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Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain.

/ Ayahuasca, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / / , , , , , ,

Abstract

The effects of hallucinogenic drugs on the human brain have been studied since the earliest days of neuroimaging in the 1990s. However, approaches are often hard to compare and results are heterogeneous. In this chapter, we summarize studies investigating the effects of hallucinogens on the resting brain, with a special emphasis on replicability and limitations. In previous studies, similarities were observed between psilocybin, LSD, and ayahuasca, with respect to decreases in cerebral blood flow and increases in global functional connectivity in the precuneus and thalamus. Additionally, LSD consistently decreased functional connectivity within distinct resting state networks. Little convergence was observed for connectivity between networks and for blood flow in other brain regions. Although these studies are limited by small sample sizes and might be biased by unspecific drug effects on physiological parameters and the vascular system, current results indicate that neuroimaging could be a useful tool to elucidate the neuronal correlates of hallucinogenic effects.
Müller, F., Liechti, M. E., Lang, U. E., Borgwardt, S., Wilson, M. R., Webb, A., … & Lutz, K. (2018). Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain. Progress in brain research, 242, 159-177. 10.1016/bs.pbr.2018.08.004
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Whole-Brain Multimodal Neuroimaging Model Using Serotonin Receptor Maps Explains Non-linear Functional Effects of LSD

/ Neuroscience, Papers, Publications / / , , , , , ,

Abstract

Understanding the underlying mechanisms of the human brain in health and disease will require models with necessary and sufficient details to explain how function emerges from the underlying anatomy and is shaped by neuromodulation. Here, we provide such a detailed causal explanation using a whole-brain model integrating multimodal imaging in healthy human participants undergoing manipulation of the serotonin system. Specifically, we combined anatomical data from diffusion magnetic resonance imaging (dMRI) and functional magnetic resonance imaging (fMRI) with neurotransmitter data obtained with positron emission tomography (PET) of the detailed serotonin 2A receptor (5-HT2AR) density map. This allowed us to model the resting state (with and without concurrent music listening) and mechanistically explain the functional effects of 5-HT2AR stimulation with lysergic acid diethylamide (LSD) on healthy participants. The whole-brain model used a dynamical mean-field quantitative description of populations of excitatory and inhibitory neurons as well as the associated synaptic dynamics, where the neuronal gain function of the model is modulated by the 5-HT2AR density. The model identified the causative mechanisms for the non-linear interactions between the neuronal and neurotransmitter system, which are uniquely linked to (1) the underlying anatomical connectivity, (2) the modulation by the specific brainwide distribution of neurotransmitter receptor density, and (3) the non-linear interactions between the two. Taking neuromodulatory activity into account when modeling global brain dynamics will lead to novel insights into human brain function in health and disease and opens exciting possibilities for drug discovery and design in neuropsychiatric disorders.

Deco, G., Cruzat, J., Cabral, J., Knudsen, G. M., Carhart-Harris, R. L., Whybrow, P. C., … & Kringelbach, M. L. (2018). Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD. Current biology, 28(19), 3065-3074., 10.1016/j.cub.2018.07.083

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Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression

/ Ketamine, Neuroscience, Papers, Psychiatry & Medicine, Psychology, Publications / / , , , , , ,

Abstract

BACKGROUND:

Ketamine has proven to have rapid, robust antidepressant effects on treatment-resistant depression. However, whether repeated ketamine infusions would cause short-and long-term neurocognitive impairments was not clear. Our aims were to investigate the neurocognitive effects of six ketamine infusions and to examine the association between these infusions and the antidepressant response in patients with unipolar and bipolar depression.

METHODS:

Six intravenous infusions of ketamine (0.5 mg/kg) over a 12-day period were administered to 84 patients with unipolar and bipolar depression. Severity of depressive symptoms and four domains of neurocognition, including speed of processing, working memory, visual learning and verbal learning, were assessed at baseline, one day following the last infusion and again two weeks post-infusion.

RESULTS:

Significant improvements were found on speed of processing ( F=9.344, p<0.001) and verbal learning ( F=5.647, p=0.004) in a linear mixed model. The Sobel test showed significant indirect effects between time and improvement in speed of processing (Sobel test=3.573, p<0.001) as well as improvement in verbal learning (Sobel test=6.649, p<0.001), which were both significantly mediated by change in depressive symptoms. Logistic regression analysis showed ketamine responders had better visual learning at baseline than non-responders (B=0.118, p<0.001).

CONCLUSIONS:

Our findings suggest that neurocognitive function would not deteriorate after six ketamine infusions, while verbal learning and speed of processing improved over 13 days and 26 days of observation, respectively. However, this change was mainly accounted for by improvements in severity of depressive symptoms over time. Greater baseline visual learning predicted an antidepressant response over six ketamine infusions.

Zhou, Y., Zheng, W., Liu, W., Wang, C., Zhan, Y., Li, H., … & Ning, Y. (2018). Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression. Journal of Psychopharmacology, 32(10), 1118-1126, 10.1177/0269881118798614
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Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy

/ Papers, Psychology, Publications / /

Abstract

A psychological model of classic psychedelic-assisted psychotherapy informed by contemporary scientific data is presented in this paper. It is suggested that classic psychedelic-occasioned mystical experience is characterized by profound awe, a discrete emotion experienced in the presence of a vast stimulus requiring accommodation of mental structures. Awe, in turn, promotes the small self, a construct that, in the extreme, is analogous to those of unitive experience and ego dissolution. The small self is conceptualized as key to understanding the downstream effects of mystical experience occasioned in the context of classic psychedelic-assisted psychotherapy. With this novel theoretical framework in mind, a number of clinical implications and recommendations are provided so as to advance this incipient field of study.
Hendricks, P. S. (2018). Awe: a putative mechanism underlying the effects of classic psychedelic-assisted psychotherapy. International Review of Psychiatry, 30(4), 331-342., 10.1080/09540261.2018.1474185
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Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models

/ Neuroscience, Papers, Psychiatry & Medicine, Publications / / , , , , , ,

Abstract

Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as “deliriants”. Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action, and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field.

Volgin, A. D., Yakovlev, O. A., Demin, K. A., Alekseeva, P. A., Kyzar, E. J., Collins, C., … & Kalueff, A. V. (2018). Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models. ACS chemical neuroscience., 10.1021/acschemneuro.8b00433

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Psychedelics and the new behaviourism: considering the integration of third-wave behaviour therapies with psychedelic-assisted therapy

/ Neuroscience, Papers, Psychology, Publications / / ,

Abstract

This narrative review examines evidence related to the potential for third wave behaviour therapies to serve as adjuncts to psychedelic-assisted therapy. It identifies shared theoretical foundations for both approaches, and notes enhanced mindfulness, decentering, emotion regulation, and distress tolerance as common mechanisms of action. It also identifies potential targets for which both approaches have demonstrated therapeutic potential, including problematic substance use, self-directed and other-directed violence, and mood disorders. Based on these commonalities, there is a call for research on the potential integration of psychedelic-assisted therapy and third wave behaviour therapies including Dialectical Behaviour Therapy, Acceptance and Commitment Therapy, and Mindfulness Based Cognitive Therapy.

Walsh, Z., & Thiessen, M. S. (2018). Psychedelics and the new behaviourism: considering the integration of third-wave behaviour therapies with psychedelic-assisted therapy. International Review of Psychiatry, 30(4), 343-349., 10.1080/09540261.2018.1474088
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Psychedelics and music: neuroscience and therapeutic implications

/ Papers, Psychology, Publications / / , ,

Abstract

From the beginning of therapeutic research with psychedelics, music listening has been consistently used as a method to guide or support therapeutic experiences during the acute effects of psychedelic drugs. Recent findings point to the potential of music to support meaning-making, emotionality, and mental imagery after the administration of psychedelics, and suggest that music plays an important role in facilitating positive clinical outcomes of psychedelic therapy. This review explores the history of, contemporary research on, and future directions regarding the use of music in psychedelic research and therapy, and argues for more detailed and rigorous investigation of the contribution of music to the treatment of psychiatric disorders within the novel framework of psychedelic therapy.
Barrett, F. S., Preller, K. H., & Kaelen, M. (2018). Psychedelics and music: neuroscience and therapeutic implications. International Review of Psychiatry, 30(4), 350-362., 10.1080/09540261.2018.1484342
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Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics

/ Neuroscience, Papers, Psychology, Publications / /

Abstract

Neural plasticity-the ability to change and adapt in response to stimuli-is an essential aspect of healthy brain function and, in principle, can be harnessed to promote recovery from a wide variety of brain disorders. Many neuropsychiatric diseases including mood, anxiety, and substance use disorders arise from an inability to weaken and/or strengthen pathologic and beneficial circuits, respectively, ultimately leading to maladaptive behavioral responses. Thus, compounds capable of facilitating the structural and functional reorganization of neural circuits to produce positive behavioral effects have broad therapeutic potential. Several known drugs and experimental therapeutics have been shown to promote plasticity, but most rely on indirect mechanisms and are slow-acting. Here, I describe psychoplastogens-a relatively new class of fast-acting therapeutics, capable of rapidly promoting structural and functional neural plasticity. Psychoplastogenic compounds include psychedelics, ketamine, and several other recently discovered fast-acting antidepressants. Their use in psychiatry represents a paradigm shift in our approach to treating brain disorders as we focus less on rectifying “chemical imbalances” and place more emphasis on achieving selective modulation of neural circuits.
Olson, D. E. (2018). Psychoplastogens: A Promising Class of Plasticity-Promoting Neurotherapeutics. Journal of experimental neuroscience, 12, 1179069518800508., 10.1177/1179069518800508
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Dimensions of consciousness and the psychedelic state

/ Anthropology & Sociology, Ayahuasca, DMT, Iboga / Ibogaine, Ketamine, LSD, MDMA, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Psychology, Publications, Salvia / Salvinorin A / / ,

Abstract

It has often been suggested in the popular and academic literature that the psychedelic state qualifies as a higher state of consciousness relative to the state of normal waking awareness. This article subjects this proposal to critical scrutiny, focusing on the question of what it would mean for a state of consciousness to be ‘higher’. We begin by considering the contrast between conscious contents and conscious global states. We then review the changes in conscious global state associated with psychedelic drug use, focusing on the effects of two serotonergic hallucinogens: psilocybin and lysergic acid diethylamide. Limiting our review to findings obtained from lab-based experiments and reported in peer-reviewed journals, we prioritize the more common and reliably induced effects obtained through subjective questionnaires and psychophysical measures. The findings are grouped into three broad categories (sensory perception, cognitive function, and experiences of unity) and demonstrate that although certain aspects of consciousness are improved or enhanced in the psychedelic state, many of the functional capacities that are associated with consciousness are seriously compromised. Psychedelic-induced states of consciousness are indeed remarkable in many ways, but it is inappropriate to regard them as ‘higher’ states of consciousness. The fact that psychedelics affect different aspects of consciousness in fundamentally different ways provides evidence against the unidimensional (or ‘level-based’) view of consciousness, and instead provides strong support for a multidimensional conception of conscious states. The final section of the article considers the implications of this analysis for two prominent theories of consciousness: the Global Workspace Theory and Integrated Information Theory.

Bayne, T., & Carter, O. (2018). Dimensions of consciousness and the psychedelic state. Neuroscience of consciousness, 2018(1), niy008., 10.1093/nc/niy008
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Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial.

/ Depressive Disorders, Ketamine, Papers, Psychology, Publications / / , , , , , ,

Abstract

BACKGROUND:
Several studies indicate that ketamine has rapid antidepressant effects in patients with treatment-resistant depression (TRD). The extent to which repeated doses of ketamine (versus placebo) reduce depression in the short and long term among outpatients with TRD and chronic, current suicidal ideation remains unknown.
METHODS:
Twenty-six medicated outpatients with severe major depressive disorder with current, chronic suicidal ideation were randomized in a double-blind fashion to six ketamine infusions (0.5 mg/kg over 45 minutes) or saline placebo over three weeks. Depression and suicidal ideation were assessed at baseline, 240 min post-infusion, and during a three-month follow-up phase.
RESULTS:
During the infusion phase, there was no differences in depression severity or suicidal ideation between placebo and ketamine (p = 0.47 and p = 0.32, respectively). At the end of the infusion phase, two patients in the ketamine group and one in the placebo group met criteria for remission of depression. At three-month follow-up, two patients in each group met criteria for remission from depression.
LIMITATIONS:
Limitations include the small sample size, uncontrolled outpatient medication regimens, and restriction to outpatients, which may have resulted in lower levels of suicidal ideation than would be seen in emergency or inpatient settings.
CONCLUSIONS:
Repeated, non-escalating doses of ketamine did not outperform placebo in this double-blind, placebo controlled study of patients with severe TRD and current, chronic suicidal ideation. This result may support our previously published open-label data that, in this severely and chronically ill outpatient population, the commonly used dose of 0.5 mg/kg is not sufficient.
Ionescu, D. F., Bentley, K. H., Eikermann, M., Taylor, N., Johnson-Akeju, O., Swee, M. B., … & Alpert, J. E. (2019). Repeat-dose ketamine augmentation for treatment-resistant depression with chronic suicidal ideation: A randomized, double blind, placebo controlled trial. Journal of Affective Disorders, 243, 516-524, 10.1016/j.jad.2018.09.037
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