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Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine

/ Depressive Disorders, Ketamine, Papers / Leave a Comment / / , , , ,

Abstract

Several studies have demonstrated the effectiveness of ketamine in rapidly alleviating depression and suicidal ideation. Intense research efforts have been undertaken to expose the precise mechanism underlying the antidepressant action of ketamine; however, the translation of findings into new clinical treatments has been slow. This translational gap is partially explained by a lack of understanding of the function of time and circadian timing in the complex neurobiology around ketamine. Indeed, the acute pharmacological effects of a single ketamine treatment last for only a few hours, whereas the antidepressant effects peak at around 24 hours and are sustained for the following few days. Numerous studies have investigated the acute and long-lasting neurobiological changes induced by ketamine; however, the most dramatic and fundamental change that the brain undergoes each day is rarely taken into consideration. Here, we explore the link between sleep and circadian regulation and rapid-acting antidepressant effects and summarize how diverse phenomena associated with ketamine’s antidepressant actions – such as cortical excitation, synaptogenesis, and involved molecular determinants – are intimately connected with the neurobiology of wake, sleep, and circadian rhythms. We review several recently proposed hypotheses about rapid antidepressant actions, which focus on sleep or circadian regulation, and discuss their implications for ongoing research. Considering these aspects may be the last piece of the puzzle necessary to gain a more comprehensive understanding of the effects of rapid-acting antidepressants on the brain.

Kohtala, S., Alitalo, O., Rosenholm, M., Rozov, S., & Rantamäki, T. (2021). Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine. Pharmacology & therapeutics, 221, 107741. https://doi.org/10.1016/j.pharmthera.2020.107741

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Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin

/ Headache Pain and Neurological Disorders, Mushrooms / Psilocybin, Papers / Leave a Comment / / , , , , , , , ,

Abstract

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, – 1.65 (95% CI: – 2.53 to – 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

Schindler, E., Sewell, R. A., Gottschalk, C. H., Luddy, C., Flynn, L. T., Lindsey, H., Pittman, B. P., Cozzi, N. V., & D’Souza, D. C. (2021). Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 18(1), 534–543. https://doi.org/10.1007/s13311-020-00962-y

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Ketamine in Bipolar Disorder: A Review

/ Depressive Disorders, Ketamine, Papers / Leave a Comment / / , ,

Abstract

Bipolar disorder (BD) is a psychiatric illness associated with high morbidity, mortality and suicide rate. It has neuroprogressive course and a high rate of treatment resistance. Hence, there is an unquestionable need for new BD treatment strategies. Ketamine appears to have rapid antidepressive and antisuicidal effects. Since most of the available studies concern unipolar depression, here we present a novel insight arguing that ketamine might be a promising treatment for bipolar disorder.

Wilkowska, A., Szałach, Ł., & Cubała, W. J. (2020). Ketamine in Bipolar Disorder: A Review. Neuropsychiatric disease and treatment, 16, 2707–2717. https://doi.org/10.2147/NDT.S282208

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Pivotal mental states

/ Papers, Psychology / Leave a Comment / / ,

Abstract

This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.

Brouwer, A., & Carhart-Harris, R. L. (2021). Pivotal mental states. Journal of psychopharmacology (Oxford, England), 35(4), 319–352. https://doi.org/10.1177/0269881120959637

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DARK Classics in Chemical Neuroscience: Salvinorin A

/ Neuroscience, Papers, Pharmacology & Chemistry, Salvia / Salvinorin A / Leave a Comment / / , , ,

Abstract

Salvinorin A is the main bioactive compound in Salvia divinorum, an endemic plant with ancestral use by the inhabitants of the Mazateca mountain range (Sierra Mazateca) in Oaxaca, México. The main use of la pastora, as locally known, is in spiritual rites due to its extraordinary hallucinogenic effects. Being the first known nonalkaloidal opioid-mediated psychotropic molecule, salvinorin A set new research areas in neuroscience. The absence of a protonated amine group, common to all previously known opioids, results in a fast metabolism with the concomitant fast elimination and swift loss of activity. The worldwide spread and psychotropic effects of salvinorin A account for its misuse and classification as a drug of abuse. Consequently, salvinorin A and Salvia divinorum are now banned in many countries. Several synthetic efforts have been focused on the improvement of physicochemical and biological properties of salvinorin A: from total synthesis to hundreds of analogues. In this Review, we discuss the impact of salvinorin A in chemistry and neuroscience covering the historical relevance, isolation from natural sources, synthetic efforts, and pharmacological and safety profiles. Altogether, the chemistry behind and the taboo that encloses salvinorin A makes it one of the most exquisite naturally occurring drugs.

Hernández-Alvarado, R. B., Madariaga-Mazón, A., Ortega, A., & Martinez-Mayorga, K. (2020). DARK Classics in Chemical Neuroscience: Salvinorin A. ACS chemical neuroscience, 10.1021/acschemneuro.0c00608. Advance online publication. https://doi.org/10.1021/acschemneuro.0c00608

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The potential use of N-methyl-3,4-methylenedioxyamphetamine (MDMA) assisted psychotherapy in the treatment of eating disorders comorbid with PTSD

/ Anxiety Disorders / PTSD, Eating Disorders, MDMA, Papers / Leave a Comment / / , ,

Abstract

Despite advances in the field, eating disorders (EDs) remain very challenging disorders to treat, especially when comorbid with posttraumatic stress disorder (PTSD). N-methyl-3,4-methylenedioxyamphetamine (MDMA)-assisted psychotherapy for treatment refractory PTSD shows great promise, with two-thirds of participants achieving full remission at 1 year or more at follow-up. PTSD is a common comorbidity associated with EDs, and patients with EDs and PTSD (ED-PTSD) are reported to have higher severities of illness, greater comorbidities, higher treatment dropouts, and poorer outcomes. We hypothesize that MDMA-assisted psychotherapy will be efficacious in the ED-PTSD population for both ED and PTSD symptoms. The rationales for and proposed mechanisms of MDMA-assisted psychotherapy for ED-PTSD are considered from neurobiological, psychological and social perspectives. MDMA is associated with unique psychopharmacological effects, including: 1) reduced fear, 2) enhanced wellbeing, 3) increased sociability/extroversion, 4) reduced self-criticism, 5) increased compassion for self/others, 6) increased interpersonal trust, and 7) alert state of consciousness. These anxiolytic and prosocial effects may counteract avoidance and hyperarousal in the context of psychotherapy for those with ED-PTSD. Other clinical features of EDs that may be amenable to MDMA-assisted psychotherapy include body image distortion, cognitive rigidity, and socio-emotional processing difficulties. To illustrate its potential, personal accounts of individuals with ED-PTSD symptoms reporting benefit from MDMA adjunctive to psychotherapy are described. In addition, the possible risks and challenges in conducting this work are addressed, and future implications of this proposal are discussed.

Brewerton, T. D., Lafrance, A., & Mithoefer, M. C. (2021). The potential use of N-methyl-3,4-methylenedioxyamphetamine (MDMA) assisted psychotherapy in the treatment of eating disorders comorbid with PTSD. Medical hypotheses, 146, 110367. https://doi.org/10.1016/j.mehy.2020.110367

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Anti-inflammatory activity of ayahuasca: therapeutical implications in neurological and psychiatric diseases

/ 5-MeO-DMT, Ayahuasca, DMT, Neuroscience, Papers, Substance / Leave a Comment / / , ,

Abstract

Ayahuasca is a decoction with psychoactive properties, used for millennia for therapeutic and religious purposes by indigenous groups and the population of amazonian countries. As described in this narrative review, it is essentially constituted by β-carbolines and tryptamines, and it has therapeutic effects on behavioral disorders due to the inhibition of the monoamine oxidase enzyme and the activation of 5-hydroxytryptamine receptors, demonstrated through preclinical and clinical studies. It was recently observed that the pharmacological response presented by ayahuasca is linked to its anti-inflammatory action, attributed mainly to dimethyltryptamines (N, N-dimethyltryptamine and 5-methoxy-N, N-dimethyltryptamine), which act as endogenous systemic regulators of inflammation and immune homeostasis, also through sigma-1 receptors. Therefore, since neuroinflammation is among the main pathophysiological mechanisms related to the development of neurological and psychiatric diseases, we suggest, based on the available evidence, that ayahuasca is a promising and very safe therapeutic strategy since extremely high doses are required to reach toxicity. However, even so, additional studies are needed to confirm such evidence, as well as the complete elucidation of the mechanisms involved.

da Silva, M. G., Daros, G. C., & de Bitencourt, R. M. (2021). Anti-inflammatory activity of ayahuasca: therapeutical implications in neurological and psychiatric diseases. Behavioural brain research, 400, 113003. https://doi.org/10.1016/j.bbr.2020.113003

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Stability of psilocybin and its four analogs in the biomass of the psychotropic mushroom Psilocybe cubensis

/ Mushrooms / Psilocybin, Papers, Pharmacology & Chemistry / Leave a Comment / / , , , , ,

Abstract

Psilocybin, psilocin, baeocystin, norbaeocystin, and aeruginascin are tryptamines structurally similar to the neurotransmitter serotonin. Psilocybin and its pharmacologically active metabolite psilocin in particular are known for their psychoactive effects. These substances typically occur in most species of the genus Psilocybe (Fungi, Strophariaceae). Even the sclerotia of some of these fungi known as “magic truffles” are of growing interest in microdosing due to them improving cognitive function studies. In addition to microdosing studies, psilocybin has also been applied in clinical studies, but only its pure form has been administrated so far. Moreover, the determination of tryptamine alkaloids is used in forensic analysis. In this study, freshly cultivated fruit bodies of Psilocybe cubensis were used for monitoring stability (including storage and processing conditions of fruiting bodies). Furthermore, mycelium and the individual parts of the fruiting bodies (caps, stipes, and basidiospores) were also examined. The concentration of tryptamines in final extracts was analyzed using ultra-high-performance liquid chromatography coupled with mass spectrometry. No tryptamines were detected in the basidiospores, and only psilocin was present at 0.47 wt.% in the mycelium. The stipes contained approximately half the amount of tryptamine alkaloids (0.52 wt.%) than the caps (1.03 wt.%); however, these results were not statistically significant, as the concentration of tryptamines in individual fruiting bodies is highly variable. The storage conditions showed that the highest degradation of tryptamines was seen in fresh mushrooms stored at -80°C, and the lowest decay was seen in dried biomass stored in the dark at room temperature.

Gotvaldová, K., Hájková, K., Borovička, J., Jurok, R., Cihlářová, P., & Kuchař, M. (2021). Stability of psilocybin and its four analogs in the biomass of the psychotropic mushroom Psilocybe cubensis. Drug testing and analysis, 13(2), 439–446. https://doi.org/10.1002/dta.2950

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Prescribing meaning: hedonistic perspectives on the therapeutic use of psychedelic-assisted meaning enhancement

/ Papers, Philosophy & Religious Studies, Psychology / Leave a Comment /

Abstract

The recent renaissance in research on psychedelic-assisted psychotherapy is showing great promise for the treatment of many psychiatric conditions. Interestingly, therapeutic outcomes for patients undergoing these treatments are predicted by the occurrence of a mystical experience-an experience characterised in part by a sense of profound meaning. This has led to hypotheses that psychedelic-assisted psychotherapy is therapeutic because it enhances perception of meaning, and consequently leads to a meaning response (a therapeutic mechanism that has been well described in the philosophical literature on the placebo effect). The putative mechanism of action of psychedelics as meaning enhancers raises normative ethical questions as to whether it can be justified to pharmacologically increase the perception of meaning in order to heal patients. Using the perspectives of hedonistic moral theories, this paper argues that if psychedelics operate as meaning enhancers, psychedelic-assisted psychotherapy can be ethically justified. An anti-hedonistic objection is presented by applying Robert Nozick’s Experience Machine thought experiment to the case of psychedelic-assisted psychotherapy. However, it is argued that this objection falls short for two reasons. First, even if pleasure and pain are not the only consequences which have moral value they are not morally irrelevant, therefore, therapeutic meaning enhancement can still be justified in cases of extreme suffering. Second, it is possible that psychedelic states of consciousness do not represent a false reality, hence their therapeutic meaning enhancement is not problematic according to Nozick’s standards.

Miceli McMillan R. (2021). Prescribing meaning: hedonistic perspectives on the therapeutic use of psychedelic-assisted meaning enhancement. Journal of medical ethics, 47(10), 701–705. https://doi.org/10.1136/medethics-2020-106619

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Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis

/ Ayahuasca, LSD, Mushrooms / Psilocybin, Papers, Psychology / Leave a Comment / / , , , , , ,

Abstract

Background: Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and lysergic acid diethylamide (LSD) on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias.

Methods: We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ⩾24 h post-administration. Effects were summarized by study design, timepoint, and outcome domain.

Results: A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges’ gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects.

Conclusions: High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.

Goldberg, S. B., Shechet, B., Nicholas, C. R., Ng, C. W., Deole, G., Chen, Z., & Raison, C. L. (2020). Post-acute psychological effects of classical serotonergic psychedelics: a systematic review and meta-analysis. Psychological medicine, 50(16), 2655–2666. https://doi.org/10.1017/S003329172000389X

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