This paper formulates the action of psychedelics by integrating the free-energy principle and entropic brain hypothesis. We call this formulation relaxed beliefs under psychedelics (REBUS) and the anarchic brain, founded on the principle that—via their entropic effect on spontaneous cortical activity—psychedelics work to relax the precision of high-level priors or beliefs, thereby liberating bottom-up information flow, particularly via intrinsic sources such as the limbic system. We assemble evidence for this model and show how it can explain a broad range of phenomena associated with the psychedelic experience. With regard to their potential therapeutic use, we propose that psychedelics work to relax the precision weighting of pathologically overweighted priors underpinning various expressions of mental illness. We propose that this process entails an increased sensitization of high-level priors to bottom-up signaling (stemming from intrinsic sources), and that this heightened sensitivity enables the potential revision and deweighting of overweighted priors. We end by discussing further implications of the model, such as that psychedelics can bring about the revision of other heavily weighted high-level priors, not directly related to mental health, such as those underlying partisan and/or overly-confident political, religious, and/or philosophical perspectives. Significance Statement Psychedelics are capturing interest, with efforts underway to bring psilocybin therapy to marketing authorisation and legal access within a decade, spearheaded by the findings of a series of phase 2 trials. In this climate, a compelling unified model of how psychedelics alter brain function to alter consciousness would have appeal. Towards this end, we have sought to integrate a leading model of global brain function, hierarchical predictive coding, with an often-cited model of the acute action of psychedelics, the entropic brain hypothesis. The resulting synthesis states that psychedelics work to relax high-level priors, sensitising them to liberated bottom-up information flow, which, with the right intention, care provision and context, can help guide and cultivate the revision of entrenched pathological priors.

https://pharmrev.aspetjournals.org/content/pharmrev/71/3/316.full.pdf

REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics.

Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics. These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.

Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders.

Classic psychedelics produce altered states of consciousness that individuals often interpret as meaningful experiences. Across a number of human studies, when the participant-rated intensity of the overall drug effects are statistically controlled for, certain subjective effects predict therapeutic and other desirable outcomes. Underlying neurobiological mechanisms are likely necessary but not sufficient to confer full and enduring beneficial effects. We propose that the subjective effects of psychedelics are necessary for their enduring beneficial effects and that these subjective effects account for the majority of their benefit.

The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects.

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.

A non-hallucinogenic psychedelic analogue with therapeutic potential

Background:A recently published randomized controlled trial compared single-dose psilocybin with single-dose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric...

Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer:

https://escholarship.org/content/qt9xb8q5z6/qt9xb8q5z6.pdf?t=q7c1km

Psychedelics Promote Structural and Functional Neural Plasticity

Cortical neuron atrophy is a hallmark of depression and includes neurite retraction, dendritic spine loss, and decreased synaptic density. Psychoplastogens, small molecules capable of rapidly promoting cortical neuron growth, have been hypothesized to produce long-lasting positive effects on behavior by rectifying these deleterious structural and functional changes. Here we demonstrate that ketamine and LSD, psychoplastogens from two structurally distinct chemical classes, promote sustained growth of cortical neurons after only short periods of stimulation. Furthermore, we show that psychoplastogen-induced cortical neuron growth can be divided into two distinct epochs: an initial stimulation phase requiring TrkB activation and a growth period involving sustained mTOR and AMPA receptor activation. Our results provide important temporal details concerning the molecular mechanisms by which next-generation antidepressants produce persistent changes in cortical neuron structure, and they suggest that rapidly excreted psychoplastogens might still be effective neurotherapeutics with unique advantages over compounds like ketamine and LSD.

Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth.

Cannabidiol (CBD)-infused pet treats are becoming a huge market for pet owners as they turn to this supplement for a non-traditional therapeutic option. However, CBD's short-term or long-term effec...

https://www.tandfonline.com/doi/pdf/10.1080/24734306.2018.1434470

Cannabinoid treats as adjunctive therapy for pets: gaps in our knowledge

Mobile electrocardiogram (ECG) devices are valuable tools for teaching ECG interpretation. The primary purpose of this follow-up study was to determine if an ECG active learning session could be safely and effectively performed during the coronavirus disease 2019 (COVID-19) pandemic using a newly developed mobile 6-lead ECG device. Additionally, we examined the educational impact of these active learning sessions on student knowledge of cardiovascular physiology and the utility of the mobile 6-lead ECG device in a classroom setting. In this study, first-year medical students (MS1) performed four active learning activities using the new mobile 6-lead ECG device. Data were collected from 42 MS1s through a quantitative survey administered in September 2020. Overall, students felt the activity enhanced their understanding of the course material and that the activity was performed safely and in compliance with local COVID-19 guidelines. These results emphasize student preference for hands-on, small group learning activities in spite of the pandemic.

Educational impact of an active learning session with 6-lead mobile electrocardiography on medical students’ knowledge of cardiovascular physiology during the COVID-19 pandemic in the United States: a survey-based observational study

Abstract Mild autonomous cortisol secretion is characterized by the failure to suppress cortisol sufficiently after dexamethasone administration but without the stigmata of overt Cushing's syndrome. This condition, diagnosed in up to 50% of adrenal incidentalomas, has low overall rates of progression and mild cases can present a treatment dilemma. Here we describe one such case of cortisol excess well managed with a surveillance strategy rather than surgical intervention. A 49-year-old female with a past medical history of hypothyroidism was evaluated in the endocrine clinic for an incidental adrenal mass. CT imaging revealed a 2.7 cm left adrenal nodule, stable in size compared to prior imaging, with features typical of benign adrenocortical adenoma. Initial 1 mg DST with 8 am cortisol of 11.7µg/dl. Late night salivary cortisol (LNSC)level was found to be elevated at 130 ng/dl (nl<100 ng/dL). At that time, 24-hour urine free cortisol (UFC) was found to be borderline at 23.98 µg/day (nl<24 µg/day). Further testing at 6 months and 1 year from initial assessment showed persistently elevated LNSC level (110 ng/dL) and stable 24-hour UFC at 24 µg/day. Morning ACTH level was 19 pg/mL. One year after initial assessment, LNSC continued to be elevated at 0.106 µg/dL (nl <0.010–0.090 µg/dL) and repeat overnight 1 mg DST with 8am cortisol was unsuppressed at 10 mcg/dL representing at least two years of autonomous, mildly elevated cortisol levels. DHEA-S was low at 13.6 µg/dl (41.2 - 243.7 µg/dL). She had no history of diabetes, hypertension, obesity, hyperlipidemia or clinical osteoporosis. Her social history was negative for tobacco or alcohol abuse. Repeated physical exams were within normal limits, and she did not have any signs of central adiposity, abdominal striae, thinning of skin or hirsutism. She continued to deny any subjective symptoms of lethargy or muscle weakness. Given low normal range ACTH values, mildly increased midnight salivary cortisol, failure to suppress after 1 mg overnight DST with no clinical evidence of overt hypercortisolism, patient was diagnosed with mild autonomous cortisol secretion. She did not show any signs of hypertension, hyperglycemia or physical changes that would warrant concern for hypercortisolemic end organ effects. As the patient was largely asymptomatic, with stable CT imaging of left adrenal adenoma, left adrenalectomy was discussed but not recommended as patient preferred an observation surveillance strategy with laboratory evaluation every 6 months to monitor for hypercortisolemia. This case demonstrates that a surveillance strategy, rather than surgery, may be appropriate in selected cases of mild autonomous cortisol secretion from an incidentally discovered adrenocortical adenoma, especially when end organ effects of cortisol excess are clinically absent. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

/pdf/psat024-a-case-of-mild-autonomous-cortisol-secretion-managed-ljzryle7.pdf

Alexandra C. Greb

Papers

Psychedelics Promote Structural and Functional Neural Plasticity

Transient Stimulation with Psychoplastogens Is Sufficient to Initiate Neuronal Growth.

Cannabinoid treats as adjunctive therapy for pets: gaps in our knowledge

Educational impact of an active learning session with 6-lead mobile electrocardiography on medical students’ knowledge of cardiovascular physiology during the COVID-19 pandemic in the United States: a survey-based observational study

PSAT024 A Case of Mild Autonomous Cortisol Secretion Managed with Active Surveillance