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Dynamic coupling of whole-brain neuronal and neurotransmitter systems

April 13, 2020 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Remarkable progress has come from whole-brain models linking anatomy and function. Paradoxically, it is not clear how a neuronal dynamical system running in the fixed human anatomical connectome can give rise to the rich changes in the functional repertoire associated with human brain function, which is impossible to explain through long-term plasticity. Neuromodulation evolved to allow for such flexibility by dynamically updating the effectivity of the fixed anatomical connectivity. Here, we introduce a theoretical framework modeling the dynamical mutual coupling between the neuronal and neurotransmitter systems. We demonstrate that this framework is crucial to advance our understanding of whole-brain dynamics by bidirectional coupling of the two systems through combining multimodal neuroimaging data (diffusion magnetic resonance imaging [dMRI], functional magnetic resonance imaging [fMRI], and positron electron tomography [PET]) to explain the functional effects of specific serotoninergic receptor (5-HT2AR) stimulation with psilocybin in healthy humans. This advance provides an understanding of why psilocybin is showing considerable promise as a therapeutic intervention for neuropsychiatric disorders including depression, anxiety, and addiction. Overall, these insights demonstrate that the whole-brain mutual coupling between the neuronal and the neurotransmission systems is essential for understanding the remarkable flexibility of human brain function despite having to rely on fixed anatomical connectivity.

 
Kringelbach, M. L., Cruzat, J., Cabral, J., Knudsen, G. M., Carhart-Harris, R., Whybrow, P. C., … & Deco, G. (2020). Dynamic coupling of whole-brain neuronal and neurotransmitter systems. Proceedings of the National Academy of Sciences, 117(17), 9566-9576., https://doi.org/10.1073/pnas.1921475117
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Registered Clinical Trials Investigating Ketamine for Psychiatric Disorders

April 9, 2020 / Anxiety Disorders / PTSD, Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

Abstract

As interest has grown in the potential psychiatric applications of ketamine, the number of registered clinical trials has grown substantially. Herein, we summarize and analyze clinical trials registered with ClinicalTrials.gov that assess the treatment of any psychiatric disorder with ketamine or ketamine enantiomers (e.g., S-ketamine, R-ketamine), with a focus on ongoing clinical trials. A ClinicalTrials.gov search on February 21, 2020 returned 140 registered trials. Frequency data was analyzed to determine the distribution of study designs. The majority of trials (70%) investigated the therapeutic effect of ketamine in mood disorders (unipolar: 60%, bipolar: 0.7%, both: 5.7%). Suicidal ideation (13.1%), post-traumatic stress disorder (5.4%), and obsessive-compulsive disorder (3.6%) were also investigated. Intravenous (IV) administration was the most common route with 87% of the studies using IV ketamine. Single-dose studies represented 50% of IV ketamine studies. Few studies were assessing maintenance treatment. Most studies were phase I or II with few definitive phase III trials registered. Given the large number of ongoing studies assessing psychiatric application of ketamine, researchers and relevant stakeholders should consider not only completed, published studies, but also ongoing registered studies in adjudicating the most relevant research questions. More definitive phase III trials and maintenance studies of IV ketamine for mood disorders are required, as numerous completed and ongoing studies have already assessed and demonstrated the proof-of-concept of acute antidepressant effects in phase I and II trials.
Peyrovian, B., McIntyre, R., Phan, L., Lui, L. M., Gill, H., Majeed, A., … & Rosenblat, J. D. (2020). Registered clinical trials investigating ketamine for psychiatric disorders. Journal of Psychiatric Research., https://doi.org/10.1016/j.jpsychires.2020.03.020
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Exposure-Response Analysis to Assess the Concentration-QTc Relationship of Psilocybin/Psilocin

April 6, 2020 / Mushrooms / Psilocybin, Papers, Psychiatry & Medicine, Publications / By / , ,

Abstract

Psilocybin is being developed for treating major depressive disorder. Psilocybin is readily dephosphorylated to psilocin upon absorption. The potential for psilocin proarrhythmic effect was assessed using a concentration-QTc interval (C-QTc) analysis from an open-label single ascending dose study of psilocybin. Psilocybin doses ranged from 0.3 to 0.6 mg/kg. This trial showed a significant but shallow C-QTc relationship. At the clinical dose of 25 mg, the mean psilocin maximum concentration is 18.7 ng/mL, and the associated mean (upper 90% confidence interval of mean) QTcF change is 2.1 (6.6) milliseconds. Given the short half-life of psilocin of about 4 hours, there would be no accumulation after monthly oral doses used in clinical trials. The upper limit of the 90% confidence interval of the model-predicted mean ΔQTcF crossed 10 milliseconds at a psilocin concentration of 31.1 ng/mL. At a supraclinical psilocin maximum concentration of about 60 ng/mL, ΔQTcF remains low, with a mean (upper limit of the 90% confidence interval) of 9.1 (17.9) milliseconds. This analysis enabled the characterization of the C-QTc relationship and prediction of QTc prolongation at the expected clinical and possible higher psilocybin doses.

Dahmane, E., Hutson, P. R., & Gobburu, J. V. (2020). Exposure‐Response Analysis to Assess the Concentration‐QTc Relationship of Psilocybin/Psilocin. Clinical Pharmacology in Drug Development.; 10.1002/cpdd.796

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Psychedelic Psychiatry’s Brave New World

April 2, 2020 / LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , ,

Abstract

After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results. Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin, show promise for addressing a range of serious disorders, including depression and addiction.

Nutt, D., Erritzoe, D., & Carhart-Harris, R. (2020). Psychedelic Psychiatry’s Brave New World. Cell, 181(1), 24-28.
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Depression, Mindfulness, and Psilocybin: Possible Complementary Effects of Mindfulness Meditation and Psilocybin in the Treatment of Depression. A Review

March 31, 2020 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / ,

Abstract

Depression is a major public health problem that affects approximately 4.4% of the global population. Since conventional pharmacotherapies and psychotherapies are only partially effective, as demonstrated by the number of patients failing to achieve remission, alternative treatments are needed. Mindfulness meditation (MM) and psilocybin represent two promising novel treatments that might even have complementary therapeutic effects when combined. Since the current literature is limited to theoretical and empirical underpinnings of either treatment alone, the present review aimed to identify possible complementary effects that may be relevant to the treatment of depression. To that end, the individual effects of MM and psilocybin, and their underlying working mechanisms, were compared on a non-exhaustive selection of six prominent psychological and biological processes that are well known to show impairments in patients suffering from major depression disorder, that is mood, executive functioning, social skills, neuroplasticity, core neural networks, and neuroendocrine and neuroimmunological levels. Based on predefined search strings used in two online databases (PubMed and Google Scholar) 1129 articles were identified. After screening title and abstract for relevance related to the question, 82 articles were retained and 11 were added after reference list search, resulting in 93 articles included in the review. Findings show that MM and psilocybin exert similar effects on mood, social skills, and neuroplasticity; different effects were found on executive functioning, neural core networks, and neuroendocrine and neuroimmune system markers. Potential mechanisms of MM’s effects are enhanced affective self-regulation through mental strategies, optimization of stress reactivity, and structural and functional adjustments of prefrontal and limbic areas; psilocybin’s effects might be established via attenuation of cognitive associations through deep personal insights, cognitive disinhibition, and global neural network disintegration. It is suggested that, when used in combination, MM and psilocybin could exert complementary effects by potentiating or prolonging mutual positive effects, for example, MM potentially facilitating psilocybin-induced peak experiences. Future placebo-controlled double-blind randomized trials focusing on psilocybin-assisted mindfulness-based therapy will provide knowledge about whether the proposed combination of therapies maximizes their efficacy in the treatment of depression or depressive symptomatology.

Heuschkel, K., & Kuypers, K. P. (2020). Depression, Mindfulness, and Psilocybin: Possible Complementary Effects of Mindfulness Meditation and Psilocybin in the Treatment of Depression. A Review. Frontiers in Psychiatry, 11., https://doi.org/10.3389/fpsyt.2020.00224
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Experience of Music Used With Psychedelic Therapy: A Rapid Review and Implications.

March 30, 2020 / Ayahuasca, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , ,

Abstract

Bonny Method of Guided Imagery and Music emerged following discontinuation of psychedelic therapy research in the early 1970s, but psychedelic therapy research has since revived. Music remains a vital component. This study examined participants’ experiences of music in psychedelic therapy research. A rapid review of qualitative and quantitative journal articles in four major databases was conducted in February to April, 2019, using the terms hallucinogens, psychedelic, “lysergic acid diethylamide,” psilocybin, ayahuasca, music, and/or “music therapy.” Of 406 articles retrieved, 10 were included (n = 180; 18-69 years old). Participants had varied backgrounds. Music was widely considered integral for meaningful emotional and imagery experiences and self-exploration during psychedelic therapy. Music transformed through its elicitation of anthropomorphic, transportive, synesthetic, and material sensations. Music could convey love, carry listeners to other realms, be something to “hold,” inspire, and elicit a deep sense of embodied transformation. Therapeutic influence was especially evident in music’s dichotomous elicitations: Music could simultaneously anchor and propel. Participant openness to music and provision of participant-centered music were associated with optimal immediate and longer-term outcomes. Many studies reported scarce details about the music used and incidental findings of music experienced. Further understanding of participants’ idiosyncratic and shared responses to music during drug therapy phases will inform optimal development of flexible music protocols which enhance psychedelic therapy. Music therapists could be involved in the psychedelic therapy research renaissance through assisting with research to optimize music-based protocols used. If psychedelics become approved medicines, music therapists may be involved in offering psychedelic therapy as part of therapeutic teams.

O’Callaghan, C., Hubik, D. J., Dwyer, J., Williams, M., & Ross, M. (2020). Experience of Music Used With Psychedelic Therapy: A Rapid Review and Implications. Journal of Music Therapy., https://doi.org/10.1093/jmt/thaa006
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Long-term effects of psychedelic drugs: A systematic review

March 15, 2020 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , ,

Abstract

Research into the basic effects and therapeutic applications of psychedelic drugs has grown considerably in recent years. Yet, pressing questions remain regarding the substances’ lasting effects. Although individual studies have begun monitoring sustained changes, no study to-date has synthesized this information. Therefore, this systematic review aims to fill this important gap in the literature by synthesizing results from 34 contemporary experimental studies which included classic psychedelics, human subjects, and follow-up latencies of at least two weeks. The bulk of this work was published in the last five years, with psilocybin being the most frequently administered drug. Enduring changes in personality/attitudes, depression, spirituality, anxiety, wellbeing, substance misuse, meditative practices, and mindfulness were documented. Mystical experiences, connectedness, emotional breakthrough, and increased neural entropy were related to these long-term changes in psychological functioning. Finally, with proper screening, preparation, supervision, and integration, limited aversive side effects were noted by study participants. Future researchers should focus on including larger and more diverse samples, lengthier longitudinal designs, stronger control conditions, and standardized dosages.

Aday, J. S., Mitzkovitz, C. M., Bloesch, E. K., Davoli, C. C., & Davis, A. K. (2020). Long-term effects of psychedelic drugs: A systematic review. Neuroscience & Biobehavioral Reviews., 10.1016/j.neubiorev.2020.03.017
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Reviewing the Potential of Psychedelics for the Treatment of PTSD.

March 14, 2020 / Anxiety Disorders / PTSD, Ayahuasca, Depressive Disorders, Ketamine, LSD, MDMA, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / , , , , ,

Abstract

There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds, but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, two psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses four types of compounds: 3,4-methylenedioxymethamphetamine (MDMA), ketamine, classical psychedelics (e.g. psilocybin and LSD) and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms, to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research.
Krediet, E., Bostoen, T., Breeksema, J., van Schagen, A., Passie, T., & Vermetten, E. (2020). Reviewing the Potential of Psychedelics for the Treatment of PTSD. International Journal of Neuropsychopharmacology., https://doi.org/10.1093/ijnp/pyaa018
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The Psychedelic Renaissance and Its Forensic Implications

March 9, 2020 / Humanities & Art, LSD, Papers, Psychology, Publications / By /

Abstract

Recent years have seen a renaissance of research into the use of psychedelic compounds to address various psychiatric conditions. The study of these substances went dormant in 1970 when the United States government passed the Controlled Substances Act, which categorized lysergic acid diethylamide, commonly known as LSD or acid, as a Schedule I drug. The rise of psychedelics in research settings raises questions regarding their risks outside of clinical trials. The available data on the impact of psychedelic use on interpersonal violence and other criminal behavior remain scant. Although Timothy Leary’s work of the 1960s failed to clearly demonstrate a reduction in criminal recidivism with psychedelic-assisted psychotherapy, recent studies suggest that the use of psychedelics may reduce individuals’ risk of interpersonal violence. Forensic psychiatrists should be aware of this research, as well as the role that psychedelics may play in various forensic assessments. This article summarizes basic information that the forensic practitioner should know about psychedelic substances, including their various effects and proposed mechanism of action; describes historical and recent research into psychedelics and criminal behavior; and offers evaluators a practical means by which to assess individuals’ psychedelic use in forensic contexts.

Holoyda, B. (2020). The Psychedelic Renaissance and Its Forensic Implications. The journal of the American Academy of Psychiatry and the Law, 48(1), 87-97., 10.29158/JAAPL.003917-20
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Use of Benefit Enhancement Strategies among 5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) Users: Associations with Mystical, Challenging, and Enduring Effects.

March 9, 2020 / DMT, Neuroscience, Papers, Psychology, Publications / By / ,

Abstract

5-Methoxy-N,N-Dimethyltryptamine (5-MeO-DMT) is a potent, fast-acting psychedelic. Anecdotal reports from 5-MeO-DMT users suggest that they employ a variety of benefit enhancement (BE) strategies aimed to increase positive effects and decrease any potential challenging effects of the substance, but no empirical study has investigated this claim. We examined the prevalence of BE strategy use using secondary data from a survey of 5-MeO-DMT users (n = 515; Mage = 35.4, SD = 11.7; Male = 79%; White/Caucasian = 86%). Results indicated that BE strategy use was common in this sample. As a secondary aim, we assessed whether the use of BE strategies was associated with acute subjective (i.e., mystical-type, challenging) and persisting effects of 5-MeO-DMT among a subset of respondents who reported using 5-MeO-DMT once in their lifetime (n = 116). Results showed that the use of several BE strategies were associated with significantly more intense mystical-type effects and enduring beliefs about the personal meaning and spiritual significance of their experience, and some BE strategies were associated with less intense or challenging experiences. Data suggests that BE strategies are commonly used, and that the use of BE strategies may be associated with increases in positive mystical-type and enduring effects. The causal influence of BE strategies on acute/persisting effects of 5-MeO-DMT should be examined in longitudinal research.

Lancelotta, R. L., & Davis, A. K. (2020). Use of benefit enhancement strategies among 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) users: Associations with mystical, challenging, and enduring effects. Journal of Psychoactive Drugs, 1-9.,10.1080/02791072.2020.1737763
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