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A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics

February 6, 2022 / Ketamine, Neuroscience, Papers / Leave a Comment / By / , ,

Abstract

Pilot studies have hinted that serotonergic psychedelics such as psilocybin may relieve depression, and could possibly do so by promoting neural plasticity. Intriguingly, another psychotomimetic compound, ketamine, is a fast-acting antidepressant and induces synapse formation. The similarities in behavioral and neural effects have been puzzling because the compounds target distinct molecular receptors in the brain. In this opinion article, we develop a conceptual framework that suggests the actions of ketamine and serotonergic psychedelics may converge at the dendrites, to both enhance and suppress membrane excitability. We speculate that mismatches in the opposing actions on dendritic excitability may relate to these compounds’ cell-type and region selectivity, their moderate range of effects and toxicity, and their plasticity-promoting capacities.

Savalia, N. K., Shao, L. X., & Kwan, A. C. (2021). A Dendrite-Focused Framework for Understanding the Actions of Ketamine and Psychedelics. Trends in neurosciences, 44(4), 260–275. https://doi.org/10.1016/j.tins.2020.11.008

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Neural network models for DMT-induced visual hallucinations

February 6, 2022 / DMT, Neuroscience, Papers / Leave a Comment / By / ,

Abstract

The regulatory role of the serotonergic system on conscious perception can be investigated perturbatorily with psychedelic drugs such as N,N-Dimethyltryptamine. There is increasing evidence that the serotonergic system gates prior (endogenous) and sensory (exogenous) information in the construction of a conscious experience. Using two generative deep neural networks as examples, we discuss how such models have the potential to be, firstly, an important medium to illustrate phenomenological visual effects of psychedelics-besides paintings, verbal reports and psychometric testing-and, secondly, their utility to conceptualize biological mechanisms of gating the influence of exogenous and endogenous information on visual perception.

Schartner, M. M., & Timmermann, C. (2020). Neural network models for DMT-induced visual hallucinations. Neuroscience of consciousness, 2020(1), niaa024. https://doi.org/10.1093/nc/niaa024

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Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder

February 6, 2022 / Ketamine, Neuroscience, Papers, Substance Use Disorder / Leave a Comment / By / ,

Abstract

Alcohol use disorder (AUD) is the most prevalent substance use disorder and causes a significant global burden. Relapse rates remain incredibly high after decades of attempting to develop novel treatment options that have failed to produce increased rates of sobriety. Ketamine has emerged as a potential treatment for AUD following its success as a therapeutic agent for depression, demonstrated by several preclinical studies showing that acute administration reduced alcohol intake in rodents. As such, ketamine’s therapeutic effects for AUD are now being investigated in clinical trials with the hope of it being efficacious in prolonging sobriety from alcohol in humans (ClinicalTrials.gov, Identifier: NCT01558063). Importantly, ketamine’s antidepressant effects only last for about 1-week and because AUD is a lifelong disorder, repeated treatment regimens would be necessary to maintain sobriety. This raises questions regarding its safety for AUD treatment since ketamine itself has the potential for addiction. Therefore, this review aims to summarize the neuroadaptations related to alcohol’s addictive properties as well as ketamine’s therapeutic and addictive properties. To do this, the focus will be on reward-related brain regions such as the nucleus accumbens (NAc), dorsal striatum, prefrontal cortex (PFC), hippocampus, and ventral tegmental area (VTA) to understand how acute vs. chronic exposure will alter reward signaling over time. Additionally, evidence from these studies will be summarized in both male and female subjects. Accordingly, this review aims to address the safety of repeated ketamine infusions for the treatment of AUD. Although more work about the safety of ketamine to treat AUD is warranted, we hope this review sheds light on some answers about the safety of repeated ketamine infusions.

Strong, C. E., & Kabbaj, M. (2020). Neural Mechanisms Underlying the Rewarding and Therapeutic Effects of Ketamine as a Treatment for Alcohol Use Disorder. Frontiers in behavioral neuroscience, 14, 593860. https://doi.org/10.3389/fnbeh.2020.593860

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Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine

January 21, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , ,

Abstract

Acute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.

Tarrés-Gatius, M., Miquel-Rio, L., Campa, L., Artigas, F., & Castañé, A. (2020). Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine. Translational psychiatry, 10(1), 427. https://doi.org/10.1038/s41398-020-01110-y

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Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience

March 16, 2022 / Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / By / , , ,

Abstract

Attachment insecurity is determined early in life, is a risk factor for psychopathology, and can be measured on two separate continuous dimensions: attachment anxiety and attachment avoidance. Therapeutic changes toward more secure attachment correlate with reduction in psychiatric symptoms. Psilocybin-assisted psychotherapy has demonstrated promise in the treatment of psychopathology, such as treatment-resistant depression and substance use disorders. We hypothesized that psilocybin-assisted psychotherapy would reduce attachment anxiety and attachment avoidance, thus increasing attachment security. We also hypothesized that baseline measures of attachment insecurity, which can reflect a diminished capacity for trust and exploration, would inform the quality of the psilocybin session. Participants were male long-term AIDS survivors with moderate-severe demoralization (n = 18). Using the Experiences in Close Relationships scale, we measured attachment insecurity at baseline as well as immediately, and 3 months, after completion of a brief group therapy course, which included a single midtreatment open-label psilocybin session conducted individually. Clinically important aspects of the psilocybin session were assessed using the revised Mystical Experience Questionnaire and the Challenging Experience Questionnaire the day following psilocybin administration. Self-reported ratings of attachment anxiety decreased significantly from baseline to 3-months post-intervention, t(16) = -2.2; p = 0.045; d rm = 0.45; 95% CI 0.01, 0.87. Attachment avoidance did not change significantly. Baseline attachment anxiety was strongly correlated with psilocybin-occasioned mystical-type experiences, r(15) = 0.53, p = 0.029, and baseline attachment avoidance was strongly correlated with psilocybin-related challenging experiences, r(16) = 0.62, p = 0.006. These findings have important implications for the general treatment of psychopathology as well as optimizing psilocybin-assisted psychotherapy as a broadly applicable treatment modality.

Stauffer, C. S., Anderson, B. T., Ortigo, K. M., & Woolley, J. (2020). Psilocybin-Assisted Group Therapy and Attachment: Observed Reduction in Attachment Anxiety and Influences of Attachment Insecurity on the Psilocybin Experience. ACS pharmacology & translational science, 4(2), 526–532. https://doi.org/10.1021/acsptsci.0c00169

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A non-hallucinogenic psychedelic analogue with therapeutic potential

January 21, 2022 / Iboga / Ibogaine, Neuroscience, Papers, Pharmacology & Chemistry, Substance Use Disorder / Leave a Comment / By / , , , , , , , , , , , , , , , , , , , ,

Abstract

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Cameron, L. P., Tombari, R. J., Lu, J., Pell, A. J., Hurley, Z. Q., Ehinger, Y., Vargas, M. V., McCarroll, M. N., Taylor, J. C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L. J., Anderson, E. I., Zhang, G., Viswanathan, J., Brown, B. M., Tjia, M., Dunlap, L. E., Rabow, Z. T., … Olson, D. E. (2021). A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842), 474–479. https://doi.org/10.1038/s41586-020-3008-z

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The entropic tongue: Disorganization of natural language under LSD

January 21, 2022 / LSD, Papers, Psychology / Leave a Comment / By / , , , , , , , , , ,

Abstract

Serotonergic psychedelics have been suggested to mirror certain aspects of psychosis, and, more generally, elicit a state of consciousness underpinned by increased entropy of on-going neural activity. We investigated the hypothesis that language produced under the effects of lysergic acid diethylamide (LSD) should exhibit increased entropy and reduced semantic coherence. Computational analysis of interviews conducted at two different time points after 75 μg of intravenous LSD verified this prediction. Non-semantic analysis of speech organization revealed increased verbosity and a reduced lexicon, changes that are more similar to those observed during manic psychoses than in schizophrenia, which was confirmed by direct comparison with reference samples. Importantly, features related to language organization allowed machine learning classifiers to identify speech under LSD with accuracy comparable to that obtained by examining semantic content. These results constitute a quantitative and objective characterization of disorganized natural speech as a landmark feature of the psychedelic state.

Sanz, C., Pallavicini, C., Carrillo, F., Zamberlan, F., Sigman, M., Mota, N., Copelli, M., Ribeiro, S., Nutt, D., Carhart-Harris, R., & Tagliazucchi, E. (2021). The entropic tongue: Disorganization of natural language under LSD. Consciousness and cognition, 87, 103070. https://doi.org/10.1016/j.concog.2020.103070

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The ritual use of ayahuasca during treatment of severe physical illnesses: a qualitative study

January 21, 2022 / Ayahuasca, Papers, Psychiatry & Medicine / Leave a Comment / By / , ,

Abstract

Diseases that threaten life raise existential questions that can be a source of psychological distress. Studies with psychedelics demonstrate therapeutic effects for anxiety and depression associated with life-threatening illnesses. Ayahuasca has been proposed as a possible therapeutic agent in the treatment of psychiatric disorders. Preliminary studies suggest that ayahuasca could promote therapeutic effects for people with physical illnesses. The aim of this study was to explore how the ritual use of ayahuasca during the treatment of severe physical illnesses (SPI) may influence the way people understand and relate to their illness, using qualitative methods to assess the participants’ perspectives. Participants who consumed ayahuasca ritualistically during the period of treatment for SPI were purposely chosen. Data were obtained through semi-structured interviews. A thematic analysis was performed with 14 individuals. The ritual experience with ayahuasca acted on the participants’ illness understanding through multiple psychological mechanisms, including introspection, self-analysis, emotional processing and catharsis, recall of autobiographical memories subjectively related to illness origin, illness resignification, and perspective changes. This study suggests that the experience with ayahuasca may facilitate illness acceptance through an influence on the meanings of the illness, life, and death. These changes may favor a more balanced relationship with illness and treatment.

Maia, L. O., Daldegan-Bueno, D., & Tófoli, L. F. (2021). The ritual use of ayahuasca during treatment of severe physical illnesses: a qualitative study. Journal of psychoactive drugs, 53(3), 272–282. https://doi.org/10.1080/02791072.2020.1854399

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The Ketamine Antidepressant Story: New Insights

January 21, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By /

Abstract

Ketamine is a versatile agent primarily utilized as a dissociative anesthetic, which acts by blocking the excitatory receptor N-methyl-d-aspartate receptor (NMDA). It functions to inhibit the current of both Na+ and K+ voltage-gated channels, thus preventing serotonin and dopamine reuptake. Studies have indicated that administering a single subanesthetic dose of ketamine relieves depression rapidly and that the effect is sustained. For decades antidepressant agents were based on the monoamine theory. Although ketamine may not be the golden antidepressant, it has opened new avenues toward mechanisms involved in the pathology of treatment-resistant depression and achieving rapid antidepressant effects. Thus, preclinical studies focusing on deciphering the molecular mechanisms involved in the antidepressant action of ketamine will assist in the development of a new antidepressant. This review was conducted to elucidate the emerging pathways that can explain the complex dose-dependent mechanisms achieved by administering ketamine to treat major depressive disorders. Special attention was paid to reviewing the literature on hydroxynorketamines, which are ketamine metabolites that have recently attracted attention in the context of depression.

Alshammari T. K. (2020). The Ketamine Antidepressant Story: New Insights. Molecules (Basel, Switzerland), 25(23), 5777. https://doi.org/10.3390/molecules25235777

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The potential synergistic effects between psychedelic administration and nature contact for the improvement of mental health

January 27, 2022 / Papers, Psychology / Leave a Comment / By / , , , , ,

Abstract

Therapeutic psychedelic administration and contact with nature have been associated with the same psychological mechanisms: decreased rumination and negative affect, enhanced psychological connectedness and mindfulness-related capacities, and heightened states of awe and transcendent experiences, all processes linked to improvements in mental health amongst clinical and healthy populations. Nature-based settings can have inherently psychologically soothing properties which may complement all stages of psychedelic therapy (mainly preparation and integration) whilst potentiating increases in nature relatedness, with associated psychological benefits. Maximising enhancement of nature relatedness through therapeutic psychedelic administration may constitute an independent and complementary pathway towards improvements in mental health that can be elicited by psychedelics.

Gandy, S., Forstmann, M., Carhart-Harris, R. L., Timmermann, C., Luke, D., & Watts, R. (2020). The potential synergistic effects between psychedelic administration and nature contact for the improvement of mental health. Health psychology open, 7(2), 2055102920978123. https://doi.org/10.1177/2055102920978123

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