A transdisciplinary exploration of synergies and crossroads in psychedelic research and therapy
Full schedule and Call for Speakers here.

Join us for a day on the integration of research across disciplines and practice, and explore with us innovative tools to solve some of the complex problems of today.

The uniMIND Symposium is a hybrid event that takes place online via Zoom and on-site at Maastricht University. Online participation is entirely free. On site tickets are limited and cost 10 Euros to refinance the event. Invitation links will be sent via mail to all registered guests.

Depending on the pandemic situation, we will start with a 50 person on site registration and may extend to a total of 150 guests. If you would like to join on site but are uncertain given the present conditions or if all seats are already booked, please register for online participation and check yes at “Add me to the waiting list”.

Concerning on site participation, the local Covid 19-protection rules apply. We’ll keep you updated with any changes.

On-site and online registration are possible:

To attend online, please register via THIS FORM.

For on-site registration, please buy your tickets below. Any money generated through ticket sales or donations will be used exclusively to refinance the event. Please consider donating to help us promote young talents in psychedelic research.


Join us for the third uniMIND Central Session with James B. Close and Julia Bornemann to discuss their research article Co-design of Guidance for Patient and Public Involvement in Psychedelic Research, Front. Psychiatry, 30 September 2021.


The uniMIND Program

uniMIND is the MIND Foundation’s international journal club network. With more than 25 groups at universities worldwide, uniMIND provides a well-connected platform for intellectual exchange and mutual academic support in the field of psychedelic research. To learn more about uniMIND, to join or start a group, visit our uniMIND page.

We also recommend connecting to our uniMIND community on the MIND Community Platform. Here we schedule events, discuss feedback and ideas, and more.


uniMIND Central Sessions

Monthly web-based journal club meetings, open to everyone in and around the uniMIND community. We invite academic authors to discuss their very own publications with us.

For every session, there will be one selected text that we share here in the event description. Please make sure to read the article in advance, prepare questions and feedback. Having the authors present at our sessions can be a huge benefit in your understanding of the text and its context.

The uniMIND Central Sessions discussion format is a semi-structured conversational exchange. It is facilitated by the session host and open to input and questions from guests at any given time.

Download the Article here

Exploring structures and processes emerging around psychedelic research

Join us for a day on the integration of research across disciplines and practice, and explore with us innovative tools to solve some of the complex problems of today.

The event is all-free and will take place via Zoom. Invitation links will be sent via mail to all registered guests (RSVP below).



Full schedule and Call for Speakers here.

Link to join Webinar



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
mars 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.

View full profile ››

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.

Our work at MIND relies on donations from people like you.

If you share our vision and want to support psychedelic research and education, we are grateful for any amount you can give.

  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

Inte I Ditt Tredje Öga

Vad Gör DMT i hjärnan?

Översatt av Evana López redigerad av Esther Björk

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

Disclaimer: This blog post has been translated and reviewed by volunteers. The contributors do not represent the MIND Foundation. If you find mistakes or inconsistencies, or if something in the translation seems unclear, please let us know – we are thankful for any improvements. (mailto:[email protected]) If you want to help our multilingual project, please contact us to join the MIND Blog Translation Group!

Finns det DMT i hjärnan? Vad har det för funktion där? Dessa frågor har funnits hos forskare av psykedelia i årtionden och det har visat sig vara en svår uppgift att försöka besvara dem. Ny forskning går bortom försöken att bevisa de romantiserade idéerna som menar att DMT frigörs från epifysen under nära-döden-erfarenheter. Genom att se på enskilda neuroner indikerar den här forskningen att DMT kan ha rollen av en icke-kanonisk neurotransmittor som är med och skyddar hjärnan från fysisk och psykologisk stress. Ett tema som uppstår inom forskningen uppdaterar nu den ursprungliga frågan till: tänk om DMT är naturligt neuroprotektiv?


Neurotransmittorer är små molekyler som frigörs i nervsystemet för att förmedla information mellan olika neuroner. Många av dem — serotonin, dopamin och adrenalin, för att nämna ett par stycken — tillhör den kemiska gruppen som kallas monoaminer. Den mest potenta naturligt förekommande psykedelian, N,N-dimetyltryptamin (DMT), tillhör samma grupp av molekyler. Spårmängder av DMT kan hittas i djurs nervsystem (inklusive i däggdjur), men det har inte blivit direkt bevisat att det där agerar som en endogen neurotransmittor.1 Det finns dock en vanligare och mer utbredd förståelse om dess funktion hos växter, där det kan hjälpa vissa arter att försvara sig mot växtätande djur.2

Människor har extraherat DMT från växter i århundraden. Det är inte aktivt vid oralt intag på grund av att det innehåller monoaminoxidas (MAO), ett enzym som degraderar DMT och som finns i människans matsmältningssystem. Shamaner från Amazonas har dock i århundraden haft kunskap om hur de kringgår det här problemet, nämligen genom att kombinera DMT-innehållande vin med växter som innehåller MAOIs, monoaminoxidasinhibitorer, som stoppar nedbrytningen av DMT. Resultatet av den här mixturen blir den psykedeliska brygden känd som ayahuasca, vilket kommer från ordet ”aya” (betyder själ) och waska (vin).3

Ayahuasca är starkt sammanflätat med mytologin och spiritualiteten hos sydamerikanska nativa stammar. Likväl När DMT sedan kom in i det västerländska medvetandet fann det sig därför lätt en plats inom litteraturen och filosofin. Dess biologiska egenskaper har även lockat till sig forskare ända sedan första syntesen år 1931. På grund av att DMT liknar serotonin är det frestande att tänka sig att det kan förekomma naturligt som en neurotransmittor i den mänskliga kroppen. Men var skulle en sådan egendomlig neurotransmittor då kunna hittas? En populär gissning, där det lånas koncept både från vetenskap och mytologi, placerar DMT i epifysen.

Den primära rollen hos epifysen är att reglera sömnmönster genom att producera melatonin. Men denna ärtstora struktur som hittas i framhjärnan har en historia som är mycket mer romantisk än så. I forna Egypten, representerade det ögat av himmelsguden Horus, medan det i Indien har varit associerat med det ”tredje ögat”, en mytomspunnen ingång till ett högre medvetande. Ett modernt förkroppsligande av dessa historier kommer från ”DMT: The Spirit Molecule”, en bok i vilken författaren och psykiatern Rick Strassman, MD, postulerar att stora mängder av DMT frigörs i en döende hjärna, vilket då möjliggör övergången av medvetande från ett liv till ett annat.4


Sedan början av Strassmans teori har närvaron och syftet med DMT i epifysen haft huvudrollen i en het debatt. Även om det fortfarande inte har blivit direkt isolerad från mänskliga hjärnor har experiment hos både människor och råttor visat att deras hjärnor — inklusive epifysen — innehåller enzym som är nödvändiga för syntes av DMT.1

DMTs potentiella inblandning i nära-döden-erfarenheter är svår att både bevisa eller motbevisa hos människor, men försök har gjorts hos råttor. Forskning har då visat att råttors hjärnor innehåller DMT och att koncentrationen ökar som en följd av inducerat hjärtstopp.1,5 Skulle det kunna betyda att dessa labbråttor har genomgått en nära-döden-upplevelse? Är denna upplevelse medierad av DMT, eller är DMT bara en metabolisk restprodukt från en stressad organism?

Experimentella resultat erbjuder oss en begränsad insikt. Om något skulle DMT också bara kunna vara en del av en ordentlig storm av neurotransmittorer (inklusive serotonin, dopamin och noradrenalin) som släpps fria som svar på den svåra stressen vid hjärtstopp.1 Dessutom, även om koncentrationen av DMT nu ökade var det inte möjligt att säkert kunna avgöra om ökningen skulle motsvara en exogen psykedelisk dos. Medan vissa forskare tror att just det är fallet finns det andra som menar att vi saknar kunskap både om hur stor fysiologisk mängd av endogent DMT som kan lagras och släppas ut vid ett tillfälle,6 samt om vilken biologisk reaktion ett sådant utsläpp skulle kunna utlösa. Nuvarande vetenskaplig kunskap saknar de slutgiltiga bevis som behövs för att direkt kunna placera DMT i nära-döden-upplevelser, nämligen en väl karaktäriserad biokemisk mekanism.


Ett svar som besvarar alla frågor är sällsynt inom biologin. Neurotransmittorer och psykedeliska föreningar verkar båda på flera olika hjärnregioner, interagerar med olika receptorer med varierande specificitet och sätter igång ett brett spektrum av biokemiska och genetiskt signalerande kaskader. DMT är inte annorlunda i det avseendet, och medan det till en början ansågs ha sin främsta effekt via serotonin-2A-receptorerna har nya måltavlor nu hittats. En av dessa, sigma-1-receptorn (Sig1R), är inte hela lösningen i DMT-pusslet, men kan trots det tillhandahålla flera intressanta pusselbitar.

Sig1R är ovanlig. Dess ursprung är ett mysterium och i evolutionära termer är det närmare besläktat med ett svampenzym vid namn sterolisomeras än med någon annan däggdjursreceptor för neurotransmittorer.7 Forskare är osäkra på hur de ska tolka detta fynd, speciellt med tanke på att detta särskilda svampenzym först isolerades från en svamp som producerar alkaloider som liknar LSD.

Medan många receptorer specialiserar sig på att förmedla signaler från neurotransmittorer antingen direkt på cellmembranet, inuti cellen eller inuti kärnan, är Sig1R ovanlig då den gör alla tre av dessa saker. På membranet kan det interagera med andra receptorer för neurotransmittorer och ändra deras funktion genom att forma komplex med dem. När den sedan är inuti cellen kan den binda antistressproteiner och hjälpa dem att utföra sina funktioner.8 Inuti kärnan rekryterar den andra proteiner som binder till DNA och aktiverar eller deaktiverar olika gener via epigenetiska mekanismer. 9

Denna multifunktionella receptor är känd som en ”föräldralös”, vilket betyder att forskare ännu inte har identifierat dess huvudsakliga aktiverande neurotransmittor. Det föreslogs först att Sig1E skulle kunna vara en subtyp av en opioidreceptor, men forskare fann senare andra föreningar som också kunde binda till den, inklusive kokain och könshormonet progesteron.10 Nyligen har bevis uppkommit som stödjer spekulationer att DMT skulle kunna aktivera denna receptor.

Den första indikationen att detta skulle vara fallet kom från forskning i cellkultur, där det visades att DMT kunde binda till Sig1R. Forskning på möss expanderade fyndet ytterligare och visade att musbeteende under påverkan av DMT inte förändrades när serotonin- och dopaminreceptorer var blockerade. Men efter att mössens Sig1R hade blivit deaktiverade, slutade mössen att reagera på DMT. Dessa resultat har lett forskare till att dra slutsatsen att Sig1R är en av DMTs huvudsakliga måltavlor.11 En annan ledtråd kommer från det faktum att hos synapserna som kopplar ihop olika neuron, är Sig1R lokaliserad nära ett enzym som är inblandat i DMTs syntes. Detta fick en del forskare att undra över om det snarare var Sig1R än 5HT-2A, som var den huvudsakliga medlaren av DMTs psykedeliska effekt.


Vad händer i cellen när DMT aktiverar Sig1R? Vissa av dessa svar kommer från forskningen av cellkultur. Nyligen utförda studier har funnit en roll för DMT i både immunförsvaret och antistress-svar hos enskilda mänskliga celler. I immunceller har DMT visat kunna aktivera en produktion av antiinflammatoriska molekyler.13

 I en liknande studie har mänskliga neuroner i cellkultur blivit utsatta för syrebrist. Neuroner dör snabbt när de inte har tillgång till tillräckligt med syre, men med behandling med DMT och den efterföljande aktiveringen av Sig1R, visade sig flera av neuronen kunna överleva.14 Detta fynd ger en koppling tillbaka till Rick Strassman: om DMT hjälper stressade celler, skulle det då också kunna hjälpa hela organismer i ett stresstillstånd — när de befinner sig nära döden och i svår syrebrist? Även om det är frestande att spekulera kring detta är det också viktigt att ha i åtanke att neuroner i hjärnan fungerar på ett komplext och kontextberoende sätt. Genom att observera individuella neuroner i kultur upptäcker forskare vad det är som händer inuti dem, men det säger väldigt lite om hur de interagerar med varandra i en levande, tredimensionell hjärna.

För närvarande har denna klyfta ännu inte blivit överbryggad. Forskare har inte testat aktiviteten hos Sig1R i intakta hjärnor som utsätts för hypoxi eller andra typer av fysiologisk stress. I en döende hjärna kan DMT kanske hjälpa neuroner att överleva — men enbart överlevnad säger oss ingenting om vad dessa neuroner gör eller hur deras aktivitet skulle kunna skapa de visioner som är karaktäristiska för nära-döden-upplevelser. I avsaknad av direkta bevis kan vi ta ledtrådarna från studier med hjärnavbildning och försöka koppla dem samman med redan kända Sig1R-mekanismer.

Genom att observera människors hjärnor under påverkan av DMT och ayahuasca har forskare kunnat se en ökad aktivitet i såväl de visuella och auditiva centra i hjärna, likväl som i regioner relaterade till minne. Dessa inkluderar centra för perception och bearbetning av negativa känslor och sorgliga minnen, centra för inhämtande av nya minnen, och amygdala (en hjärnregion som ofta associeras med social och emotionell bearbetning, inklusive rädsla, ångest och aggressivitet). 15,16

Dr. Antonio Inserra, en forskare från Flinders University i Adelaide, gjorde ett försök att förena de molekylära perspektiven med ett helhetsperspektiv av hjärnan och formulerade en intressant hypotes kring de roller som Sig1R skulle kunna ha i dessa hjärnaktiviteter.7 Hans analys fokuserade specifikt på den roll som DMT har i bearbetning av trauma — ett fenomen som fångade hans intresse efter att ha tagit del av de anekdotiska reporter från PTSD-patienter, vars symptom minskade efter ayahuasca sessioner. Han spekulerade kring att Sig1R skulle kunna forma komplex ihop med andra receptorer och öka signaltransmissionen och synapsplasticiteten i minnescentra, vilket kan underlätta i processen att återfå och återbearbeta traumatiska minnen. Han påpekar dessutom att Sig1R agerar som en epigenetisk regulator inuti kärnan,9 vilket innebär att det rekryterar enzym som binder olika slags etiketter på DNA och histoner (de protein som DNA är lindade kring i en cell) för att kunna aktivera och avaktivera gener. Det har länge varit etablerat att epigenetiska mekanismer har en viktig roll i alla aspekter av skapande av minnen och ommodellering. På grund av detta föreslår Inserra att vissa av de mekanismer som ayahuasca behandlar trauma på kan vara medierade av Sig1R epigenetik i hjärnans minnescentra.


I en ny studie från Dr. Simon Ruffell, en forskningsassistent på King’s College London, kopplas DMT, Sig1R och epigenetisk reglering också ihop. Hans team, som övervakas av Professor Celia Morgan (University of Exeter), följde med deltagare i ayahuascaceremonier i Amazonas för att undersöka hur dessa erfarenheter påverkade deras traumatiska minnen. Deltagarna rapporterade signifikanta och långvariga minskningar avseende depression, ångest och generell olycka. För att ta reda på varför, samlade Ruffells team in salivprov från deltagarna och analyserade ändringarna i epigenetiska etiketter i deras DNA. De upptäckte då att Sig1R-genen var epigenetiskt förändrad hos en del av deltagarna (ej publicerade resultat som presenterades på ICPR2020-konferensen). Eftersom vi vet att receptorn själv är involverad i epigenetisk modulering skulle detta kunna vara början av en ny förståelse. Vilka andra gener kan vi se bli epigenetiskt modifierade efter ayahuascasessioner? Ruffells epigenetiska forskning skulle kunna erbjuda fler ledtrådar, inte bara om hur DMT arbetar ihop med Sig1R på en epigenetisk nivå, utan också allmänt om epigenetiken hos minnen. Oavsett vilka andra resultat studien för med sig är den redan en viktig brygga mellan laboratoriska fynd och ceremonien; mellan cellen, hjärnan och själva upplevelsen.

Det nuvarande tillståndet hos forskningen av DMT liknar osammanhängande pusselbitar. Medan det finns flera indikatorer som tyder på att det skulle kunna finnas naturligt förekommande DMT i den mänskliga hjärnan, förblir dess lokalisation och funktioner svårfångade. Mer data är tillgängligt kring hur ayahuasca och exogent DMT fungerar, både inuti cellen och i hjärnan, men vi kan ännu inte utifrån dessa fynd rättfärdiga en härledning av hur endogent DMT fungerar.

Trots detta har en mängd av spekulativa teorier nyligen uppkommit. Medan vissa forskare fokuserar på DMTs potentiella antiinflammatoriska och neuroskyddande roller, ser andra på hjärnavbildning och traumastudier och pekar på dess möjliga effekter på minnesremodellering. Båda teorier kan bevisas vara riktiga och båda kan bli placerad i kontexten av Rick Straussmans teori om att DMT närvarar i mänskliga hjärnor för att lindra effekterna av massiv fysiologisk stress, som sådan hos neuroner med syrebrist under nära-döden-erfarenheter. Kan det vara så att den döende hjärnan släpper ut endogent DMT för att hålla sig själv levande så länge som möjligt? Om så är fallet, skulle de vanliga karaktäristiska rapporterna om nära-döden-upplevelser — inklusive visioner och att ens liv ”passerar revy” — lätt kunna vara sidoeffekter. I de fall som rör sig om neuronöverlevnad och bearbetning av minnen tyder forskning hittills på att en multifunktionell, mystisk Sig1R innehar en nyckelroll i dessa processer.

Även om de invecklade molekylära mekanismerna ännu inte har blivit fullständigt beskrivna är den multifunktionella Sig1R nu ordentligt etablerad som en måltavla för DMT, vilket öppnar upp för nya undersökningsområden. Kanske kommer den mest intressanta nya forskningen att inkludera undersökningar om hur DMT och Sig1R påverkar epigenetisk reglering. Information om vilka gener de aktiverar eller inaktiverar skulle kunna placera fynden från forskning av cellkultur i en kontext som rör hela organismer. Epigenetiska mekanismer ligger i själva grunden av vår dynamiska interaktion med världen och med våra egna sinnen. Genom att förstå hur dessa mekanismer hjälper till att lagra och ommodellera minnen kan det hjälpa oss formulera en sammanhängande biologisk modell för de terapeutiska effekter som kan fås från psykedeliska erfarenheter.

Our work at MIND relies on donations from people like you.

If you share our vision and want to support psychedelic research and education, we are grateful for any amount you can give.

  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
  • Interview
  • 14 minutes
januari 26, 2021

Associate Professor of Neuroscience

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

View full profile ››

“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.


Our work at MIND relies on donations from people like you.

If you share our vision and want to support psychedelic research and education, we are grateful for any amount you can give.


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

View full profile ››

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?

Our work at MIND relies on donations from people like you.

If you share our vision and want to support psychedelic research and education, we are grateful for any amount you can give.

  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

This post is also available in:


  • Blog
  • Science
  • News
  • 3 minutes
december 1, 2020

Research & Knowledge Exchange Associate, Resources Manager

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

View full profile ››

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.


7. Recommended Readings – Ketamine

This selection of research articles on ketamine for mental health will explore its promise in treating not only depression but also the positive effects on suicidal ideation, addiction, and further symptoms of mental health disorders.


8. Recommended Readings – Ketamine

This list presents press articles discussing the therapeutic use of ketamine in mental health treatments and its potential modes of action.


Our work at MIND relies on donations from people like you.

If you share our vision and want to support psychedelic research and education, we are grateful for any amount you can give.