Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics.

Clinical studies suggest the therapeutic potential of psychedelics, including ayahuasca, DMT, psilocybin, and LSD, in stress-related disorders. These substances induce cognitive, antidepressant, anxiolytic, and antiaddictive effects suggested to arise from biological changes similar to conventional antidepressants or the rapid-acting substance ketamine. The proposed route is by inducing brain neuroplasticity. This review attempts to summarize the evidence that psychedelics induce neuroplasticity by focusing on psychedelics' cellular and molecular neuroplasticity effects after single and repeated administration. When behavioral parameters are encountered in the selected studies, the biological pathways will be linked to the behavioral effects. Additionally, knowledge gaps in the underlying biology of clinical outcomes of psychedelics are highlighted. The literature searched yielded 344 results. Title and abstract screening reduced the sample to 35; eight were included from other sources, and full-text screening resulted in the final selection of 16 preclinical and four clinical studies. Studies (n = 20) show that a single administration of a psychedelic produces rapid changes in plasticity mechanisms on a molecular, neuronal, synaptic, and dendritic level. The expression of plasticity-related genes and proteins, including Brain-Derived Neurotrophic Factor (BDNF), is changed after a single administration of psychedelics, resulting in changed neuroplasticity. The latter included more dendritic complexity, which outlasted the acute effects of the psychedelic. Repeated administration of a psychedelic directly stimulated neurogenesis and increased BDNF mRNA levels up to a month after treatment. Findings from the current review demonstrate that psychedelics induce molecular and cellular adaptations related to neuroplasticity and suggest those run parallel to the clinical effects of psychedelics, potentially underlying them. Future (pre)clinical research might focus on deciphering the specific cellular mechanism activated by different psychedelics and related to long-term clinical and biological effects to increase our understanding of the therapeutic potential of these compounds.

The Effects of Early Life Stress, Postnatal Diet Modulation, and Long-Term Western-Style Diet on Later-Life Metabolic and Cognitive Outcomes.

Early life stress (ES) increases the risk to develop metabolic and brain disorders in adulthood. Breastfeeding (exclusivity and duration) is associated with improved metabolic and neurocognitive health outcomes, and the physical properties of the dietary lipids may contribute to this. Here, we tested whether early life exposure to dietary lipids mimicking some physical characteristics of breastmilk (i.e., large, phospholipid-coated lipid droplets; Concept Nuturis® infant milk formula (N-IMF)), could protect against ES-induced metabolic and brain abnormalities under standard circumstances, and in response to prolonged Western-style diet (WSD) in adulthood. ES was induced by exposing mice to limited nesting material from postnatal day (P) 2 to P9. From P16 to P42, male offspring were fed a standard IMF (S-IMF) or N-IMF, followed by either standard rodent diet (SD) or WSD until P230. We then assessed body composition development, fat mass, metabolic hormones, hippocampus-dependent cognitive function, and neurogenesis (proliferation and survival). Prolonged WSD resulted in an obesogenic phenotype at P230, which was not modulated by previous ES or N-IMF exposure. Nevertheless, ES and N-IMF modulated the effect of WSD on neurogenesis at P230, without affecting cognitive function, highlighting programming effects of the early life environment on the hippocampal response to later life challenges at a structural level.

Differences between physicians' and nurse practitioners' viewpoints on reasons for clozapine underprescription.

INTRODUCTION: Clozapine (CLZ) is the only proven effective therapy for treatment-resistant schizophrenia, but it is underutilized across the globe. Previous findings suggest a lack of experience with CLZ prescription and concerns about CLZ's pharmacological characteristics are the prime reasons for CLZ underutilization. To our knowledge, it is currently unknown whether the reasons for underutilization and suggested solutions differ between physicians and nurse practitioners. Such differences are important as nurse practitioners are becoming increasingly involved in prescribing CLZ. METHODS: To examine to what degree physicians and nurse practitioners differ with regard to their take on reasons for CLZ underutilization and suggested solutions, an online questionnaire was distributed to physicians and nurse practitioners. The primary outcome was to compare the patient-related and prescriber-related reasons for CLZ underprescription between physicians and nurse practitioners, while secondary outcome measures included the potential solutions to prevent this underprescription. RESULTS: Physicians (N = 112) and nurse practitioners (N = 41) agreed that the two most common reasons for underprescription (patient-related and prescriber-related) were refusal to undergo regular blood tests and side-effect concerns. They also agreed that the third most common prescriber-related reason was medical complications. Physicians rated patients' unwillingness to switch medication as the third most common reason for CLZ underprescription, whereas nurse practitioners rated refusal to undergo baseline bloodtests as the third most common reason. The solutions to reduce underprescription largely corresponded between both groups. CONCLUSIONS: We conclude that slight differences exist between physicians' and nurse practitioners' viewpoints on patient-related and prescriber-related reasons for CLZ underprescription. Future research projects should involve patients to elucidate whether the patient-related factors put forward by prescribers align with the patients' opinions.

Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation.

Phosphoinositide 3-kinase (PI3K) defines a family of lipid kinases that direct a wide range of cellular processes and cell fate decisions. Since its discovery, and that of its enzymatic antagonist PTEN, much of the focus on PI3K has been on its oncogenic potential. In recent years, studies on PI3K signaling in B lymphocytes have established the importance of this pathway in effecting B cell differentiation and associated molecular events such as V(D)J recombination and class switch recombination. Intriguing new findings also indicate that there is specificity in the PI3K pathway in B cells, including preferential expression or usage of particular PI3K isoforms and counter-regulation by the PTEN and SHIP phosphatases. The role of PI3K adaptor proteins (CD19, BCAP, and TC21) has also undergone revision to reflect both shared and unique properties. The emergence of Foxo1 as a critical PI3K regulatory target for B cell differentiation has united membrane proximal regulatory events orchestrated by PI3K/PTEN/SHIP with key transcriptional targets. Insights into the regulation and impact of PI3K signaling have been brought to bear in new treatments for B cell malignancies, and will also be an important topic of consideration for B cell-dependent autoimmune diseases.