Neurobiologie und Wirkmodelle zu Psychedelika

ZUSAMMENFASSUNG

Zur Beantwortung der Frage, ob Psychedelika eine therapeutische Wirkung bei psychischen Erkrankungen aufweisen, ist entscheidend, sich mit möglichen Wirkmechanismen auseinanderzusetzen. Solche können auf psychopharmakologischer, neurobiologischer, neurosystemischer und psychotherapeutischer Ebene beschrieben werden. Neben der klassischen Pharmakologie befasst sich der Artikel mit neurobiologischen Befunden zur Emotionsregulation, der Wahrnehmungsverarbeitung und dem Ruhemodus-Netzwerk unter dem Einfluss von Psychedelika. Hieraus können Hypothesen zur Wirkweise aus einer neurodynamischen Perspektive abgeleitet werden. Letztlich wird der Übergang zu psychotherapeutischen Wirkfaktoren beschrieben. Eine neurobiologisch und psychotherapeutisch integrative Betrachtung der Psychedelikawirkung kann helfen, gezielte psychotherapeutische Interventionen bzw. eine psychotherapeutische Basis für die Einbettung einer Psychedelikaanwendung zu gestalten.

ABSTRACT

Understanding the therapeutic potential of psychedelics in mental illness necessitates an exploration of their underlying mechanisms of action across various levels. This includes psychopharmacological, neurobiological, neurosystemic, and psychotherapeutic dimensions. In addition to traditional neurochemical and receptor physiology considerations, this article delves into neurobiological insights regarding emotion regulation, perceptual processing, and the default mode network modulation induced by psychedelics. These insights provide a foundation for formulating hypotheses on the neurodynamic information processings involved. Furthermore, the transition to psychotherapeutic effects is discussed, emphasizing the integration of neurobiological and psychotherapeutic perspectives. Adopting a comprehensive view of psychedelics’ effects can inform the development of targeted psychotherapeutic interventions or establish a psychotherapeutic framework for incorporating psychedelic use in therapeutic settings.

Schlüsselwörter

Psychedelika - Psychopharmakologie - Systemische Neurobiologie - Neurodynamik - Psychotherapie

Key words

Psychedelics - psychopharmacology - systemic neurobiology - neurodynamics - psychotherapy

Publication History

Article published online:
11 June 2024

• Literatur

• 1 Herwig U, Mertens L, Rosal SP. et al [Psychedelics in Psychiatry – Development and Current State in Germany]. Fortschr Neurol Psychiatr 2023; 91: 311-318 DOI: 10.1055/a-1981-3152.
• 2 Vollenweider FX, Kometer M. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders. Nat Rev Neurosci 2010; 11: 642-651 DOI: 10.1038/nrn2884.
• 3 Acero VP, Cribas ES, Browne KD. et al Bedside to bench: the outlook for psychedelic research. Front Pharmacol 2023; 14: 1240295 DOI: 10.3389/fphar.2023.1240295.
• 4 Carhart-Harris RL, Friston KJ. REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics. Pharmacol Rev 2019; 71: 316-344 DOI: 10.1124/pr.118.017160.
• 5 Vollenweider FX, Preller KH. Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci 2020; 21: 611-624 DOI: 10.1038/s41583-020-0367-2.
• 6 Doss MK, Madden MB, Gaddis A.. et al Models of psychedelic drug action: modulation of cortical-subcortical circuits. Brain 2021 DOI: 10.1093/brain/awab406
• 7 Holze F, Ley L, Muller F. et al Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology 2022; 47: 1180-1187 DOI: 10.1038/s41386-022-01297-2.
• 8 Holze F, Singh N, Liechti ME.. et al Serotonergic Psychedelics – a Comparative review Comparing the Efficacy, Safety, Pharmacokinetics and Binding Profile of Serotonergic Psychedelics. Biol Psychiatry Cogn Neurosci Neuroimaging 2024 DOI: 10.1016/j.bpsc.2024.01.007
• 9 Ley L, Holze F, Arikci D. et al Comparative acute effects of mescaline, lysergic acid diethylamide, and psilocybin in a randomized, double-blind, placebo-controlled cross-over study in healthy participants. Neuropsychopharmacology 2023; 48: 1659-1667 DOI: 10.1038/s41386-023-01607-2.
• 10 Nutt D, Erritzoe D, Carhart-Harris R. Psychedelic Psychiatry’s Brave New World. Cell 2020; 181: 24-28 DOI: 10.1016/j.cell.2020.03.020.
• 11 Goodwin GM, Malievskaia E, Fonzo GA. et al Must Psilocybin Always “Assist Psychotherapy”?. Am J Psychiatry 2024; 181: 20-25 DOI: 10.1176/appi.ajp.20221043.
• 12 Grunder G, Brand M, Mertens LJ. et al Treatment with psychedelics is psychotherapy: beyond reductionism. Lancet Psychiatry 2024; 11: 231-236 DOI: 10.1016/S2215-0366(23)00363-2.
• 13 Moliner R, Girych M, Brunello CA. et al Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat Neurosci 2023; 26: 1032-1041 DOI: 10.1038/s41593-023-01316-5.
• 14 Casarotto P, Umemori J, Castren E. BDNF receptor TrkB as the mediator of the antidepressant drug action. Front Mol Neurosci 2022; 15: 1032224 DOI: 10.3389/fnmol.2022.1032224.
• 15 Belge JB, Mulders P, Van Diermen L. et al Reviewing the neurobiology of electroconvulsive therapy on a micro- meso- and macro-level. Prog Neuropsychopharmacol Biol Psychiatry 2023; 127: 110809 DOI: 10.1016/j.pnpbp.2023.110809.
• 16 Sohn MN, Brown JC, Sharma P. et al Pharmacological adjuncts and transcranial magnetic stimulation-induced synaptic plasticity: a systematic review. J Psychiatry Neurosci 2024; 49: E59-E76 DOI: 10.1503/jpn.230090.
• 17 Flanagan TW, Nichols CD. Psychedelics as anti-inflammatory agents. Int Rev Psychiatry 2018; 30: 363-375 DOI: 10.1080/09540261.2018.1481827.
• 18 Herwig U, Baumgartner T, Kaffenberger T. et al Modulation of anticipatory emotion and perception processing by cognitive control. Neuroimage 2007; 37: 652-662 DOI: 10.1016/j.neuroimage.2007.05.023.
• 19 Herwig U, Kaffenberger T, Jancke L. et al Self-related awareness and emotion regulation. Neuroimage 2010; 50: 734-741 DOI: 10.1016/j.neuroimage.2009.12.089.
• 20 Kraehenmann R, Preller KH, Scheidegger M. et al Psilocybin-Induced Decrease in Amygdala Reactivity Correlates with Enhanced Positive Mood in Healthy Volunteers. Biol Psychiatry 2015; 78: 572-581 DOI: 10.1016/j.biopsych.2014.04.010.
• 21 Mertens LJ, Wall MB, Roseman L. et al Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. J Psychopharmacol 2020; 34: 167-180 DOI: 10.1177/0269881119895520.
• 22 Mueller F, Lenz C, Dolder PC. et al Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Transl Psychiatry 2017; 07: e1084 DOI: 10.1038/tp.2017.54.
• 23 Carhart-Harris RL, Roseman L, Bolstridge M. et al Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep 2017; 07: 13187 DOI: 10.1038/s41598-017-13282-7.
• 24 Avram M, Grothe MJ, Meinhold L. et al Lower cholinergic basal forebrain volumes link with cognitive difficulties in schizophrenia. Neuropsychopharmacology 2021; 46: 2320-2329 DOI: 10.1038/s41386-021-01070-x.
• 25 Muller F, Lenz C, Dolder P. et al Increased thalamic resting-state connectivity as a core driver of LSD-induced hallucinations. Acta Psychiatr Scand 2017; 136: 648-657 DOI: 10.1111/acps.12818.
• 26 Preller KH, Burt JB, Ji JL. et al Changes in global and thalamic brain connectivity in LSD-induced altered states of consciousness are attributable to the 5-HT2A receptor. Elife 2018: 7 DOI: 10.7554/eLife.35082
• 27 Avram M, Muller F, Rogg H.. et al Characterizing thalamocortical (dys)connectivity following d-amphetamine, LSD, and MDMA administration. Biol Psychiatry Cogn Neurosci Neuroimaging 2022 DOI: 10.1016/j.bpsc.2022.04.003
• 28 Delli Pizzi S, Chiacchiaretta P, Sestieri C. et al LSD-induced changes in the functional connectivity of distinct thalamic nuclei. Neuroimage 2023; 283: 120414 DOI: 10.1016/j.neuroimage.2023.120414.
• 29 Avram M, Muller F, Preller KH.. et al Effective Connectivity of Thalamocortical Interactions Following d-Amphetamine, LSD, and MDMA Administration. Biol Psychiatry Cogn Neurosci Neuroimaging 2023 DOI: 10.1016/j.bpsc.2023.07.010
• 30 Preller KH, Razi A, Zeidman P. et al Effective connectivity changes in LSD-induced altered states of consciousness in humans. Proc Natl Acad Sci U S A 2019; 116: 2743-2748 DOI: 10.1073/pnas.1815129116.
• 31 Vollenweider FX, Geyer MA. A systems model of altered consciousness: integrating natural and drug-induced psychoses. Brain Res Bull 2001; 56: 495-507 DOI: 10.1016/s0361-9230(01)00646-3.
• 32 Avram M, Müller F, Borgwardt S. et al 53C5Lysergic acid diethylamide: In search of the wonder drug. In: Psychedelics as Psychiatric Medications. Oxford: University Press; 2023
• 33 Avram M, Rogg H, Korda A. et al Bridging the Gap? Altered Thalamocortical Connectivity in Psychotic and Psychedelic States. Frontiers in Psychiatry 2021: 12 DOI: 10.3389/fpsyt.2021.706017
• 34 Broyd SJ, Demanuele C, Debener S. et al Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev 2009; 33: 279-296 DOI: 10.1016/j.neubiorev.2008.09.002.
• 35 Carhart-Harris RL, Erritzoe D, Williams T. et al Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci U S A 2012; 109: 2138-2143 DOI: 10.1073/pnas.1119598109.
• 36 Smigielski L, Scheidegger M, Kometer M. et al Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. Neuroimage 2019; 196: 207-215 DOI: 10.1016/j.neuroimage.2019.04.009.
• 37 Sampedro F, de la Fuente Revenga M, Valle M. et al Assessing the Psychedelic “After-Glow” in Ayahuasca Users: Post-Acute Neurometabolic and Functional Connectivity Changes Are Associated with Enhanced Mindfulness Capacities. Int J Neuropsychopharmacol 2017; 20: 698-711 DOI: 10.1093/ijnp/pyx036.
• 38 Pasquini L, Palhano-Fontes F, Araujo DB. Subacute effects of the psychedelic ayahuasca on the salience and default mode networks. J Psychopharmacol 2020; 34: 623-635 DOI: 10.1177/0269881120909409.
• 39 Klaassens BL, van Gorsel HC, Khalili-Mahani N. et al Single-dose serotonergic stimulation shows widespread effects on functional brain connectivity. Neuroimage 2015; 122: 440-450 DOI: 10.1016/j.neuroimage.2015.08.012.
• 40 Muller F, Holze F, Dolder P. et al MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogens. Neuropsychopharmacology 2021; 46: 545-553 DOI: 10.1038/s41386-020-00906-2.
• 41 Carhart-Harris RL, Leech R, Hellyer PJ. et al The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs. Front Hum Neurosci 2014; 08: 20 DOI: 10.3389/fnhum.2014.00020.
• 42 Girn M, Roseman L, Bernhardt B. et al Serotonergic psychedelic drugs LSD and psilocybin reduce the hierarchical differentiation of unimodal and transmodal cortex. Neuroimage 2022; 256: 119220 DOI: 10.1016/j.neuroimage.2022.119220.
• 43 Daws RE, Timmermann C, Giribaldi B. et al Increased global integration in the brain after psilocybin therapy for depression. Nat Med 2022; 28: 844-851 DOI: 10.1038/s41591-022-01744-z.
• 44 McCulloch DE, Knudsen GM, Barrett FS. et al Psychedelic resting-state neuroimaging: A review and perspective on balancing replication and novel analyses. Neurosci Biobehav Rev 2022; 138: 104689 DOI: 10.1016/j.neubiorev.2022.104689.
• 45 Hipólito I, Mago J, Rosas FE. et al Pattern breaking: a complex systems approach to psychedelic medicine. Neurosci Conscious 2023; 2023 (01) niad017 DOI: 10.1093/nc/niad017.
• 46 Nardou R, Sawyer E, Song YJ. et al Psychedelics reopen the social reward learning critical period. Nature 2023; 618: 790-798 DOI: 10.1038/s41586-023-06204-3.
• 47 Yaden DB, Earp D, Graziosi M. et al Psychedelics and Psychotherapy: Cognitive-Behavioral Approaches as Default. Front Psychol 2022; 13: 873279 DOI: 10.3389/fpsyg.2022.873279.
• 48 Watts R, Day C, Krzanowski J. et al Patients’ Accounts of Increased “Connectedness” and “Acceptance” After Psilocybin for Treatment-Resistant Depression. Journal of Humanistic Psychology 2017; 57: 520-564 DOI: 10.1177/0022167817709585.
• 49 Carhart-Harris RL, Erritzoe D, Haijen E. et al Psychedelics and connectedness. Psychopharmacology (Berl) 2018; 235: 547-550 DOI: 10.1007/s00213-017-4701-y.
• 50 Roseman L, Nutt DJ, Carhart-Harris RL. Quality of Acute Psychedelic Experience Predicts Therapeutic Efficacy of Psilocybin for Treatment-Resistant Depression. Front Pharmacol 2017; 08: 974 DOI: 10.3389/fphar.2017.00974.
• 51 Ponomarenko P, Seragnoli F, Calder A. et al Can psychedelics enhance group psychotherapy? A discussion on the therapeutic factors. J Psychopharmacol 2023; 37: 660-678 DOI: 10.1177/02698811231155117.
• 52 Mertens LJ, Preller KH. Classical Psychedelics as Therapeutics in Psychiatry – Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders. Pharmacopsychiatry 2021; 54: 176-190 DOI: 10.1055/a-1341-1907.
• 53 Barber GS, Aaronson ST. The Emerging Field of Psychedelic Psychotherapy. Curr Psychiatry Rep 2022; 24: 583-590 DOI: 10.1007/s11920-022-01363-y.
• 54 Reiff CM, Richman EE, Nemeroff CB. et al Psychedelics and Psychedelic-Assisted Psychotherapy. Am J Psychiatry 2020; 177: 391-410 DOI: 10.1176/appi.ajp.2019.19010035.
• 55 Wolff M, Evens R, Mertens LJ. et al Learning to Let Go: A Cognitive-Behavioral Model of How Psychedelic Therapy Promotes Acceptance. Front Psychiatry 2020; 11: 5 DOI: 10.3389/fpsyt.2020.00005.
• 56 Passie T, Guss J, Krahenmann R. Lower-dose psycholytic therapy – A neglected approach. Front Psychiatry 2022; 13: 1020505 DOI: 10.3389/fpsyt.2022.1020505.
• 57 Sloshower J, Skosnik PD, Safi-Aghdam H. et al Psilocybin-assisted therapy for major depressive disorder: An exploratory placebo-controlled, fixed-order trial. J Psychopharmacol 2023; 37: 698-706 DOI: 10.1177/02698811231154852.