Altered State Research Articles

Cerebrale ischemie als oorzaak van verminderd bewustzijn: het Percheron-infarct

Artery of Percheron infarction as an unusual cause of a reduced level of consciousness An acute onset of hemiparesis, aphasia or hemianopsia will promptly lead to the diagnosis of a stroke. However, a thalamic infarction does not always manifest with these classical symptoms due to its crucial role as a relay station between cortical brain structures, subcortical areas and the brainstem. The case of an 87-year-old woman with an altered state of consciousness due to bilateral thalamic ischemia as a result of an artery of Percheron infarction is reported. This case illustrates the clinical and diagnostic challenges in patients with an altered consciousness. The differential diagnosis is broad. One has to exclude a bilateral thalamic infarction since an early diagnosis of an ischemic stroke is crucial to initiate a proper treatment and thereby prevent morbidity and mortality.

A review of methods of age estimation based on postmortem computed tomography

Abstract Age at death is one of the key elements of the ‘biological profile’ prepared when analysing unidentified human remains. Biological age is determined according to physiological indicators and developmental stage, which can be determined by bone assessment. It is worth remembering that the researcher must interpret each case individually and in accordance with the current state of knowledge. One of the most developed tools for analysing human remains is postmortem computed tomography. This allows for the visualisation not only of bones without maceration but also of the entire body under various altered states, including corpses in advanced stages of decomposition and burnt bodies. The aim of this review is to present the current methods for age estimation based on postmortem computed tomography evaluation, comparing the results presented in 18 research projects published between 2013 and 2023 on foetuses, children, and adults from contemporary populations. Recent literature includes assessment of bones and characteristics such as skulls, teeth, vertebrae, pelvises, and long bones to estimate age at death. We cover the methods used in this recent literature, including machine learning, and discuss the advantages and disadvantages of them.

The psychedelic mind: Current user perceptions of psychedelic drugs and their use

Purpose Psychedelic drugs can induce altered states of consciousness characterised by changes in visual perception, tactile sensation, cognition, and emotion. Although there is a history of misinformation surrounding these drugs, recent investigation has reinvigorated interest. However, little research has assessed the attitudes of psychedelic consumers regarding these substances. The current study aims to explore the attitudes and perceptions of people with experience with psychedelic drugs, specifically surrounding psychedelic drugs themselves and their use within Aotearoa New Zealand. Design/methodology/approach Nineteen individuals with experience of psychedelic use were recruited to participate across eight groups in semi-structured, exploratory interviews, where a range of topics associated with psychedelics were discussed. Reflexive thematic analysis of the data focussed on participants’ current perceptions and attitudes. Findings Four themes were produced: (1) a negative historical influence on current perceptions of psychedelics; (2) knowledge is key but not everyone has it; (3) prohibition is not working, policy needs to change; (4) psychedelics have therapeutic potential. These themes emphasise key features of people with experience of psychedelic drugs’ current views and highlight potential areas for future investigation and intervention. Social implications Findings indicate a need for greater public knowledge and awareness of psychedelics in Aotearoa society. Findings also inform information, education and policy, which in turn will reduce the stigma and associated harm that those who have used or use psychedelic drugs may experience. Originality/value To the best of the authors’ knowledge, qualitative research aiming to understand attitudes and perspectives surrounding psychedelic drugs and their use from a drug users’ perspective have not yet been assessed.

Altered states of consciousness caused by a mindfulness-based programme up to a year later: Results from a randomised controlled trial.

Mindfulness-based programmes (MBPs) have shown beneficial effects on mental health. There is emerging evidence that MBPs may also be associated with marked deviations in the subjective experience of waking consciousness. We aimed to explore whether MBPs can have a causal role in different types of such states. We conducted a pragmatic randomised controlled trial (ACTRN12615001160527). University of Cambridge students without severe mental illness were randomised to an 8-week MBP plus mental health support as usual (SAU), or to SAU alone. We adapted the Altered States of Consciousness Rating Scale (OAV, 0-100-point range) to assess spontaneous experiences in daily life, and included it as a post-hoc secondary outcome at the end of the one-year follow-up questionnaire. Two-part model analyses compared trial arms, and estimated dose-response effects of formal (meditation) and informal (daily activities) mindfulness practice during the year. Sensitivity analyses correcting for multiple comparisons were conducted. We randomised 670 participants; 205 (33%) completed the OAV. In comparison with SAU, MBP participants experienced unity more frequently and intensively (two-part marginal effect (ME) = 6.26 OAV scale points, 95% confidence interval (CI) = 2.24, 10.27, p = 0.006, Cohen's d = 0.33) and disembodiment more frequently (ME = 4.84, 95% CI = 0.86, 8.83, p = 0.019, Cohen's d = 0.26). Formal practice predicted spiritual, blissful and unity experiences, insightfulness, disembodiment, and changed meanings. Informal practice predicted unity and blissful experiences. Trial arm comparisons and informal practice effects lost significance after corrections for multiple comparisons, but formal practice dose-response effects remained significant. Results provide a novel suggestion of causal links between mindfulness practice and specific altered states of consciousness. To optimise their impact, practitioners and teachers need to anticipate and handle them appropriately. Future studies need to confirm findings and assess mechanisms and clinical implications.

Herbal medicines in Alzheimer's disease and the involvement of gut microbiota.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive impairment. It severely affects the quality of life of victims. The prevalence of AD has been increasing in recent years. Therefore, it is of great importance to elucidate the pathogenic mechanism of AD and search for effective therapeutic approaches. Gut microbiota dysbiosis, an altered state of gut microbiota, has been well known for its involvement in the pathogenesis of AD. Much effort has been made in searching for approaches capable of modulating the composition of gut microbiota in recent years. Herbal medicines have attracted extensive attention in recent decades for the prevention and treatment of AD. Here, we gave an overview of the recent research progress on the modulatory effects of herbal medicines and herbal formulae on gut microbiota as well as the possible beneficial effects on AD, which may provide new insights into the discovery of anti-AD agents and their therapeutic potential for AD through modulating the composition of gut microbiota.

Palinacousis in amyloidosis: exploring the hallucinatory phenomenon in brain pathology—a case report

BackgroundHereditary transthyretin amyloidosis, caused by transthyretin gene mutations, progresses with systemic impact and often presents peripheral neuropathy. Recent research reveals central nervous system involvement, marked by leptomeningeal amyloid accumulation and transient focal neurological episodes displaying cortical dysfunction.Case presentationA 47-year-old Caucasian man with hereditary transthyretin amyloidosis presented with motor aphasia, right hemiparesis, fever, and an altered state of consciousness. Tests ruled out stroke or infection. While improving, the patient reported an ongoing auditory repetition phenomenon for 48 hours despite efforts to shift focus or introduce new stimuli.ConclusionThis represents the first known case report documenting palinacousis in hereditary transthyretin amyloidosis attributed to central nervous system involvement. This case highlights the complexities in assessment and management of patients when neurological and psychiatric symptoms overlap.

Direct evidence from high-field magnetotransport for a dramatic change of quasiparticle character in van der Waals ferromagnet Fe3−xGeTe2

Magnetometry and magnetoresistance (MR) data taken on the van der Waals ferromagnet Fe3−xGeTe2 (FGT) reveal three distinct contributions to the MR: a linear negative component, a contribution from closed Fermi-surface orbits, and an enhancement proportional to the square of the applied magnetic field which is linked to a noncoplanar spin arrangement. Contrary to earlier studies on FGT, by accounting for the field dependence of the anomalous Hall effect, we find that the ordinary Hall coefficient decreases markedly below 80 K, indicating a significant change in character of the electrons and holes on the Fermi-surface at this temperature. The resulting altered ground state eventually causes the Hall coefficient to reverse sign at 35 K. Our Hall data support the proposal that Kondo-lattice behavior develops in this d-electron material below 80 K. Additional evidence comes from the negative linear component of the MR, which arises from electron-magnon scattering with an atypical temperature dependence attributable to the onset of Kondo screening. Published by the American Physical Society 2024

Methods, precision, and analytical sensitivity of a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction.

Fibrinolysis is a critical aspect of the hemostatic system, with assessment of fibrinolytic potential being critical to predict bleeding and clotting risk. We describe the method for a novel low-plasma-volume assay of fibrinolytic capacity utilizing the euglobulin fraction (the "modified mini-euglobulin clot lysis assay [ECLA]"), its analytic sensitivity to alterations in key fibrinolytic substrates/regulators, and its initial applications in acute and convalescent disease cohorts. The modified mini-ECLA requires 50 μL of plasma, a maximal read time of 3 h (with most results available within 60 min), and is entirely performed in a 96-well microplate. Assay measurements were obtained in a variety of commercial control and deficient plasmas representing clinically relevant hypo- and hyperfibrinolytic states, and in three distinct adolescent cohorts with acute or convalescent illness: critically ill, following endotracheal intubation; acute COVID-19-related illness; and ambulatory, 3 months following a venous thromboembolic event. In 100% and 75% deficient plasmas, hypofibrinolysis for plasminogen-deficient, fibrinolysis for alpha-2-antiplasmin-deficient, and hyperfibrinolysis for plasminogen activator inhibitor-1-deficient plasmas were observed. The modified mini-ECLA Clot Lysis Time Ratio ("CLTR") demonstrated moderate-strength correlations with the Clot Formation and Lysis (CloFAL) assay, is analytically sensitive to altered fibrinolytic states in vitro, and correlates with clinical outcomes in preliminarily-studied patient populations.

Sleep and circadian rhythm activity alterations during adolescence in a mouse model of neonatal fentanyl withdrawal syndrome.

Fentanyl, a highly potent synthetic opioid, is a major contributor to the ongoing opioid epidemic. During adulthood, fentanyl is known to induce pronounced sleep and circadian disturbances during use and withdrawal. Children exposed to opioids in utero are likely to develop neonatal opioid withdrawal syndrome, and display sleep disturbances after birth. However, it is currently unknown how neonatal opioid withdrawal from fentanyl impacts sleep and circadian rhythms in mice later in life. To model neonatal opioid withdrawal syndrome, mice were treated with fentanyl from postnatal days 1 through 14, analogous to the third trimester of human gestation. After weaning, fentanyl and saline treated mice underwent non-invasive sleep and circadian rhythm monitoring during adolescence postnatal days 23 through 30. Neonatal fentanyl exposure led to reduced duration of wake and a decrease in the number of bouts of non-rapid eye movement sleep. Further, neonatally exposed mice displayed an increase in the average duration of rapid eye movement sleep bouts, reflecting an overall increase in the percent time spent in rapid eye movement sleep across days. Neonatal fentanyl exposure leads to altered sleep-wake states during adolescence in mice.

A Short Sequence Targets Transmembrane Proteins to Primary Cilia.

Primary cilia are finger-like sensory organelles that extend from the bodies of most cell types and have a distinct lipid and protein composition from the plasma membrane. This partitioning is maintained by a diffusion barrier that restricts the entry of non-ciliary proteins, and allows the selective entry of proteins harboring a ciliary targeting sequence (CTS). However, CTSs are not stereotyped and previously reported sequences are insufficient to drive efficient ciliary localisation across diverse cell types. Here, we describe a short peptide sequence that efficiently targets transmembrane proteins to primary cilia in all tested cell types, including human neurons. We generate human-induced pluripotent stem cell (hiPSC) lines stably expressing a transmembrane construct bearing an extracellular HaloTag and intracellular fluorescent protein, which enables the bright, specific labeling of primary cilia in neurons and other cell types to facilitate studies of cilia in health and disease. We demonstrate the utility of this resource by developing an image analysis pipeline for the automated measurement of primary cilia to detect changes in their length associated with altered signaling or disease state.

Suicide Following a Near-Death Experience.

Background: Sometimes during real or presumed life-threatening and/or near-death circumstances, an individual undergoes an altered state of consciousness referred to as a near-death experience (NDE). The prevalent position in the field of NDE research for the last several decades has been that such experiences result in positive antisuicidal attitudes and that it is highly unlikely that experients will try to kill themselves afterward. In addition, the important consideration of passive suicidal ideation is neglected in NDE research. Aims: To question the premature assumption that people are highly unlikely to die by suicide after an NDE. Method: Four case studies of suicide after an NDE are provided and examined. Results: Although important quantitative data are still needed, it can no longer be argued that people do not die by suicide after an NDE. Limitations: Only four cases were available for examination, and the degree of impact that the NDE had on their suicide is uncertain. Conclusion: Much more research is needed on suicide risk post NDE. In the meantime, the NDE should not be ignored in suicide assessments, but therapists and other relevant professionals need to be attentive to any possible indications of either active or passive suicidal ideation post NDE.

Psychothérapie assistée par psychédéliques (PAP) : le modèle genevois

BackgroundIn this article, we aim to describe an interdisciplinary model for psychedelic assisted psychotherapy (PAP) that we have developed at the Geneva University Hospitals, in an institutional setting. Our model integrates the collaborative efforts of psychiatrists, psychologists, and nurses establishing a structured framework for administering PAP in a safe, controlled, and standardized manner. IntroductionPsychedelic assisted psychotherapy (PAP) is a psychotherapeutic approach that utilizes the profound alteration of the state of consciousness induced by psychedelic substances to enhance therapeutic outcomes. This innovative approach, which has been neglected due to historical biases rather than empirical evidence, is now experiencing a renewed interest among clinicians. Contemporary research, equipped with advanced methodologies and a rigorous scientific approach, is showing significant therapeutic potential for a range of mental health disorders. In Switzerland, the legal framework authorizes the medicinal use since 2014 for exceptional authorizations for the medicinal use of LSD and psilocybin for therapeutic purposes, under strict regulations. MethodWe provide a comprehensive description of the PAP protocol implemented at the Geneva University Hospitals, beginning with its inception in September 2020. Our methodological outline includes the administrative and clinical selection criteria for patient eligibility; the preparatory sessions designed to introduce the patients with psychoeducation interventions and the analysis of intention and therapeutical objectives; the controlled administration of psychedelics in a supportive environment; and the integration sessions that follow psychedelic experiences. Our protocol emphasizes safety, ethical considerations, and the importance of a supportive therapeutic relationship throughout the process. We also describe questionnaires we use to qualify and assess the alteration in the state of consciousness, namely The Five Dimension Altered States of Consciousness (5AD-ASC) and the Mystical Experience Questionnaire (MEQ). Since the start of the program in September 2020 and up to February 2024, a total of 224 personal authorizations (114 LSD, 110 Psilocybin) have been issued to the Geneva University Hospital PAP team, for a total of 396 individual sessions. DiscussionThe core argument presented in this article is that the psychedelic-induced alteration of consciousness is a novel therapeutic tool, which works as a potent catalyst that can be synergistically combined with traditional dialogue-based psychotherapy. This combination has the potential to support the psychotherapeutic processes and enable breakthroughs in cases where conventional therapy has reached its limits. We discuss the implications of this approach, reflecting on both its challenges and its transformative potential within its clinical application. ConclusionThe conclusion of our article is an endorsement of the continued basic and clinical research on PAP. By presenting a detailed framework of the PAP process, including its preparatory, experiential, and integrative phases, we advocate for a structured and scientifically grounded exploration of its therapeutic efficacy. Our conclusion calls for a broader acceptance and integration of PAP within clinical practice, provided it is underpinned by ongoing research, ethical practice, and institutional support.

Low-Dose Baclofen-Induced Encephalopathy in a Patient with End-Stage Renal Disease: A Case Report

Baclofen, a gamma-aminobutyric acid-B receptor agonist, is commonly used for central-origin muscle spasticity and spasm and neuropathic pain. Baclofen toxicity has been reported to cause a range of symptoms including drowsiness, confusion, respiratory depression, seizures, and even coma, particularly with dosage significantly exceeding therapeutic levels. Given that the baclofen is predominantly eliminated through the kidneys, patients with renal failure are at substantial risk for neurotoxic effects. We report a case of baclofen-induced encephalopathy in a patient with end-stage renal disease, characterized by an altered mental state with myoclonus following the consumption of a low dose of baclofen.

“The Pop Quiz That Does Everything but Write Itself” Pilot Examination of the Suggestive or Acting Potential of the Word

“Then God said, ‘Let there be light! And there was light.” These words are not only said, but they bring into being what is said. That God created man in his image and likeness is reflected in our speech. By their very nature, our words are creative: when they are uttered, they always create something. In psychological terms, words are the basis of our relationships, successes and failures, and our moods. They define and shape our social environment and govern our thoughts and actions. They influence our self-esteem, well-being, the development of our abilities, and performance and, last but not least, they can affect the functioning of our cells and bodily processes. Suggestion is the term used to describe any message, generally verbal, that has an involuntary effect on the receiver, who can transform words into action as a result. It is an essential element of communication that can occur in many social situations. In our pilot study, we used the tools of suggestive communication in instructions and questions related to a school essay and investigated their impact on performance. Keywords: suggestive communication, altered state of consciousness, performance anxiety, school performance, pop quiz

LEADERSHIP IN THE DIGITAL AGE: NAVIGATING COMPLEXITY THROUGH CRITICAL THINKING, CREATIVITY, AND UNCONVENTIONAL APPROACHES

This paper explores various dimensions of leadership in contexts of a new age, emphasising critical thinking, mental flexibility, and innovative development methods. It addresses challenges posed by technological advancements and leaders' need to cultivate adaptability, creativity, and foresight. Using unconventional approaches, such as the sweat lodge method and exploration of altered states of consciousness, provides intriguing avenues for enhancing leadership qualities. Additionally, the role of substances like psilocybin in fostering creativity and well-being is examined. Ultimately, this paper underscores the irreplaceable role of human cognition and leadership amidst technological progress, advocating for continual development in leadership practices to navigate modern complexities.

New perspectives on the role of biological factors in anorexia nervosa: Brain volume reduction or oxidative stress, which came first?

Anorexia nervosa (AN) is an eating disorder (ED) that has seen an increase in its incidence in the last thirty years. Compared to other psychosomatic disorders, ED can be responsible for many major medical complications, moreover, in addition to the various systemic impairments, patients with AN undergo morphological and physiological changes affecting the cerebral cortex. Through immunohistochemical studies on portions of postmortem human brain of people affected by AN and healthy individuals, and western blot studies on leucocytes of young patients and healthy controls, this study investigated the role in the afore-mentioned processes of altered redox state. The results showed that the brain volume reduction in AN could be due to an increase in the rate of cell death, mainly by apoptosis, in which mitochondria, main cellular organelles affected by a decreased dietary intake, and a highly compromised intracellular redox balance, may play a pivotal role

Volumetric imaging of the tumor microvasculature reflects outcomes and genomic states of clear cell renal cell carcinoma.

Tumor structure is heterogeneous and complex, and it is difficult to obtain complete characteristics by two-dimensional analysis. The aim of this study was to visualize and characterize volumetric vascular information of clear cell renal cell carcinoma (ccRCC) tumors using whole tissue phenotyping and three-dimensional light-sheet microscopy. Here, we used the diagnosing immunolabeled paraffin-embedded cleared organs pipeline for tissue clearing, immunolabeling, and three-dimensional imaging. The spatial distributions of CD34, which targets blood vessels, and LYVE-1, which targets lymphatic vessels, were examined by calculating three-dimensional density, vessel length, vessel radius, and density curves, such as skewness, kurtosis, and variance of the expression. We then examined those associations with ccRCC outcomes and genetic alteration state. Formalin-fixed paraffin-embedded tumor samples from 46 ccRCC patients were included in the study. Receiver operating characteristic curve analyses revealed the associations between blood vessel and lymphatic vessel distributions and pathological factors such as a high nuclear grade, large tumor size, and the presence of venous invasion. Furthermore, three-dimensional imaging parameters stratified ccRCC patients regarding survival outcomes. An analysis of genomic alterations based on volumetric vascular information parameters revealed that PI3K-mTOR pathway mutations related to the blood vessel radius were significantly different. Collectively, we have shown that the spatial elucidation of volumetric vasculature information could be prognostic and may serve as a new biomarker for genomic alterations. High-end tissue clearing techniques and volumetric immunohistochemistry enable three-dimensional analysis of tumors, leading to a better understanding of the microvascular structure in the tumor space.

Ketamine reduces the neural distinction between self- and other-produced affective touch: a randomized double-blind placebo-controlled study

A coherent sense of self is crucial for social functioning and mental health. The N-methyl-D-aspartate antagonist ketamine induces short-term dissociative experiences and has therefore been used to model an altered state of self-perception. This randomized double-blind placebo-controlled cross-over study investigated the mechanisms for ketamine’s effects on the bodily sense of self in the context of affective touch. Thirty healthy participants (15 females/15 males, age 19–39) received intravenous ketamine or placebo while performing self-touch and receiving touch by someone else during functional MRI – a previously established neural measure of tactile self-other-differentiation. Afterwards, tactile detection thresholds during self- and other-touch were assessed, as well as dissociative states, interoceptive awareness, and social touch attitudes. Compared to placebo, ketamine administration elicited dissociation and reduced neural activity associated with self-other-differentiation in the right temporoparietal cortex, which was most pronounced during other-touch. This reduction correlated with ketamine-induced reductions in interoceptive awareness. The temporoparietal cortex showed higher connectivity to somatosensory cortex and insula during other- compared to self-touch. This difference was augmented by ketamine, and correlated with dissociation strength for somatosensory cortex. These results demonstrate that disrupting the self-experience through ketamine administration affects neural activity associated with self-other-differentiation in a region involved in touch perception and social cognition, especially with regard to social touch by someone else. This process may be driven by ketamine-induced effects on top-down signaling, rendering the processing of predictable self-generated and unpredictable other-generated touch more similar. These findings provide further evidence for the intricate relationship of the bodily self with the tactile sense.

Adult Inception of Ketogenic Diet Therapy Increases Sleep during the Dark Cycle in C57BL/6J Wild Type and Fragile X Mice.

Sleep problems are a significant phenotype in children with fragile X syndrome. Our prior work assessed sleep-wake cycles in Fmr1KO male mice and wild type (WT) littermate controls in response to ketogenic diet therapy where mice were treated from weaning (postnatal day 18) through study completion (5-6 months of age). A potentially confounding issue with commencing treatment during an active period of growth is the significant reduction in weight gain in response to the ketogenic diet. The aim here was to employ sleep electroencephalography (EEG) to assess sleep-wake cycles in mice in response to the Fmr1 genotype and a ketogenic diet, with treatment starting at postnatal day 95. EEG results were compared with prior sleep outcomes to determine if the later intervention was efficacious, as well as with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. The data replicated findings that Fmr1KO mice exhibit sleep-wake patterns similar to wild type littermates during the dark cycle when maintained on a control purified-ingredient diet but revealed a genotype-specific difference during hours 4-6 of the light cycle of the increased wake (decreased sleep and NREM) state in Fmr1KO mice. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of NREM sleep in both wild type and Fmr1KO mice during the dark cycle. Differences in sleep microstructure (length of wake bouts) supported the altered sleep states in response to ketogenic diet. Commencing ketogenic diet treatment in adulthood resulted in a 15% (WT) and 8.6% (Fmr1KO) decrease in body weight after 28 days of treatment, but not the severe reduction in body weight associated with starting treatment at weaning. We conclude that the lack of evidence for improved sleep during the light cycle (mouse sleep time) in Fmr1KO mice in response to ketogenic diet therapy in two studies suggests that ketogenic diet may not be beneficial in treating sleep problems associated with fragile X and that actigraphy is not a reliable surrogate for sleep EEG in mice.

Cortisol, Stress, and Disease-Bidirectional Associations; Role for Corticosteroid-Binding Globulin?

Selye described stress as a unified neurohormonal mechanism maintaining homeostasis. Acute stress system activation is adaptive through neurocognitive, catecholaminergic, and immunomodulation mechanisms, followed by a reset via cortisol. Stress system components, the sympathoadrenomedullary system, hypothalamic-pituitary-adrenal axis, and limbic structures are implicated in many chronic diseases by establishing an altered homeostatic state, allostasis. Consequent "primary stress system disorders" were popularly accepted, with phenotypes based on conditions such as Cushing syndrome, pheochromocytoma, and adrenal insufficiency. Cardiometabolic and major depressive disorders are candidates for hypercortisolemic etiology, contrasting the "hypocortisolemic symptom triad" of stress sensitivity, chronic fatigue, and pain. However, acceptance of chronic stress etiology requires cause-and-effect associations, and practical utility such as therapeutics altering stress system function. Inherent predispositions to stress system perturbations may be relevant. Glucocorticoid receptor (GR) variants have been associated with metabolic/neuropsychological states. The SERPINA6 gene encoding corticosteroid-binding globulin (CBG), was the sole genetic factor in a single-nucleotide variation-genome-wide association study linkage study of morning plasma cortisol, a risk factor for cardiovascular disease, with alterations in tissue-specific GR-related gene expression. Studies showed genetically predicted high cortisol concentrations are associated with hypertension and anxiety, and low CBG concentrations/binding affinity, with the hypocortisolemic triad. Acquired CBG deficiency in septic shock results in 3-fold higher mortality when hydrocortisone administration produces equivocal results, consistent with CBG's role in spatiotemporal cortisol delivery. We propose some stress system disorders result from constitutional stress system variants rather than stressors themselves. Altered CBG:cortisol buffering may influence interstitial cortisol ultradian surges leading to pathological tissue effects, an example of stress system variants contributing to stress-related disorders.