Behandlung seelischer Erkrankungen? 

Die Anwendung von Psychedelika in der Psychotherapie ist keine neue Erfindung. Bereits vor 80 Jahren entdeckten TherapeutInnen diese Substanzklasse, die in der Lage ist, das Bewusstsein in einer besonderen Art zu verändern. 

Seit den 90erJahren erleben wir ein Wiederaufleben der psychedelischen Forschung. Die Menge an wissenschaftlichen Studien mit positiven Ergebnissen für die Behandlung von Depressionen, posttraumatischen Belastungsstörungen und Angstzuständen mit Psychedelika nimmt mit jedem Jahr zu. 

In diesem Vortrag wird Sergio Pérez (MIND Academy Director) Ihnen einen Überblick über den Stand der Forschung, sowie Hoffnungen und Grenzen dieser Substanzklasse präsentieren. 

 blog-treated_cptsd (1)  blog-treated_cptsd (1)

Ketamine in Contextual Trauma Therapy: 

The Paradox of Dissociation in (Complex) PTSD 

  • Blog
  • Science
  • Perspective
  • 15 minutes
March 12, 2021

Founding Director of NSU's Trauma Resolution & Integration Program

Steven N. Gold, PhD, is retired from a full professorship but continues to be active in the areas of Clinical Psychology and Forensic Psychology, with an emphasis on psychological trauma, dissociative disorders, Complex PTSD, and Contextual Trauma Therapy.

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Clinical Psychologist

Michael Quinones, PhD, research and clinical interests focus on the neurobiology and phenomenology of altered states of consciousness and their therapeutic implications in trauma and dissociation.

View full profile ››

Ketamine-induced dissociation in the context of psychotherapy may exert a therapeutic effect for (complex) PTSD by creating experiential distance through dissociation which allows trauma survivors to face and resolve traumatic material without being overwhelmed by it.

Steven Gold, PhD and Michael Quinones, PhD, are both clinical psychologists working with survivors of C-PTSD in private practice. In this blog post, they share their perspective on C-PTSD, dissociation and ketamine speaking from their personal work experience with ketamine-assisted psychotherapy.

What Is Complex PTSD?

Exactly 40 years following the official recognition of posttraumatic stress disorder (PTSD) as a diagnosable mental health condition1, it is remarkable both how much and how little has changed. It seems that the recognition of trauma and its impact is ubiquitous. Accounts of traumatic incidents, their psychological toll, and a potpourri of treatments for traumatization are legion in the popular media. The research literature on trauma has expanded exponentially in the last few decades, from practically non-existent in the mid-twentieth century to literally thousands of publications per year in recent times. And yet, as practitioners who specialize in treating trauma-related disorders, we are regularly contacted by prospective clients, including those residing in the largest metropolitan areas of the U.S., who are unable to locate a mental health professional who truly seems adept at trauma treatment. Instead, they report dead-end courses of therapy and ill-timed or ill-conceived interventions that have exacerbated rather than ameliorated their trauma-related difficulties.

Although some forms of therapy for traumatization have been extensively researched and identified as highly efficacious, there is growing evidence that outside the laboratory, under real-world conditions, the level of effectiveness of these approaches is considerably lower. Research studies show that in community settings, on average, around 50% of patients drop out of treatment prematurely.2,3 Due to the treatment, some patients even experience a worsening of symptoms and a decrease in various domains of functioning.3,4

Further complicating matters, it is well-documented that trauma is related to a host of syndromes other than (and often comorbidly in addition to) PTSD. Dissociative disorders, addictive and compulsive disorders, severe depression, and borderline personality disorder are among the most prominent but by no means the only diagnoses that can be associated with a history of trauma.5,6 When these disorders arise from trauma, failure to recognize this origin can seriously limit treatment effectiveness.

A less well-known but prevalent syndrome is Complex PTSD (C-PTSD), a constellation of difficulties first introduced by Harvard psychiatrist Judith Herman in the early 1990s.7  Long a source of controversy,8 research decisively supporting the validity of C-PTSD has only very recently emerged.9,10 This, in turn, led to the explicit acknowledgment of the disorder in the eleventh edition of the International Classification of Diseases (ICD-11).10,11 C-PTSD encompasses all the markers of PTSD but also includes a triad of features collectively designated disturbances of self-organization: an enduringly negative self-concept, ongoing problems in interpersonal relationships, and difficulties regulating emotions.12 The inclusion of C-PTSD in the classification scheme marks a particularly important turning point in trauma psychology in that some empirical studies indicate that C-PTSD is appreciably more common than the more limited set of difficulties comprising PTSD alone.12

C-PTSD was originally proposed to result from repeated or prolonged encounters with traumatic events.7 While this seems to be the case, research findings suggest that C-PTSD is in particular associated with extensive traumatic experiences in childhood.6, 12-14 Taking a closer look at this rooting in early-life adversity can change how we view this disorder. Namely, the three components of disturbances of self-organization can be understood not merely as direct consequences of the traumatic event, but also as developmental impairments resulting from being reared in interpersonal environments that do not adequately support psychological development.

The Neurobiology of C-PTSD

To appreciate the potential of psychedelic-assisted approaches to promote the psychological transformations undergirding the resolution of C-PTSD, it is vital to attain familiarity with the developmental neurobiology of the disorder. The neurological structures of the brain develop in networks of connectivity (intrinsic connectivity networks), each of which is associated with specific functions such as attending to tasks, recalling autobiographical information or past experiences, maintaining a self-concept, and attending to the external environment.20 Research has shown that secure attachment experiences, including receiving affection and attention, and caregiver responsiveness, are essential for the development and growth of the human brain and adaptive patterns of functional connectivity among its neurological structures.16,17

Research on the neurobiology and phenomenology of traumatization has shown that both, traumatic experiences and the absence of experiences like secure attachment, which are necessary for adequate development, can negatively affect biological processes in brain development and lead to aberrant patterns of neural function and connectivity.18,19 This includes issues with the proliferation and pruning of neurons and synapses, resulting in aberrant brain activity within and between specific neurological structures.21,22 Studies strongly support that these forms of adversity can impair the development of several essential neurological structures such as the hippocampus, amygdala, cingulate and insular cortices, and the prefrontal, temporal, and parietal cortices.23-25

Adults diagnosed with PTSD, dissociative, and borderline personality symptomology seem to have significantly altered functional connectivity between these neurological structures, which in turn can disrupt intrinsic connectivity networks.26-28 These disruptions can be seen to correspond to the range of symptom profiles such as hyperarousal, dissociation, depressed mood, negative thoughts, negative self-concept, and flashbacks which comprise PTSD, C-PTSD, and the range of comorbid trauma-related disorders.

An Overview of Contextual Trauma Therapy

For about 30 years now, we have been working on an evolving conceptual framework for understanding C-PTSD and a treatment approach based on that conceptual perspective: Contextual Trauma Therapy.15 In several respects, the Contextual Trauma Therapy model is entirely consistent with the recently emerging major research findings regarding C-PTSD. We propose that C-PTSD results not only from deleterious events that have happened to a child (thus, trauma) but also from the lack of beneficial influences (thus, developmental deprivation). The traumatic impact of an abusive treatment is captured by the symptoms of PTSD. In addition, the three components of disturbances of self-organization encapsulate major consequences of developmental deprivation. These developmental deprivations can be attributed to having grown up in an insufficiently stimulating interpersonal context and the failure to meet the child’s basic developmental needs for affection and validation. Hence the term contextual in Contextual Trauma Therapy.

This context of deprivation fosters vulnerability to being targeted for abuse, heightened risk for traumatization in response to instances of interpersonal violence, augment the likelihood for continued victimization (known as revictimization) later in life, and promote the forms of dysfunction that comprise disturbances of self-organization.

Consequently, Contextual Trauma Therapy theory proposes that the resolution of C-PTSD requires, first and foremost, the remediation of developmental deficits to bolster functional resiliency. Increases in resiliency and stability can be seen as a prelude to the potentially debilitating prospect of confronting and resolving traumatization. Due to many possible impairments in development, C-PTSD survivors can be limited in their adaptation and coping abilities and are therefore vulnerable to deterioration rather than resolution when confronted directly with intense traumatic material. To circumvent this, one may first tackle the three components of the disturbances of self-organization in C-PTSD by: 1) developing a consistent, trusting therapeutic relationship that can serve as a “laboratory” for acquiring interpersonal skills; 2) facilitating cognitive processing of irrational beliefs that sustain a negative self-image; and 3) training in behavioral skills to promote sufficient regulation of impulses and emotional expression.

Summing up, Contextual Trauma Therapy is an eclectic treatment, drawing on a large range of approaches that are guided by the central premise that disturbances of self-organization are not primarily attributable to deleterious events of childhood trauma but rather to having grown up in an interpersonal environment that did not adequately model and transmit adaptive capacities of self-organization. This being the case, trauma reprocessing alone cannot be expected to ameliorate these types of difficulties. On the contrary, because it is taxing and potentially destabilizing, a direct, intensive focus on trauma early in treatment can instead radically compound problems of self-organization.

The Potential of Ketamine as an Adjunct to Therapy to Foster Resolution of C-PTSD

The last decades were marked by substantial progress in the research on the application of psychedelics (such as psilocybin, ayahuasca, LSD, MDMA, and Ketamine) for the treatment of a wide range of mental health difficulties and psychological disorders. Among the classical and non-classical psychedelics, Ketamine is of specific interest to us for several reasons. Most importantly, it was found to benefit patients with various psychological disorders including PTSD, dissociation, depression, anxiety, and substance use disorders.29-31

In contrast to classic psychedelics, Ketamine has been referred to as a “dissociative psychedelic” or “dissociative drug”. In fact, the dissociative effects of Ketamine were already highlighted around the time of its discovery and its initial use as an anesthetic.32  More recent studies describe how the administration of Ketamine provides dose-dependent dissociative experiences such as depersonalization, derealization, time distortion, and amnesia.33,34  And, interestingly, acute depersonalization and derealization after Ketamine have been found to predict the anti-depressant effects of the drug.35,36

Recent research on the neurobiological effects of Ketamine sheds light on how Ketamine may induce its therapeutic effects. Ketamine promotes neuroplasticity through both ‘synaptogenesis’ (creation of new synapses between neurons) and ‘neurogenesis’ (growth of new neurons).30 Furthermore, Ketamine directly affects receptors of the neurotransmitter glutamate, which seems to change the functional connectivity between several neurological structures (prefrontal cortex, hippocampus, anterior cingulate cortex, and basal ganglia), and thus alters the functional connectivity of large-scale networks in the brain through both respectively “decoupling” and “coupling” certain network hubs.37,38 In a therapeutic setting, this may help ameliorate the altered connectivity within and between neural structures that otherwise may be impaired due to the impact of trauma and curtailed development.

Accordingly, these neurobiological changes correlate with the individual’s altered experience of consciousness after Ketamine, such as reduced anhedonia (the inability to feel pleasure), time distortion, and depersonalization.37,39 As part of the debilitating symptomology of C-PTSD and other trauma-related disorders, dissociative experiences are typically associated with experiences of both trauma and deprivation. When provoked by Ketamine, in contrast, dissociation appears to exert a therapeutic effect through neurobiological and phenomenological alterations in consciousness. We believe that this is because there are two qualities of Ketamine that are therapeutic for this population: 1) experiential distance produced by Ketamine’s dissociative effects allows trauma survivors to face and resolve traumatic material without being overwhelmed by it, and 2) ketamine’s neuroplasticity-promoting properties provides a foundation for developmental remediation.

While dissociation is usually thought of in terms of manifestations such as depersonalization and amnesia, we find it conceptually useful to keep in mind that the word dissociation essentially means disconnection. Dissociation can manifest as disconnection from one’s own subjective experience (as in depersonalization, where the person’s thoughts, feelings, sensations, and so on seem not to belong to them), from one’s surroundings (as in derealization, in which the person feels their surroundings are distant and unreal), or from other people (the relative absence of the ability to feel an experiential bond with others, a common characteristic of various forms of insecure attachment).

For traumatized individuals, dissociative capacities appear to act as a two-edged sword. They have a protective function in coping with the chronic psychological, emotional, and physical distress associated with constant childhood adversity and traumatization. However, the automaticity of dissociation as a protective mechanism can also create chronic difficulties in life. Gratifying relationships, maintaining employment, and general success in day-to-day living require the ability to tolerate varying levels of stress and maintain experiential presence. Such experiential presence is further required to access positive emotional states associated with mutual connection, fulfilling relationships, joy, spontaneity, and creativity. As it is exactly this experiential presence that is disrupted by dissociation, it is hard for patients with chronic dissociation to thrive and live a happy, fulfilling life.

An integral component of treating C-PTSD is helping affected individuals reduce dissociative reactions to episodic distress by supporting them develop the capacity for experiential connection to the self, others, and the surrounding environment. In children, these capacities are acquired through the felt connection to attentive and responsive parents, which stimulates the development of rich and adaptive neuronal connections in the brain.40 The development of a therapeutic and collaborative relationship, a cornerstone of both Contextual Trauma Therapy and trauma therapy in general, is essential to fostering these neuronal and corresponding experiential connections. Our clinical experience strongly suggests that ketamine-assisted therapy can greatly accelerate this process.

Therapeutic Implications

We have been fortunate to make contact with ketamine centers that have enthusiastically welcomed our participation in providing ketamine-assisted therapy to some of our existing clients with C-PTSD. In conjunction with our exploration of the relevant biopsychological research literature, it is our impression at this point that the therapeutic potential of Ketamine for people with C-PTSD may represent a paradox, an instance of fighting fire with fire. Although episodes of dissociation are a major source of difficulty for those with C-PTSD, the dissociative qualities of Ketamine appear to be integral, both on a phenomenological and a biopsychological level, to remediating developmental gaps and warps.

Phenomenologically, the calming influence of ketamine-induced dissociation may provide enough experiential distance to neutralize habitual difficulties such as distrust, feelings of unsafety, and compromised capacities to tolerate distress and regulate emotions. Ketamine’s calming influence may even make it appreciably easier to confront traumatic material and become desensitized to it.

In biopsychological terms, the decoupling of disturbed neurological connections and promotion of new, more productive ones may lead to enduring treatment gains in radically less time than trauma-responsive psychotherapy alone. Our limited experience thus far with ketamine-assisted therapy for C-PTSD is consistent with these suppositions. We have seen remarkable leaps in psychological development and trauma resolution after relatively few ketamine-assisted sessions. Now it remains for additional clinical observation and empirical findings to determine whether our initial clinical impressions are borne out.

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  1. American Psychiatric Association. American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders. 3rd 3rd ed. Washington, DC: American Psychiatric Association; 1980.
  2. Schottenbauer, M. A., Glass, C. R., Arnkoff, D. B., Tendick, V., & Gray, S. H. Nonresponse and dropout rates in outcome studies on PTSD: Review and methodological considerations. Psychiatry: Interpersonal and Biological Processes. 2008;71 2 :134–68.
  3. Najavits L. M. The problem of dropout from “gold standard” PTSD therapies. F1000 Prime Reports. 2015;7 43 .
  4. Alpert E, Hayes AM, Barnes JB, Sloan DM. Predictors of Dropout in Cognitive Processing Therapy for PTSD: An Examination of Trauma Narrative Content. Behavior Therapy. 2020;51 5 :774–88.
  5. Briere J, Kaltman S, Green BL. Accumulated childhood trauma and symptom complexity. J Trauma Stress. 2008 Apr;21 2 :223–6.
  6. Cloitre M, Stolbach BC, Herman JL, van der Kolk B, Pynoos R, Wang J, et al. A developmental approach to complex PTSD: childhood and adult cumulative trauma as predictors of symptom complexity. J Trauma Stress. 2009 Oct;22 5 :399–408.
  7. Herman JL. Complex PTSD: A syndrome in survivors of prolonged and repeated trauma. Journal of traumatic stress. 1992;5 3 :377–91.
  8. Resick PA, Bovin MJ, Calloway AL, Dick AM, King MW, Mitchell KS, et al. A critical evaluation of the complex PTSD literature: Implications for DSM-5. Journal of Traumatic Stress. 2012;25 3 :241–51.
  9. Cloitre M, Garvert DW, Weiss B, Carlson EB, Bryant RA. Distinguishing PTSD, Complex PTSD, and Borderline Personality Disorder: A latent class analysis. Eur J Psychotraumatol. 2014;5.
  10. Ford JD, Courtois CA. Complex PTSD, affect dysregulation, and borderline personality disorder. Borderline Personality Disorder and Emotion Dysregulation. 2014;1 1 :9.
  11. Brewin CR, Cloitre M, Hyland P, Shevlin M, Maercker A, Bryant RA, et al. A review of current evidence regarding the ICD-11 proposals for diagnosing PTSD and complex PTSD. Clin Psychol Rev. 2017 Dec;58:1–15.
  12. Karatzias T, Shevlin M, Fyvie C, Hyland P, Efthymiadou E, Wilson D, et al. Evidence of distinct profiles of posttraumatic stress disorder (PTSD) and complex posttraumatic stress disorder (CPTSD) based on the new ICD-11 trauma questionnaire (ICD-TQ). Journal of Affective Disorders. 2017;207:181–7.
  13. Cook A, Spinazzola J, Ford J, Lanktree C, Blaustein M, Cloitre M, et al. Complex Trauma in Children and Adolescents. Psychiatr Ann. 2017 Aug 15;35 5 :390–8.
  14. Wamser‐Nanney R, Vandenberg BR. Empirical Support for the Definition of a Complex Trauma Event in Children and Adolescents. Journal of Traumatic Stress. 2013;26 6 :671–
  15. Menon V. Large-scale brain networks and psychopathology: a unifying triple network model. Trends Cogn Sci. 2011 Oct;15 10 :483–506.
  16. Schore AN. Effects of a secure attachment relationship on right brain development, affect regulation, and infant mental health. Infant Mental Health Journal. 2001;22(1–2):7–66.
  17. Meyer D, Wood S, Stanley B. Nurture Is Nature Integrating Brain Development, Systems Theory, and Attachment Theory. The Family Journal. 2013 Apr 1;21:162–9.
  18. Herzog JI, Schmahl C. Adverse childhood experiences and the consequences on neurobiological, psychosocial, and somatic conditions across the lifespan. Frontiers in psychiatry. 2018;9:420.
  19. Teicher MH, Samson JA. Annual Research Review: Enduring neurobiological effects of childhood abuse and neglect. J Child Psychol Psychiatry. 2016 Mar;57 3 :241–66.
  20. Gold SN. Contextual trauma therapy: Overcoming traumatization and reaching full potential. American Psychological Association; 2020.
  21. Busso DS, McLaughlin KA, Brueck S, Peverill M, Gold AL, Sheridan MA. Child Abuse, Neural Structure, and Adolescent Psychopathology: A Longitudinal Study. J Am Acad Child Adolesc Psychiatry. 2017 Apr;56 4 :321-328.e1.
  22. McLaughlin KA, Sheridan MA, Lambert HK. Childhood adversity and neural development: deprivation and threat as distinct dimensions of early experience. Neurosci Biobehav Rev. 2014 Nov;47:578–91.
  23. Lanius RA, Bluhm RL, Frewen PA. How understanding the neurobiology of complex post-traumatic stress disorder can inform clinical practice: a social cognitive and affective neuroscience approach. Acta Psychiatr Scand. 2011 Nov;124 5 :331–48.
  24. Lutz P-E, Tanti A, Gasecka A, Barnett-Burns S, Kim JJ, Zhou Y, et al. Association of a History of Child Abuse With Impaired Myelination in the Anterior Cingulate Cortex: Convergent Epigenetic, Transcriptional, and Morphological Evidence. Am J Psychiatry. 2017 Dec 1;174 12 :1185–94.
  25. Thomaes K, Dorrepaal E, Draijer NPJ, de Ruiter MB, Elzinga BM, van Balkom AJ, et al. Increased activation of the left hippocampus region in Complex PTSD during encoding and recognition of emotional words: a pilot study. Psychiatry Res. 2009 Jan 30;171 1 :44–53.
  26. Akiki TJ, Averill CL, Abdallah CG. A Network-Based Neurobiological Model of PTSD: Evidence From Structural and Functional Neuroimaging Studies. Curr Psychiatry Rep. 2017 Sep 19
  27. Krause-Utz A, Elzinga B. Current Understanding of the Neural Mechanisms of Dissociation in Borderline Personality Disorder. Curr Behav Neurosci Rep. 2018;5 1 :113–23.
  28. Schlumpf YR, Reinders AATS, Nijenhuis ERS, Luechinger R, van Osch MJP, Jäncke L. Dissociative part-dependent resting-state activity in dissociative identity disorder: a controlled FMRI perfusion study. PLoS One. 2014;9 6 :e98795.
  29. Dore J, Turnipseed B, Dwyer S, Turnipseed A, Andries J, Ascani G, et al. Ketamine assisted psychotherapy (KAP): Patient demographics, clinical data and outcomes in three large practices administering Ketamine with psychotherapy. Journal of psychoactive drugs. 2019;51 2 :189–98.
  30. Ezquerra-Romano II, Lawn W, Krupitsky E, Morgan CJA. Ketamine for the treatment of addiction: Evidence and potential mechanisms. Neuropharmacology. 2018;142:72–82.

31. Feder A, Parides MK, Murrough JW, Perez AM, Morgan JE, Saxena S, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA psychiatry. 2014;71 6 :681–8.

32. Chang LC, Rajagopalan S, Mathew SJ. The History of Ketamine Use and Its Clinical Indications. In: Mathew SJ, Zarate, CA, editors. Ketamine for Treatment-Resistant Depression [Internet]. Cham: Springer International Publishing; 2016 [cited 2021 Jan 17]. p. 1–12. Available from: http://link.springer.com/10.1007/978-3-319-42925-0_1

33. Castle C, Gray A, Neehoff S, Glue P. Effect of ketamine dose on self-rated dissociation in patients with treatment refractory anxiety disorders. J Psychopharmacol. 2017 Oct;31 10 :1306–11.

34. Radford KD, Park TY, Lee BH, Moran S, Osborne LA, Choi KH. Dose-response characteristics of intravenous Ketamine on dissociative stereotypy, locomotion, sensorimotor gating, and nociception in male Sprague-Dawley rats. Pharmacology Biochemistry and Behavior. 2017 Feb 1;153:130–40.

35. Luckenbaugh DA, Niciu MJ, Ionescu DF, Nolan NM, Richards EM, Brutsche NE, et al. Do the dissociative side effects of Ketamine mediate its antidepressant effects? J Affect Disord. 2014 Apr;159:56–61.

36. Niciu MJ, Shovestul BJ, Jaso BA, Farmer C, Luckenbaugh DA, Brutsche NE, et al. Features of dissociation differentially predict antidepressant response to Ketamine in treatment-resistant depression. J Affect Disord. 2018 May;232:310–5.

37. Li L, Vlisides PE. Ketamine: 50 Years of Modulating the Mind. Front Hum Neurosci. 2016;10:612.

38. Scheidegger M, Boeker H, Seifritz E, Boesiger P, Bajbouj M, Walter M, et al. The effect of a pharmacological ketamine challenge on working memory and brain metabolism. In Elsevier; 2011 [cited 2021 Jan 17]. p. 164. Available from: https://www.sciencedirect.com/science/article/pii/S000632231100309X

39. Krystal JH, Abdallah CG, Sanacora G, Charney DS, Duman RS. Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron. 2019 Mar 6;101 5 :774–8.

40. Siegel, D.J. The Developing Mind: How relationships and the brain interact to shape who we are, 2nd Ed. 2012. New York, Guilford.

 blog-treated_thirdeye  blog-treated_thirdeye

Not in Your Third Eye

What Does DMT Do in the Brain?

  • Blog
  • Science
  • Essay
  • 10 minutes
February 4, 2021

Is there DMT in the brain? What could it be doing there? These questions have been on the minds of psychedelic researchers for decades, and answering them was never going to be simple. New research goes beyond attempts to prove romantic ideas about DMT release from the pineal gland during near-death experiences. Through looking at individual neurons, this research indicates that DMT might have a role as a non-canonical neurotransmitter involved in protecting the brain from physical and psychological stress. A theme emerging from the research updates the original question: what if DMT is naturally neuroprotective?

From the Amazon to the West and Back to Ancient Egypt

Neurotransmitters are small molecules secreted in the nervous system to relay information between different neurons. Many of them – serotonin, dopamine, and adrenaline, to name a few – belong to the chemical class of monoamines. The most potent naturally occurring psychedelic, N,N-dimethyltryptamine (DMT), belongs to this same class of molecules. DMT can be found in trace amounts in animal nervous systems (including mammals), but it hasn’t been directly proven to act as an endogenous neurotransmitter.1 It is more common and better understood in plants, where it helps defend some species from herbivorous animals.2

Humans have been extracting DMT from plants for centuries. It isn’t orally active due to the presence of monoamine oxidase (MAO), an enzyme that degrades DMT, in the human digestive tract. Amazonian shamans have known how to circumvent this for centuries, combining a DMT-containing vine with plants containing MAOIs, or monoamine oxidase inhibitors, that stop the degradation of DMT. The psychedelic brew resulting from this mixture is known as ayahuasca, from aya (spirit) and waska (vine).3

Ayahuasca is inseparably intertwined with the mythogenesis and spirituality of South American indigenous tribes. Analogously, as DMT entered Western awareness, it easily found its place in literature and philosophy. Its biological properties have also intrigued scientists since its first synthesis in 1931. Because of DMT’s similarity with serotonin, it was tempting to hypothesise that it might naturally occur as a neurotransmitter in the human body. Where could such a peculiar neurotransmitter be found? Popular conjecture, borrowing concepts from both science and mythology, placed it in the pineal gland.

The primary role of the pineal gland is regulating sleep patterns by producing melatonin. But the history of this pea-sized structure in the forebrain is much more romantic. In ancient Egypt, it represented the eye of the sky god Horus, while in India it has been associated with the “third eye”, a mythical gate to higher consciousness. A modern incarnation of these stories originated from DMT: The Spirit Molecule, a book in which author and psychiatrist Rick Strassman, MD, postulates that large quantities of DMT may be secreted in the dying brain, enabling the transition of consciousness from one life to the next.4

Life and Death

Since the inception of Strassman’s theory, the presence and purpose of DMT in the pineal gland have been subjects of heated debate. While it hasn’t thus far been isolated directly from human brains, experiments in both humans and rats demonstrate that their brains – including the pineal gland – contain enzymes necessary for the synthesis of DMT.1

DMT’s potential involvement in near-death experiences is hard to either prove or disprove in humans, but attempts have been made in rats. Research has shown that rat brains contain DMT and that its concentration increases following induced cardiac arrest.1,5 Could this mean that these lab rats have gone through a near-death experience? Is this experience mediated by DMT, or is DMT just a metabolic waste product of a stressed organism?

Experimental results offer limited insight. If anything, DMT might be just one part of the veritable brainstorm of neurotransmitters (including serotonin, dopamine and, noradrenaline) that gets released in response to the severe stress of cardiac arrest.1 Moreover, even though the concentration of DMT increased, it was not possible to determine whether the increase corresponded to an exogenous psychedelic dose. While some researchers believe this to be the case, others point out it is unknown how low physiological quantities of endogenous DMT could be stored to be released en masse,6 as well as the biological reaction that such a release would trigger. Current scientific knowledge lacks the smoking gun needed to directly implicate DMT in near-death experiences: a well-characterised biochemical mechanism.

The Smoking Gun?

One-size-fits-all solutions are rare in biology. Neurotransmitters and psychedelic compounds alike act upon multiple brain regions, interact with different receptors with varying specificity, and trigger a wide spectrum of biochemical and genetic signalling cascades. DMT is no different, and while it was originally considered to exert its effects mainly via the serotonin 2A receptors, new targets for it have been found. One of these new targets, the sigma-1 receptor (Sig1R), is not the answer to the puzzle of DMT. It does, however, present us with several intriguing puzzle pieces.

Sig1R is unusual. Its origins are a mystery: In evolutionary terms, it is more closely related to a fungal enzyme called sterol isomerase than to any mammalian neurotransmitter receptor.7 Scientists are uncertain about how to interpret this finding, especially considering the fact that this particular fungal enzyme was first isolated from a fungus that produces alkaloids similar to LSD.

While many receptors specialise in relaying neurotransmitter signals either on the cell membrane, inside the cell, or in the nucleus, Sig1R is unusual because it can do all three. On the membrane, it can interact with other neurotransmitter receptors and change their function by forming complexes with them. When it’s inside the cell, it binds anti-stress proteins and aids them in performing their functions.8 In the nucleus, it recruits other proteins that bind to DNA and activate or deactivate different genes via epigenetic mechanisms.9

This multifunctional receptor is known as an ‘’orphan’’, which means scientists haven’t yet identified its main activating neurotransmitter. It was first suggested that Sig1R could be a subtype of opioid receptors, but scientists later found that other compounds bind to it as well, including cocaine and the sex hormone progesterone.10 More recently, evidence has mounted for speculations that DMT might activate this receptor.

The first indication that this might be the case came from cell culture research, where it was demonstrated that DMT can bind to Sig1R. Mouse research expanded on this finding and showed that mouse behaviour under the influence of DMT doesn’t change when serotonin and dopamine receptors were blocked. But after their Sig1R receptor had been deactivated, the mice stopped reacting to DMT. These results have led the researchers to conclude that Sig1R is one of DMT’s main targets.11 Another clue comes from the fact that in the synapses connecting different neurons, Sig1R is located close to an enzyme involved in DMT synthesis.12 This led some researchers to wonder whether Sig1R, rather than 5HT-2A, is the main mediator of DMT’s psychedelic effects.

The Powers of the Sigma 1 Receptor

What happens in the cell when DMT activates Sig1R? Some answers come from cell culture research. Recent studies have found a role for DMT in both the immune response and the anti-stress response of individual human cells. In immune cells, DMT was shown to activate the production of anti-inflammatory molecules.13

In a similar study, human neurons in cell culture were deprived of oxygen. Neurons quickly die when they don’t have enough oxygen, but treatment with DMT and the subsequent activation of Sig1R enabled more of them to survive.14 This finding offers a link back to Rick Strassman: If DMT helps stressed cells, could it also be helping whole organisms in states of stress – when close to death and severely oxygen-deprived? While it is tempting to speculate, it is important to keep in mind that neurons in the brain function in a complex, context-dependent way. Observing individual neurons in culture shows scientists what is happening inside them, but says little about how they interact with each other in a living, 3D brain.

Presently, this gap has not yet been bridged. Researchers have not tested Sig1R activity in intact brains undergoing hypoxia or other types of physiological stress. In a dying brain, DMT might be helping neurons to survive—but survival alone doesn’t tell us what those neurons are doing or how their activity might create the visions characteristic of near-death experiences. Lacking direct evidence, we may take some hints from brain imaging studies and attempt to connect them with known Sig1R mechanisms.

Looking at people’s brains on DMT and ayahuasca, researchers observe altered activity in the visual and auditory centres of the brain, as well as memory-related regions. These include centres for perception and processing of negative emotions and sad memories, memory retrieval centres, and the amygdala (a brain region commonly associated with social and emotional processing, including fear, anxiety and aggression).15,16

Dr. Antonio Inserra, a researcher from Flinders University in Adelaide, attempted to reconcile the molecular and whole-brain perspectives and formulated an intriguing hypothesis about the roles Sig1R could play in these brain activities.7 His analysis focuses specifically on the role of DMT in trauma processing, a phenomenon which garnered his interest due to anecdotal reports from PTSD patients whose symptoms were reduced after ayahuasca sessions. He speculates that Sig1R might form complexes with other receptors and boost signal transmission and synaptic plasticity in memory centres, which could help retrieve and reprocess traumatic memories. He further points out that Sig1R in the nucleus serves as an epigenetic regulator,9 meaning that it recruits enzymes that add different tags to DNA and histones (the proteins around which DNA is coiled in the cell) in order to turn genes on and off. It has long been understood that epigenetic mechanisms have an important role in all aspects of memory forming and remodelling. Because of this, Inserra suggests that some of the mechanisms through which ayahuasca treats trauma may be mediated by Sig1R epigenetics in the brain’s memory centres.

Back to the Amazon:  Will New Research Bridge the Gap?

A new study from Dr. Simon Ruffell, a research associate at the King’s College London, also links DMT, Sig1R, and epigenetic regulation. His team, supervised by Prof. Celia Morgan (University of Exeter), followed participants in ayahuasca ceremonies in the Amazon to investigate how these experiences impacted their traumatic memories. The participants reported significant, long-lasting decreases in depression, anxiety, and general distress. In order to find out why, Ruffell’s team collected saliva samples from them and analysed changes in the epigenetic tags on their DNA. They discovered that the Sig1R gene is epigenetically changed in some participants (unpublished results presented at the ICPR2020 conference). Since we know the receptor itself is involved in epigenetic modulation, this might be just the beginning. Which other genes do we see epigenetically modified after ayahuasca sessions? Ruffell’s epigenetic research may offer more clues not only about how DMT works with Sig1R on an epigenetic level but also about the epigenetics of memory as such. No matter what other results come out of this study, it already serves as an important bridge between the lab and the ceremony; between the cell, the brain, and the experience.

The current state of DMT research resembles disjointed puzzle pieces. While there are several indicators that there might be naturally occurring DMT in the human brain, its locations and functions remain elusive. More data is available about how ayahuasca and exogenous DMT work, both in the cell and in the brain, but we can’t yet justify extrapolating the roles of endogenous DMT from these findings.

Nevertheless, a variety of speculative theories have recently surfaced. While some researchers are focusing on DMT’s potential anti-inflammatory and neuroprotective roles, others look at the brain imaging and trauma studies and point towards its possible effects on memory-remodelling. Both might prove to be true, and both can be placed in the context of Rick Strassman’s theory that DMT is present in human brains to alleviate the effects of massive physiological stress, such as in oxygen-deprived neurons during near-death experiences. Could the dying brain be releasing endogenous DMT to keep itself alive for as long as possible? If so, the commonly reported characteristics of near-death experiences—including visions and one’s “life flashing before one’s eyes” —might simply be side effects. In the cases of neuron survival and memory processing, research so far points towards the multifunctional, mysterious Sig1R receptor as a key actor in these processes.

While the intricacies of its molecular mechanisms have yet to be fully described, the multifunctional Sig1 receptor is now firmly established as a target of DMT, and this opens new lines of inquiry. Perhaps the most exciting new research will include investigations into how DMT and Sig1R affect epigenetic regulation. Information about which genes they activate or deactivate could put the findings from cell culture research into the context of whole organisms. Epigenetic mechanisms lie at the very foundation of our dynamic interactions with the world, and with our own minds. Understanding how these mechanisms help store and remodel memories may help us formulate a coherent biological model of the therapeutic effects of the psychedelic experience.


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  1. Dean, J. G. et al. Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain. Sci. Rep.9, 9333. 2019.
  2. Marten, G. C. Alkaloids in Reed Canarygrass. in Anti-Quality Components of Forages 15–31. Crop Science Society of America. 2015.
  3. Luna, L. E. Indigenous and mestizo use of ayahuasca: an overview. The ethnopharmacology of ayahuasca 2, 01–21. 2011.
  4. Strassman, R. DMT: The Spirit Molecule: A Doctor’s Revolutionary Research into the Biology of Near-Death and Mystical Experiences. Simon and Schuster. 2000.
  5. Barker, S. A., Borjigin, J., Lomnicka, I. & Strassman, R. LC/MS/MS analysis of the endogenous dimethyltryptamine hallucinogens, their precursors, and major metabolites in rat pineal gland microdialysate: LC/MS/MS of endogenous DMTs in rat pineal gland microdialysate. Biomed. Chromatogr. 27, 1690–1700. 2013.
  6. Barker, S. A. N,N-dimethyltryptamine facts and myths. J. Psychopharmacol. 32, 820–821. 2018.
  7. Inserra, A. Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1 Receptor-Mediated Epigenetic-Mnemonic Process. Front. Pharmacol. 9, 330. 2018.
  8. Mori, T., Hayashi, T., Hayashi, E. & Su, T.-P. Sigma-1 Receptor Chaperone at the ER-Mitochondrion Interface Mediates the Mitochondrion-ER-Nucleus Signaling for Cellular Survival. PLoS One 8, e76941. 2013.
  9. Tsai, S.-Y. A. et al. Sigma-1 receptor mediates cocaine-induced transcriptional regulation by recruiting chromatin-remodeling factors at the nuclear envelope. Proc. Natl. Acad. Sci. U. S. A. 2015. doi:10.1073/pnas.1518894112.
  10. Su, T.-P. & Hayashi, T. Understanding the Molecular Mechanism of Sigma-1 Receptors: Towards A Hypothesis that Sigma-1 Receptors are Intracellular Amplifiers for Signal Transduction.. 2003.
  11. Fontanilla, D. et al. The hallucinogen N,N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science 323, 934–937. 2009.
  12. Mavlyutov, T. A. et al. Development of the sigma-1 receptor in C-terminals of motoneurons and colocalization with the N,N’-dimethyltryptamine forming enzyme, indole-N-methyl transferase. Neuroscience 206, 60–68. 2012.
  13. Szabo, A., Kovacs, A., Frecska, E. & Rajnavolgyi, E. Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. PLoS One 9, e106533. 2014.
  14. Szabo, A. et al. The Endogenous Hallucinogen and Trace Amine N,N-Dimethyltryptamine (DMT) Displays Potent Protective Effects against Hypoxia via Sigma-1 Receptor Activation in Human Primary iPSC-Derived Cortical Neurons and Microglia-Like Immune Cells. Front. Neurosci. 10, 423. 2016.
  15. Riba, J. et al. Increased frontal and paralimbic activation following ayahuasca, the pan-Amazonian inebriant. Psychopharmacology 186, 93–98. 2006.
  16. Palhano-Fontes, F. et al. The psychedelic state induced by ayahuasca modulates the activity and connectivity of the default mode network. PLoS One 10, e0118143. 2015.
 MDMA-therapy-social  MDMA-therapy-social

Beyond the Therapeutic Alliance

How MDMA and Classic Psychedelics Modify Social Learning – An interview with Gül Dölen
  • Blog
  • Science
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  • 14 minutes
January 26, 2021

Associate Professor of Neuroscience

Gul Dolen studies the synaptic and circuit mechanisms that enable social behaviors.

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Journalist, Managing Editor

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

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“Rather than having the MDMA-assisted psychotherapy and then sending them home with a journal and some happy thoughts, what we really ought to be saying is that the therapeutic window is actually for weeks, if not months after the acute psychedelic effects have worn off.”

At the Johns Hopkins University School of Medicine, Department of Neuroscience, neurobiologist and MIND’s scientific advisory board member Gül Dölen, MD-PhD, studies the mechanisms by which psychedelic drugs work to treat diseases of the social brain like PTSD, addiction, and severe forms of autism. Dölen spoke to me about her 2019 Nature paper,1 which showed that MDMA re-opens a “social critical period” in the mouse brain when it is sensitive to learning the reward value of social behaviors – but only if the mouse is in a social setting. Based on this research, Dölen and her colleagues believe two things are required for MDMA, and potentially all psychedelics, to be therapeutic in the context of social brain diseases: 1) the re-opening of the critical period and 2) the right social context for the memory to be reshaped. Not only does this view challenge current psychedelic therapy models; it also suggests a way forward for psychiatric treatments more generally.

Priming the brain for psychedelics

Saga Briggs (SB): Based on your animal studies, how do you think psychedelic drugs might work in humans to treat social brain diseases like PTSD?

Gül Dölen (GD): When we think about what happens when someone has PTSD, what we’re dealing with is that during their childhood or youth [during this maximum sensitivity to the social environment, or “social critical period”], they were in a social environment and something bad happened to them, and in that moment, their response was very adaptive. They were protecting themselves by putting up walls, by guarding themselves from whatever was causing that injury.

But then the critical period closes, and over time, that adaptive response starts to become less and less adaptive until they reach adulthood and they’re unable to form intimate relationships. They’re unable to keep a job. They have a very negative view of themselves in terms of self-esteem, that they’re not deserving of love and being in the world. The memory becomes an extremely well-ingrained worldview, and it’s hard to dislodge it. And so the idea is that what we’re doing with MDMA is going back and allowing them to rewrite that memory in a way that’s adaptive, now that the traumatic event has been removed from their environment.

And so I think that in the end of the Nature paper1, we kind of ended with, “Oh, well, [psychedelic drugs] might be just making the therapeutic alliance stronger,” but based on other more recent data and thinking about it longer, I think that it’s more than just the therapeutic alliance. It’s about making available those memories to modification.

SB: How does this memory modification work exactly?

GD: The way I’m talking about it now is I call it “open state engram modification.” So you put the brain on MDMA in an open state where you’re going to be sensitive to your social environment again, and then –either through therapy or through processing your own memories or looking at photographs or journaling—what you’re doing is bringing back the memory engram that is relevant to the trauma in this state where you are available to manipulate it and make those memories malleable and rewrite them to respond to the realities of your current world.

SB: And do you think that has to happen in a social setting, per se? I think in your Nature paper you mention this phenomenon only happened when mice were with other mice. But of course, many people have transformational experiences taking psychedelics on their own.

GD: I actually think probably one of the most surprising and profound findings of the paper is the setting dependence, because every other explanation that has been made of how these psychedelic drugs work from literally everybody else has always overlooked the fact that these experiences are very much modified by the set and setting, that they’re context dependent. You know, it’s not like people who have PTSD are taking MDMA and going to raves and coming back cured. Yes, you can have profound experiences that are important in a therapeutic way outside of a doctor’s office. But you’re not going to have it if you spent the whole time just partying. In that case you’re not engaging those [traumatic] memories.

Going beyond the acute effects

SB: Is this the same mechanism you believe could work to treat severe forms of autism?

GD: Before we can dive in on the human trials for autism, we kind of want to get a little bit more information about autism. One of the things that happened when I was a graduate student is that, my graduate advisor Mark Bear and I, we put forward this theory that if you turn down the signaling of a specific glutamate receptor [mGluR5], it balances out the exaggerated protein synthesis observed in autism.2 This theory had a lot of enthusiasm and excitement and seemed to be validated by animal research that was replicated by twenty-eight other labs. After those preclinical animal studies got so much press, the big pharmaceutical companies jumped on board and they thought they were going to cure autism with this mGluR modification. And then the clinical trials failed, and it was a big disappointment for the whole field of translational neuroscience. It was devastating because we all thought it was going to work, and then it didn’t. So in trying to think about why it didn’t work, there were a lot of different possible explanations. But I think it’s that every single one of the animal studies was carried out either from genesis [doing the manipulation genetically so they were born with the modified gene] or they were given [the modification] very early in development and just given it chronically for their whole lives. Whereas, in the human trials, the youngest recruited patients were sixteen years old, but most of them were adults—well past the age when their social critical period would be closed.

So, the idea that I would love to pursue is, well, maybe the reason that the clinical trials failed is because the mGluR therapy was right, but the critical period was closed. What we really needed to do is give a mGluR modulator, plus a psychedelic, to reopen the critical period. So that under the conditions of an open social critical period, the biochemical imbalance would be corrected and then you would get therapeutic efficacy.

SB: Would open state engram modification be a lasting treatment for these diseases? How long did the effect last for the mice in your study?

GD: Yeah, actually, I think that’s the second most important thing that we found in this study: Every other study trying to figure out the mechanisms of this has really focused on the acute effects of the drugs. And what we found is that after MDMA, the critical period starts to open about six hours after the acute dose. And then it kind of peaks out at 40 hours and stays up for at least two weeks, and then by a month it comes back down. So just to kind of put that into perspective, two weeks in a mouse is probably more like two months in a human.

I think that also informs how we might want to be doing these clinical trials. Rather than having the MDMA-assisted psychotherapy and then sending them home with a journal and some happy thoughts, what we really ought to be saying is that the therapeutic window here is actually for weeks, if not months after the acute psychedelic effects have worn off. We need to treat that period of time as precious and really make there be a lot of intensive focus and therapeutic activity happening during that window rather than just kind of setting them off and letting them be on their own.

Where therapy meets big pharma

SB: In what other ways could these findings influence treatment models?

GD: This speaks to a debate that’s going on right now in psychedelic therapy. The pharmaceutical companies are really wedded to this idea that if we can understand the mechanisms of these drugs, on a pharmacological level, then eventually we can design a drug that activates whatever mechanism is curing depression or PTSD or whatever it is, and then we can design out all of those nasty psychedelic side effects. The psychedelic journey can be gone, right? Like, that’s their dream.

And then you have on the other side the psychologists, who say, “No, that can’t be right because we know that we can achieve these psychedelic therapeutic effects even without the drug, as long as we can get them to this mystical place. We can do it with meditation, we can do it with a little bit of breath work, etc. And furthermore, the strength of that mystical experience correlates with the strength of the therapeutic effects.”

So these are the two sides of the debate. And I think our finding about the setting dependence of psychedelics in opening the critical period kind of offers a middle ground between these two worldviews. What it says is that the binding of the drug to the receptor opens a critical period—that’s the pharmacological effect that the drug companies have been so furiously searching for. Our hypothesis is that that is the mechanism. Any drug or any manipulation that can reopen the critical period has the potential for that therapeutic effect. But then on top of that, the setting dependence of it means to me that what the psychedelic journey is doing and the setting is doing is priming the brain so that the right memory and the right circuit is being brought into reactivation or made available for modification in this open state.

It’s a middle ground between these two different views of how the [drug] is working. And I think it really says, mechanistically when we are evaluating a potential hypothesis or a new compound or a new way of doing these clinical trials, we need to address this issue of “are we opening the critical period and are we effectively triggering the relevant engram?” Because if we’re not doing either of those things, it’s not going to work.

Future Directions

It remains to be seen whether critical period reopening will become a deliberate aim of psychedelic therapies, especially as other labs begin to claim therapeutic efficacy with trip-less synthetic versions3 of psychedelic drugs. Regardless, there appears to be significant, untapped therapeutic potential to be explored in the months following standard psychedelic treatment. In the case of PTSD, this window could prove invaluable. In the case of autism, which is not universally considered a disease, the conversation is more complex. While the notion of “curing” autism has been and should be challenged, for example by questioning the ethics of fundamentally changing core aspects of an individual’s personality, Dölen’s work stands as a pivotal contribution to the field for those who might seek treatment.


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1.       Nardou, R., Lewis, E., Rothhaas, R., Xu, R., Yang, A., Boyden, E. and Dölen, G., 2019. Oxytocin-dependent reopening of a social reward learning critical period with MDMA. Nature, 569(7754), pp.116-120.

2.       Dölen, G. and Bear, M., 2009. Fragile x syndrome and autism: from disease model to therapeutic targets. Journal of Neurodevelopmental Disorders, 1(2), pp.133-140.

3.       Cameron LP, Tombari RJ, Lu J, Pell AJ, Hurley ZQ, Ehinger Y, et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature. 2020;589(7842):474–9.

 machine therapist filtered  machine therapist filtered

Would You Talk to a Machine Therapist?

  • Blog
  • Science
  • Perspective
  • 3 minutes
December 11, 2020

Professor of Psychiatry

Prof. Dr. Gerhard Gründer is head of the Molecular Neuroimaging Department at the Central Institute of Mental Health, Mannheim.

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In my recent blog post, I reported on the optimistic view that “digital phenotyping” with smartphone technology would improve psychiatric diagnosis and possibly even treatment. Building on this, I discussed general advancements towards including big data in psychiatry. Another important aspect of the digitization of psychiatry is the development of machine therapists in mental health care, working with artificial intelligence. Adam Miner and colleagues from Stanford University give a brief overview of the current status in their article “Talking to machines about personal mental health problems”.1

Machine therapists that communicate with patients are already in use in the USA and in China. These “conversational agents” are called “Gabby” or “Ellie”. They perform psychiatric interviews and might even someday be able to perform formal psychotherapy. Miner and colleagues are optimistic about the potential usefulness of conversational agents. “Optimism is growing that conversational agents can now be deployed in mental health to automate some aspects of clinical assessment and treatment.”1 According to them, “Some data suggests that people respond to them as though they are human.”1 This could be helpful, “especially to improve access for underserved populations.”1 And interestingly, one study suggests that people who know that they are talking to a computer are more willing to open up.

Miner et al. further state: “The bridge from human responses and machine responses has already been crossed in ways that are not always made clear to users. Chinese citizens engage in intimate conversations with a text-based conversational agent named Xiaoice.”1 The authors admit, however, that conversational agents have not been evaluated in clinical trials and that they might not only be ineffective, but also cause harm. Additional future problems with the technology might be issues of confidentiality. Does a machine therapist have to be as secretive as a human?

Furthermore, most of the current technology seems to be based on text communication, meaning it is based on semantics. Communication in psychiatry, by contrast, is highly contextual. Empathy cannot be coded in words.

While we once believed that psychiatry is the most human medical specialty, scientists now seem to believe that this is the first specialty that will be replaced by computers. Would you talk to a machine therapist about your emotions, your conflicts, your desires?

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  1. Miner AS, Milstein A, Hancock JT. Talking to Machines About Personal Mental Health Problems. JAMA. 2017;318(13):1217-8. doi:10.1001/jama.2017.14151
 psychedelic research articles  psychedelic research articles

The Psychedelic Compendium

A New Resource for Research on Psychedelics
From the ASC Study Monitor

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  • Science
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  • 3 minutes
December 1, 2020

Research & Knowledge Exchange Associate, Resources Manager

Jagoda runs the ASC Study Monitor, a database of publications in the psychedelic research area.

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The Psychedelic Compendium is a series of curated lists of research articles introducing specific topics in a nutshell. Since psychedelic research is a rapidly growing field and new articles are published almost daily, we understand that it might be overwhelming to skim through a multitude of publications searching for the right one. To make it easier to find relevant research, we are introducing lists of article recommendations carefully selected by our team.  

Comprised of both open and closed access articles, our lists of recommended readings aim to lay the foundations for understanding distinct aspects of psychedelic research. Starting from basic overviews and then diving deeper into specific research perspectives, the lists highlight the most important publications in the field.  

To make the lists a handy tool for not only researchers and professionals but also journalists and the general public, we will provide a brief summary of each article. We believe that bridging the information flow between academia and society will significantly benefit both parties. High quality research combined with clear channels of communication with the public will facilitate responsible policy making and therefore result in sustainable development of the relations between science, governments, and the population. 

This post will be continually updated – stay tuned for the incoming recommendation lists! 


1. Recommended Readings for Psychedelic Novices

These ten articles will give you a solid foundation to start your psychedelic research journey. You will gain an overview of state-of-the-art of psychedelic research, the history of psychedelic exploration, the many applications of psychedelic substances in various fields, and most importantly, their therapeutic potential. 


2. Recommended Readings Introducing Psychedelic-Assisted Therapy

Psychedelic-assisted therapy has the potential to help improve global mental health. In this list, we will introduce the history and current state of the research on psychedelic-assisted therapy, as well as challenges and future perspectives. 


3. Recommended Readings on Psychedelics for the Treatment of Depression

Psychedelics offer a new avenue in the treatment of mood disorders. In this list, we will explore the advantages of psychedelics over mainstream antidepressants and summarize essential studies investigating the potential of psychedelics in the treatment of depression and anxiety. 


4. Recommended Readings – Serotonin Receptors

This list of recommended readings explores the diversity among serotonin receptors, the history of their discovery, their relations with psychedelics, and their mechanisms of mediating subjective experiences and therapeutic effects.


5. Recommended Readings – Psilocybin

In this list, we focus on general press articles about psilocybin research and therapy that were published mainly in larger international newspaper outlets.


6. Recommended Readings – Top 2020

This list of Top 10 Articles of 2020 will discuss a ground-breaking trial with psilocybin for major depressive disorder, long-term outcomes of MDMA-assisted psychotherapy for PTSD, how psychedelics work in the brain, and how to produce psychedelics at a larger scale.


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 big data psychiatry filtered  big data psychiatry filtered

Big Data in Psychiatry Brave New World?

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  • 4 minutes
November 27, 2020

Professor of Psychiatry

Prof. Dr. Gerhard Gründer is head of the Molecular Neuroimaging Department at the Central Institute of Mental Health, Mannheim.

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Every day in the press, but also in the medical literature, the promises of “Big Data,” “Precision Medicine,” and “Machine Learning” for medicine can be found. These proclamations usually begin with sentences such as: “Mental health (including substance abuse) is the fifth greatest contributor to the global burden of disease, with an economic cost of $ 2.5 trillion in 2010, and expected to double by 2030.”1

And then these articles point to the sheer endless possibilities for digitization in medicine. “Big Data” is praised as the solution to all problems in psychiatry: it would supposedly improve not only early detection of mental disorders, but also therapy. These promises sound heavenly: “The emerging field of ‘predictive analytics in mental health’ has recently generated tremendous interest with the bold promise to revolutionize clinical practice in psychiatry.”2 Does anyone really believe that? And more importantly, do we want that?

In my recent blog post “Does Your Phone Know You Better Than Your Therapist?“, I described what “digital phenotyping” means and what great expectations are associated with it. I have also expressed my skepticism. “Big Data” in psychiatry goes beyond that. It purports to infer our state of mind from the pictures we post on Facebook or Instagram. Initial studies have already been published in which an algorithm diagnosed “depression” or “post-traumatic stress disorder” based on Instagram photos or Twitter posts, sometimes long before a clinical diagnosis was made. Very soon, machines should be able to analyze speech in order to derive diagnoses like depression or incipient dementia. There are also claims that the kind of music we hear could allow conclusions about our emotional state. Some hope in all seriousness that by analyzing the troves of data collected about us – and these are not only our digital data traces, but also biological data like genes, epigenetic patterns, hormones, values, and anything which one can “measure” – mental illnesses can be “discovered” so early that they do not even occur anymore.

If you want an idea of what this vision might mean, watch Steven Spielberg’s great film “Minority Report”, in which crimes are prevented before they are even committed. But the future vision of “Big Data Psychiatry” goes far beyond that, and it raises many questions. Who will make a medical diagnosis in the future? A doctor? Or the machines from Google and Apple? And if the data collectors have found evidence that I’m suffering from depression, who will be informed? A public health system? A higher „authority for mental health“? Will I be contacted by this authority for treatment? And if I do not want that, will I be „monitored“ to prevent my possible suicide? What happens to someone whose data suggests he will be diagnosed with psychosis at 90% certainty in the next six months? And if we believe – as some actually do, seeing humans as deterministic biological machines – that this occurs with 100% certainty, then what? Do we treat them prophylactically? Do we even have a right to warn them?

Who will define what is “normal”? When is a “depression” in need of treatment when a machine makes the “diagnosis”? In a thoughtful article, Manrai, Patel (both Harvard University) and Ioannidis (Stanford University) recently asked the question, “In the Era of Precision Medicine and Big Data, Who Is Normal?”3 The concept of the Research Domain Criteria (RDoC), a dimensional framework for the integrative research of mental (dys)function across different levels of information and organization, also suggests that in the future – though this may be a bit exaggerated – one no longer treats the suffering person, but the disturbed brain function. Will there be cut-off values, as is usual in laboratory settings, outside of which one should advise treatment?

Finally, emotions like depression, fear, or despair have their evolutionary meaning. Especially Western industrialized societies tend to regard these as unwanted and want to turn them off at any cost. I am convinced that this is one reason why the use (or perhaps better – consumption?) of antidepressants has increased dramatically in the last twenty years and continues to increase each year. Have we become healthier? The answer can be found in the first paragraph of this post. Big data psychiatry is the answer to social developments. Yet it causes many people at least as much discomfort as these developments themselves.

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  1. Conway M, O’Connor D. Social Media, Big Data, and Mental Health: Current Advances and Ethical Implications. Curr Opin Psychol. 2016;9:77-82. doi:10.1016/j.copsyc.2016.01.004 
  2. Hahn T, Nierenberg AA, Whitfield-Gabrieli S. Predictive analytics in mental health: applications, guidelines, challenges and perspectives. Molecular psychiatry. 2017;22(1); 37–43. https://doi.org/10.1038/mp.2016.201 
  3. Manrai AK, Patel CJ, Ioannidis JPA. In the Era of Precision Medicine and Big Data, Who Is Normal? JAMA. 2018;319(19):1981-2. doi:10.1001/jama.2018.2009 
 digital phenotyping filtered  digital phenotyping filtered

Does Your Phone Know You Better Than Your Therapist?

The Promise and Peril of Digital Phenotyping
  • Blog
  • Science
  • Perspective
  • 4 minutes
October 30, 2020

Professor of Psychiatry

Prof. Dr. Gerhard Gründer is head of the Molecular Neuroimaging Department at the Central Institute of Mental Health, Mannheim.

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In 2017, Tom Insel, the former director of the National Institute of Mental Health (NIMH) published a brief “viewpoint” article with the title “Digital Phenotyping – Technology for a New Science of Behavior” in the prestigious Journal of the American Medical Association (JAMA).1 Earlier in 2017, Insel left his former employer Alphabet (formerly Google) for the California-based Mindstrong Health, a company which, according to its website, is dedicated to “Transforming Brain Health: Better outcomes through measurement-based care.”

What exactly is “digital phenotyping”? This again is described on Mindstrong’s website:

“Digital phenotyping is the core of our measurement approach. Digital phenotyping is simply assessment based on smartphone use.  As smartphones have become ubiquitous, their increasing use provides an unprecedented opportunity to measure mood, cognition, and behavior – passively, objectively, and continuously.”

According to Insel, “even though smartphone technology promises to transform many aspects of health care, no area of medicine is likely to be changed more by this technology than psychiatry. Digital phenotyping is the term now used for describing this new approach to measuring behavior from smartphone sensors, keyboard interaction, and various features of voice and speech.”

Sachin Jain and colleagues give a typical example of the application in their influential article “The digital phenotype”, published in 2015: “For a bipolar patient whose mania is manifested in rapid, uninterruptible speech or hypergraphia, their disease could be characterized by the frequency, length and content of participation in social media. Through these varied applications, digital phenotypes can help ensure that early manifestations of disease do not go unnoticed and allow the healthcare system to develop more nimble, targeted and prompt interventions.”2

Insel further states that “over the past 4 decades, behavioral expertise, once the strength of psychiatry, has diminished in importance as psychiatric research focused on pharmacology, genomics, and neuroscience, and much of psychiatric practice has become a series of brief clinical interactions focused on medication management. In research settings, assigning a diagnosis from the Diagnostic and Statistical Manual of Mental Disorders has become a surrogate for behavioral observation. In practice, few clinicians measure emotion, cognition, or behavior with any standard, validated tools.”

Do we really believe all this? Can the complexities of human behavior, and even more so of psychiatric disorders, be depicted by traces we leave on our smartphones? When we do not have a consistent concept of “psychosis”, how can we believe that “semantic coherence from speech samples [is] a predictor of psychosis”? 1 When we have no way to explain the enormous heterogeneity of mood disorders, how can we believe that “variation in several sensor measures [are] a correlate of mood ratings”? 1

Looking back at his time at the NIMH, Insel admitted that in his 13 years as the director of the NIMH he doesn’t think they “moved the needle in reducing suicide, reducing hospitalizations, improving recovery for the tens of millions of people who have mental illness. I hold myself accountable for that.”3 Now, in the form of digital phenotyping, he presents an even more reductionist concept of psychiatric disorders than the one that is expressed in the Research Domain Criteria (RDoC) of the NIMH, a dimensional framework supporting the integrative research of mental (dys)function across different levels of information and organization.

Insel concludes: “After 40 years of psychiatry becoming more mindless than brainless, perhaps digital phenotyping will help the pendulum swing back toward a fresh look at behavior, cognition, and mood. It has been said that new directions in science are launched by new tools much more often than new concepts. In this case, a tool that is inexpensive and ubiquitous may change the direction of the field.”1

My personal belief is that “digital phenotyping” might be an interesting tool to better understand certain aspects of human behavior, but it is far from being able to “change the direction of the field”. Such a direction would not only be more mindless, but even more “human-less”.

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  1. Insel TR. Digital Phenotyping: Technology for a New Science of Behavior. JAMA. 2017;318(13):1215-6. doi:10.1001/jama.2017.11295
  2. Jain SH, Powers BW, Hawkins JB, Brownstein JS. The digital phenotype. National Biotechnology 2015;33(5):462-463. doi:10.1038/nbt.3223
  3. Rogers A. Star Neuroscientist Tom Insel Leaves the Google-Spawned Verily for … a Startup? WIRED [Internet]. 2017 Nov 5; Available from: https://www.wired.com/2017/05/star-neuroscientist-tom-insel-leaves-google-spawned-verily-startup/