A transdisciplinary exploration of synergies and crossroads in psychedelic research and therapy

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 online via Zoom and on-site at Maastricht University. Invitation links will be sent via mail to all registered guests (RSVP below).

 

 

Full schedule and Call for Speakers 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).

With

and

Full schedule and Call for Speakers here.

Link to join Webinar

https://us02web.zoom.us/j/89167259444

 

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
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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.

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References
  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.

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En dehors de votre troisième œil

Qu’est-ce que la DMT fait dans le cerveau ?

Traduit par Alice Krahenbuhl, édité par Anastasie Manon Lorance

  • Blog
  • Science
  • Essay
  • 10 minutes
février 4, 2021
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Disclaimer : la traduction de cet article a été rédigée et révisée par des bénévoles. Les contributeurs ne représentent pas la MIND Foundation. Si vous trouvez des erreurs ou des incohérences, ou si quelque chose dans la traduction ne semble pas clair, veuillez nous en informer – nous vous remercions pour toute amélioration. Si vous souhaitez aider avec vos compétences linguistiques, vous pouvez également utiliser le lien et rejoindre les traducteurs du blog!

Y a-t-il de la DMT dans le cerveau ? Que pourrait-elle bien y faire ? Répondre à ces questions présentes depuis des décennies dans l’esprit des chercheurs dans le domaine psychédélique, ne sera jamais simple. De nouvelles recherches vont au-delà de l’idée romantique sur la libération de la DMT par la glande pinéale au cours des expériences de mort imminentes. En examinant des neurones individuels, ces recherches indiquent que la DMT pourrait avoir un rôle en tant que neurotransmetteur non-canonique et serait impliquée dans la protection du cerveau contre le stress physique et psychologique. Un thème émerge alors de cette actualisation des connaissances scientifiques : Et si la DMT était naturellement neuroprotectrice ?

Intéressés par les dernières recherche sur les effets neuronaux de la DMT ? Renseignez vous sur notre conférence INSIGHT 2021 en septembre, qui inclut une coférence sur ce sujet, présentée par  Carla Pallavicini, Ph.D. et Christopher Timmermann, Ph.D.

De l’Amazonie à l’Occident puis de retour à l’Egypte Ancienne

Les neurotransmetteurs sont de petites molécules sécrétées dans le système nerveux afin de relayer les informations entre différents neurones. Beaucoup d’entre elles – la sérotonine, la dopamine et l’adrénaline pour ne citer qu’elles – appartiennent à la catégorie des monoamines. Le psychédélique naturel le plus puissant, la N,N-diméthyltryptamine (DMT), appartient également à cette famille de molécules. La DMT se retrouve en faible quantité dans le système nerveux des animaux (y compris celui des mammifères), mais nous n’avons pas de preuve directe qu’elle y agisse en tant que neurotransmetteur endogène.1 Elle est plus commune et mieux comprise chez les plantes, où elle aide à défendre certaines espèces contre les herbivores.2

Depuis des siècles, les êtres humains ont extrait la DMT des plantes. Elle est inactive lorsque prise oralement en raison de la présence de monoamine oxydase (MAO), une enzyme qui dégrade la DMT, dans le système digestif humain. Depuis des siècles, les chamans d’Amazonie savent comment contourner cet effet en combinant une vigne contenant de la DMT avec des plantes contenant des IMAOs, ou inhibiteurs de la monoamine oxydase, qui vont empêcher la dégradation de la DMT. La boisson psychédélique résultant de cette mixture est connue en tant qu’ayahuasca, de aya (l’esprit) et wasca (la vigne).3

L’ayahuasca est indissociable de la mythogenèse et de la spiritualité des tribus indigènes Sud-Américaines. De même, lorsque la DMT entra dans la conscience occidentale, elle trouva rapidement sa place dans les champs littéraires et philosophiques. Ses propriétés biologiques ont également intrigué les scientifiques depuis sa première synthèse en 1931. De par sa ressemblance à la sérotonine, il était tentant de faire l’hypothèse qu’elle serait un neurotransmetteur naturellement produit dans le corps humain. Où pourrait bien se trouver un neurotransmetteur si particulier ? La conjecture populaire, empruntant à la fois des concepts scientifiques et mythologiques, l’a alors située dans la glande pinéale.

Le rôle principal de la glande pinéale est de réguler le sommeil en produisant la mélatonine. Pourtant l’histoire de cette structure du cerveau antérieur et de la taille d’un petit pois est bien plus extraordinaire. En Egypte Ancienne, elle représentait l’œil du dieu du ciel Horus alors qu’en Inde, elle était associée au « troisième œil », une porte mythique vers une conscience supérieure. Une incarnation plus moderne de ces histoires provient du livre DMT : La Molécule de l’Esprit, dans lequel l’auteur et psychiatre Rick Strassman, postule que de grandes quantités de DMT pourraient être sécrétées dans le cerveau mourant, permettant la transition de la conscience d’une vie à la suivante.4

La vie et la mort

 Depuis l’avènement de la théorie de Strassman, la présence et le rôle de la DMT dans la glande pinéale ont fait l’objet de débats animés. Bien que la DMT n’ait pas encore été isolée directement du cerveau humain, des expériences sur le cerveau d’hommes et de rats démontrent que celui-ci – glande pinéale comprise – contient les enzymes nécessaires pour la synthétiser.1

L’implication potentielle de la DMT dans les expériences de mort imminente est difficile à prouver ou à réfuter chez l’Homme mais des tentatives ont été faites chez le rat. Des recherches ont montré que le cerveau des rats contient de la DMT et que sa concentration augmente après induction d’arrêts cardiaques.1,5 Cela signifierait-il que ces rats de laboratoires ont vécu une expérience de mort imminente ? Cette expérience serait-elle attribuable à la DMT, ou cette dernière ne serait-elle simplement qu’un déchet métabolique produit lorsqu’un organisme est stressé ?

Les résultats expérimentaux offrent un aperçu limité. En fait, la DMT pourrait n’être qu’une partie de la tempête de neurotransmetteurs (incluant la sérotonine, la dopamine et la noradrénaline) émise en réponse au stress sévère d’un arrêt cardiaque1. De plus, même si la concentration de DMT augmente, il reste impossible de déterminer si cette augmentation correspond à une dose exogène de psychédélique. Alors que certains chercheurs pensent que tel est le cas, d’autres soulignent que nous ne savons ni comment de faibles quantités de DMT endogènes seraient stockées et libérées en masse,6 ni ce que cette libération déclencherait comme réaction biologique. L’état actuel des connaissances scientifiques manque encore de preuves nécessaires pour impliquer directement la DMT dans les expériences de mort imminente s: un mécanisme biochimique bien caractérisé.

La preuve flagrante

Les solutions toutes faites sont rares en biologie. Les neurotransmetteurs, aussi bien que les substances psychédéliques, agissent sur plusieurs régions cérébrales, interagissent avec différents récepteurs avec une spécificité variable et déclenchent un large spectre de cascades de signalisation biochimiques et génétiques. La DMT n’est pas différente et bien qu’il ait été initialement envisagé qu’elle exerce ses effets principalement sur les récepteurs de la sérotonine 2A (5-HT2A), de nouvelles cibles ont été trouvées. Une de ces nouvelles cibles, le récepteur sigma-1 (Sig1R), n’est pas la réponse au puzzle de la DMT mais en révèle tout de même plusieurs pièces intrigantes.

Sig1R est atypique. Ses origines sont un mystère : en termes d’évolution, il est plus étroitement lié à une enzyme fongique appelée stérol isomérase qu’à un récepteur de neurotransmetteur mammalien.7 Les scientifiques restent perplexes quant à l’interprétation de cette découverte, particulièrement compte tenu du fait que cette enzyme fongique a tout d’abord été isolée d’un champignon produisant des alcaloïdes similaires au LSD.

Alors que de nombreux récepteurs relaient les signaux de neurotransmetteurs spécifiquement sur la membrane cellulaire, à l’intérieur de la cellule ou dans le noyau, Sig1R est inhabituel car il peut agir sur les trois. Sur la membrane, il peut interagir avec d’autres récepteurs de neurotransmetteurs et modifier leur rôle en formant des complexes avec eux. A l’intérieur de la cellule, il se lie à des protéines anti-stress et les aide à remplir leurs fonctions.8 Dans le noyau, il recrute d’autres protéines qui se lient à l’ADN et activent ou désactivent différents gènes via des mécanismes épigénétiques.9

Ce récepteur multifonctionnel est qualifié d’« orphelin » car les scientifiques n’ont pas encore identifié son principal neurotransmetteur activateur. Il a tout d’abord été suggéré que Sig1R serait un sous-type de récepteur opiacé, mais les scientifiques ont plus tard découvert que d’autres substances s’y attachaient, dont la cocaïne et une hormone sexuelle, la progestérone.10 Plus récemment, des preuves nourrissant les spéculations selon lesquelles la DMT pourrait activer ce récepteur sont apparues.

La première indication que tel pourrait être le cas est venue de la recherche sur la culture cellulaire qui a démontré que la DMT pouvait se lier à Sig1R. Des recherches sur les souris ont continué à développer cette idée. Elles montrent que le comportement de la souris sous influence de DMT ne change pas après blocage de leurs récepteurs sérotoninergiques et dopaminergiques, alors que les souris arrêtent de réagir à la DMT lorsque leur récepteur Sig1R est désactivé. Ces résultats ont mené les chercheurs à conclure que Sig1R est l’une des cibles principales de la DMT.11 Un autre indice vient du fait qu’au niveau des synapses connectant les différents neurones, Sig1R est localisé à proximité d’une enzyme impliquée dans la synthèse de la DMT.12 Cela a mené certains chercheurs à se demander si Sig1R, plutôt que 5-HT2A, ne serait pas le principal médiateur des effets psychédéliques de la DMT.

Les pouvoirs du récepteur Sigma 1

 Que se passe-t-il dans la cellule lorsque la DMT active Sig1R ? Certaines réponses proviennent de la recherche sur la culture cellulaire. Des études récentes ont montré que la DMT jouait un rôle à la fois dans la réponse immunitaire et dans la réponse anti-stress de cellules individuelles humaines. Dans les cellules immunitaires, il a été démontré que la DMT activait la production de molécules anti-inflammatoires.13

Dans une étude similaire, l’apport en oxygène à des neurones humains en culture cellulaire a été appauvri. Les neurones, qui périssent rapidement par manque d’oxygène, ont survécu en plus grand nombre après le traitement par DMT et l’activation ultérieure de Sig1R.14 Cette découverte offre un retour vers l’idée de Rick Strassman : si la DMT aide les cellules stressées, pourrait-elle alors aussi aider l’organisme entier en état de stress – lorsque proche de la mort et sévèrement privé d’oxygène ? Bien qu’il soit tentant de spéculer, il est important de garder à l’esprit que les neurones cérébraux fonctionnent de manière complexe et dépendante du contexte. Observer des neurones individuels en culture montre aux scientifiques les mécanismes intracellulaires, mais en dit peu sur la façon dont les neurones interagissent les uns avec les autres dans un cerveau vivant et en trois dimensions.

Ces lacunes restent encore à combler. Les chercheurs n’ont pas testé l’activité de Sig1R dans des cerveaux entiers sous hypoxie ou autres types de stress physiologiques. Dans un cerveau mourant, la DMT pourrait aider les neurones à survivre, mais la survie seule ne peut entièrement déterminer comment les neurones agissent, ni comment leur activité crée les visions caractéristiques des expériences de mort imminentes. En l’absence de preuves directes, nous pouvons tout de même essayer de relier des indices venant d’études d’imagerie cérébrale avec les mécanismes d’action connus de Sig1R.

En examinant le cerveau de personnes sous DMT et ayahuasca, les chercheurs observent une activité altérée dans les centres auditifs et visuels du cerveau ainsi que dans les régions liées à la mémoire. Il s’agit notamment des centres de perception et de traitement des émotions négatives et des souvenirs tristes, des centres de récupération de la mémoire et de l’amygdale (une région cérébrale plus communément associée au traitement social et émotionnel, dont la peur, l’anxiété et l’agression).15,16

Dr. Antonio Inserra, chercheur à l’Université Flinders à Adelaïde, a tenté de réconcilier les perspectives moléculaires avec celles du cerveau entier. Il a formulé une hypothèse intrigante à propos du rôle de Sig1R dans les activités cérébrales.7 Son analyse se focalise spécifiquement sur le rôle de la DMT dans le traitement du traumatisme, un phénomène qui a suscité son intérêt suite à des témoignages anecdotiques de patients souffrant de stress post-traumatique dont les symptômes ont été atténués après des sessions d’ayahuasca. Il spécule que Sig1R, en formant des complexes avec d’autres récepteurs, stimule la transmission de signaux et la plasticité synaptique des centres de mémoire, et pourrait par ce biais aider à récupérer puis réévaluer les souvenirs traumatiques. Il souligne en outre que Sig1R sert de régulateur épigénétique dans le noyau.9 c’est à dire qu’il recrute des enzymes et ajoute différents marqueurs à l’ADN et aux histones (protéines autour desquelles l’ADN s’enroule dans la cellule) afin d’activer ou de désactiver des gènes. Depuis longtemps, nous savons que les changements épigénétiques tiennent un rôle important dans tous les aspects de la formation et du remodelage de la mémoire. Pour cette raison, Inserra suggère que certains mécanismes de traitement des traumatismes par l’ayahuasca pourraient être médiés par des changements épigénétiques liés à l’activité de Sig1R dans les centres cérébraux de la mémoire.

De retour en Amazonie, la nouvelle recherche comblera-t-elle le fossé ?

Une nouvelle étude du Dr. Simon Ruffell, chercheur associé au King’s College de Londres, lie également la DMT, Sig1R et la régulation épigénétique. Son équipe, supervisée par le professeur Celia Morgan (de l’Université d’Exeter), a suivi les participants à des cérémonies d’ayahuasca en Amazonie afin d’étudier l’impact de ces expériences sur leurs souvenirs traumatiques. Les participants ont signalé une diminution significative et durable de leur dépression, anxiété et détresse générale. Afin de comprendre pourquoi, l’équipe de Ruffell a prélevé des échantillons salivaires et analysé les modifications de marqueurs épigénétiques de leur ADN. Ils ont découvert que le gène de Sig1R montrait des changements épigénétiques chez certains participants (résultats non publiés, présentés à la conférence ICPR2020). Puisque nous savons que le récepteur est lui-même impliqué dans la modulation épigénétique, cela pourrait n’être que le début. Sur quels autres gènes voyons-nous des changements épigénétiques après les séances d’ayahuasca ? La recherche sur l’épigénétique de Ruffell pourrait offrir d’autres pistes, non seulement sur la façon dont la DMT fonctionne avec Sig1R au niveau épigénétique, mais aussi sur l’épigénétique de la mémoire en tant que telle. Quelles que soient les autres conclusions tirées de cette étude, elle fait le pont entre le laboratoire et la cérémonie ; entre la cellule, le cerveau et l’expérience.

L’état actuel de la recherche sur la DMT ressemble à des pièces de puzzle éparpillées. Bien qu’il existe plusieurs indicateurs de la présence naturelle de la DMT dans le cerveau humain, ses emplacements et ses fonctions restent mystérieuses. Plus de données sont disponibles sur le fonctionnement de l’ayahuasca et de la DMT exogène, à la fois dans la cellule et dans le cerveau, mais nous ne pouvons pas encore justifier d’extrapoler les rôles de la DMT endogène depuis ces résultats.

Néanmoins, diverses théories spéculatives ont récemment fait surface. Alors que certains chercheurs se focalisent sur les potentiels rôles anti-inflammatoire et neuro-protecteur de la DMT, d’autres se penchent sur l’imagerie cérébrale et les études sur les traumatismes et soulignent ses effets possibles sur le remodelage de la mémoire. Les deux pourraient être vraies, et les deux peuvent être placées dans le contexte de la théorie de Rick Strassman selon laquelle la DMT est présente dans le cerveau humain pour atténuer les effets de stress physiologiques majeurs, tel que l’hypoxie neuronale lors d’expériences de mort imminentes. Le cerveau mourant produirait-il de la DMT endogène pour survivre aussi longtemps que possible ? Si tel est le cas, les caractéristiques communément rapportées des expériences de mort imminentes – comme les visions et le fait de voir sa « vie défiler devant ses yeux » – pourraient simplement être des effets secondaires. En ce qui concerne la survie neuronale et le traitement de la mémoire, les recherches indiquent jusqu’à présent que Sig1R, ce récepteur multifonctionnel et mystérieux, est un acteur clé.

Bien que les subtilités de ses mécanismes moléculaires n’aient pas encore été complètement décrites, le récepteur multifonctionnel Sig1R est à présent formellement reconnu en tant que cible de la DMT, ce qui ouvre de nouvelles pistes de recherche. Peut-être que les plus passionnantes d’entre elles se pencheront sur la façon dont la DMT et Sig1R influencent la régulation épigénétique. Des informations sur les gènes qu’ils activent ou désactivent pourraient remplacer les résultats obtenus par la recherche sur la culture cellulaire dans le contexte d’organismes entiers. Les mécanismes épigénétiques sont à la base de nos interactions dynamiques avec le monde et avec notre propre esprit. Comprendre comment ces mécanismes aident à stocker et remodeler nos souvenirs pourrait nous aider à formuler un modèle biologique cohérent quant aux effets thérapeutiques de l’expérience psychédélique.

Pour aller plus loin sur ce sujet mais également encore bien d’autres dans le domaine de la recherche psychédélique, rendez vous sur le programme de notre conférence INSIGHT 2021 ansi que ses ateliers pré-conférence.

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Références
  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
janvier 26, 2021
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Associate Professor of Neuroscience

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

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Journalist, Managing Editor at InformED

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

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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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References

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?

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  • Science
  • Perspective
  • 3 minutes
décembre 11, 2020
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Professor of Psychiatry

Prof. Dr. med. 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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References
  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

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German

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décembre 1, 2020
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Research & Knowledge Exchange Associate, Resources Manager

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

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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.

 

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.

 

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

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Big Data en Psychiatrie – Le Meilleur Des Mondes?

Traduit par Gnana Prasoon Rupanagunta

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novembre 27, 2020
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Professor of Psychiatry

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

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Disclaimer : la traduction de cet article a été rédigée et révisée par des bénévoles. Les contributeurs ne représentent pas la MIND Foundation. Si vous trouvez des erreurs ou des incohérences, ou si quelque chose dans la traduction ne semble pas clair, veuillez nous en informer – nous vous remercions pour toute amélioration. Si vous souhaitez aider avec vos compétences linguistiques, vous pouvez également utiliser le lien et rejoindre les traducteurs du blog!

Chaque jour dans la presse mais aussi dans la littérature médicale, on retrouve les promesses du «Big Data», de la «médecine de précision» et du «Machine Learning» pour la médecine. Ces proclamations commencent généralement par des phrases telles que: «La santé mentale (incluant l’abus de substance) est la cinquième plus grande cause mondiale de morbidité, avec un coût de 2 500 milliards de dollars en 2010, qui devrait doubler d’ici 2030».1

Ensuite, ces articles soulignent les possibilités infinies de numérisation en médecine. Le «Big Data» est vanté comme la solution à tous les problèmes en psychiatrie: il pourrait améliorer non seulement la détection précoce des troubles mentaux, mais aussi la thérapie. Ces promesses semblent paradisiaques: «Le domaine émergent de “l’analyse prédictive en santé mentale” a récemment suscité un vif intérêt avec la promesse audacieuse de révolutionner la pratique clinique en psychiatrie».2 Quelqu’un y croit-il vraiment? Et plus important encore, est-ce vraiment ce que nous souhaitons?

Dans mon récent article de blog «Votre téléphone vous connaît-il mieux que votre thérapeute?», j’ai décrit ce que signifie le «phénotypage numérique» et les grandes attentes qui y sont associées. J’ai également exprimé mon scepticisme. Le «Big Data» en psychiatrie va au-delà du phénotypage numérique. Il prétend déduire notre état d’esprit à partir des photos que nous publions sur Facebook ou Instagram. Des premières études ont déjà été publiées, dans lesquelles un algorithme diagnostique une «dépression» ou un «état de stress post-traumatique» sur la base de photos Instagram ou de publications Twitter, parfois bien avant qu’un diagnostic clinique ne soit posé. Bientôt, les machines devraient être capables d’analyser la parole afin d’en déduire des diagnostics comme la dépression ou la démence naissante. Il semblerait également que le type de musique que nous écoutons puisse permettre de tirer des conclusions sur notre état émotionnel. Certains espèrent très sérieusement qu’en analysant les trésors de nos données – et ce ne sont pas seulement nos traces de données numériques mais aussi des données biologiques comme les gènes, les modèles épigénétiques, les hormones, les valeurs et tout ce que l’on peut «mesurer» – les maladies mentales puissent être «découvertes» de sorte qu’elles n’apparaîtraient même plus.

Si vous voulez avoir une idée de ce que cette vision pourrait signifier, regardez le chef d’œuvre de Steven Spielberg «Minority Report», dans lequel les crimes sont empêchés avant même qu’ils ne soient commis. Mais la vision future du «Big Data en Psychiatrie» va bien au-delà et soulève de nombreuses questions. Qui fera un diagnostic médical à l’avenir? Un médecin? Ou bien les machines de Google et Apple? Et si les collecteurs de données ont trouvé des preuves que je souffre de dépression, qui en sera informé? Un système de santé publique? Une «autorité supérieure pour la santé mentale»? Serai-je contacté par cette autorité pour un traitement? Et si je ne le souhaite pas, serai-je« surveillé» pour éviter mon éventuel suicide? Qu’arrivera-t-il à quelqu’un dont les données suggèrent qu’il recevra un diagnostic de psychose à 90% de certitude au cours des six prochains mois? Et si nous croyons – comme certains le font réellement, considérant les humains comme des machines biologiques déterministes – que cela se produira avec une certitude à 100%, alors que se passera-t-il? Les traiterons-nous de manière prophylactique? Aurons-nous seulement le droit de les avertir?

Qui définit ce qui est «normal»? Quand une «dépression» a-t-elle besoin d’un traitement lorsqu’une machine en fait le «diagnostic»? Dans un article sérieux, Manrai et Patel (tous deux à l’Université de Harvard) et Ioannidis (Université de Stanford) ont récemment posé la question: «À l’ère de la médecine de précision et du Big Data, qui est considéré comme normal?»3  Le concept des Critères de Domaine de Recherche (RDoC), cadre dimensionnel pour la recherche intégrative de la (dys)fonction mentale à différents niveaux d’information et d’organisation, suggère également qu’à l’avenir – bien que cela puisse être un peu exagéré – on ne traitera plus la personne souffrante, mais la fonction cérébrale qui est perturbée. Y aura-t-il des valeurs seuil, comme c’est habituellement le cas en laboratoire, en dehors desquelles il faudrait conseiller un traitement ?

Enfin, les émotions telles que la dépression, la peur ou le désespoir ont leur sens dans l’évolution. Les sociétés industrialisées, occidentales en particulier, ont tendance à les considérer comme indésirables et veulent les anéantir à tout prix. Je suis convaincu que c’est l’une des raisons pour lesquelles l’utilisation (ou plutôt – la consommation?) d’antidépresseurs a augmenté de façon spectaculaire au cours des vingt dernières années et continue d’augmenter chaque année. Sommes-nous en meilleure santé? La réponse se trouve dans le premier paragraphe de cet article. La psychiatrie du Big Data est la réponse au progrès social. Pourtant, cela cause au moins autant d’inconfort chez de nombreuses personnes que ces progrès eux-mêmes .

Notre travail chez MIND repose sure les dons de personnes comme vous.

Si vous partagez notre vision et souhaitez soutenir la recherche et l’éducation sur les psychédéliques, nous vous serions reconnaissants, peu importe le montant que vous pourrez donner.

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References
  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