Content analysis of Reddit posts about coadministration of selective serotonin reuptake inhibitors and psilocybin mushrooms.

RATIONALE: Treatments with the serotonergic psychedelic psilocybin are being investigated for multiple neuropsychiatric disorders. Because many patients with these disorders use selective serotonin reuptake inhibitors (SSRIs), understanding interactions between psilocybin and SSRIs is critical for evaluating the safety, efficacy, and scalability of psilocybin-based treatments. Current knowledge about these interactions is limited, as most clinical psilocybin research has prohibited concomittant SSRI use. OBJECTIVES: We aimed to explore potential interactions between psilocybin and SSRIs by characterizing peoples' real-world experiences using psilocybin mushrooms and SSRIs together. METHODS: We conducted a systematic search of Reddit for posts describing psilocybin mushroom and SSRI coadministration. We identified 443 eligible posts and applied qualitative content analysis to each. RESULTS: 8% of posts reported negative physical or psychological effects resulting from coadministration. These included 13 reports that may reflect serotonin toxicity, and 1 concerning for a psychotic/manic episode. 54% of posts described reduced intensity of the acute psilocybin experience, but 39% reported unchanged intensity with SSRI coadministration. CONCLUSIONS: Psilocybin's interactions with SSRIs are likely complex and may depend on multiple factors. Prospective studies are needed to evaluate whether psilocybin treatments are reliably safe and effective in the setting of SSRI use.

Conditioned place avoidance is associated with a distinct hippocampal phenotype, partly preserved pattern separation, and reduced reactive oxygen species production after stress.

Stress is associated with contextual memory deficits, which may mediate avoidance of trauma-associated contexts in posttraumatic stress disorder. These deficits may emerge from impaired pattern separation, the independent representation of similar experiences by the dentate gyrus-Cornu Ammonis 3 (DG-CA3) circuit of the dorsal hippocampus, which allows for appropriate behavioral responses to specific environmental stimuli. Neurogenesis in the DG is controlled by mitochondrial reactive oxygen species (ROS) production, and may contribute to pattern separation. In Experiment 1, we performed RNA sequencing of the dorsal hippocampus 16 days after stress in rats that either develop conditioned place avoidance to a predator urine-associated context (Avoiders), or do not (Non-Avoiders). Weighted genome correlational network analysis showed that increased expression of oxidative phosphorylation-associated gene transcripts and decreased expression of gene transcripts for axon guidance and insulin signaling were associated with avoidance behavior. Based on these data, in Experiment 2, we hypothesized that Avoiders would exhibit elevated hippocampal (HPC) ROS production and degraded object pattern separation (OPS) compared with Nonavoiders. Stress impaired pattern separation performance in Non-Avoider and Avoider rats compared with nonstressed Controls, but surprisingly, Avoiders exhibited partly preserved pattern separation performance and significantly lower ROS production compared with Non-Avoiders. Lower ROS production was associated with better OPS performance in Stressed rats, but ROS production was not associated with OPS performance in Controls. These results suggest a strong negative association between HPC ROS production and pattern separation after stress, and that stress effects on these outcome variables may be associated with avoidance of a stress-paired context.

Modulation of nigral dopamine signaling mitigates parkinsonian signs of aging: evidence from intervention with calorie restriction or inhibition of dopamine uptake.

Identifying neurobiological mechanisms of aging-related parkinsonism, and lifestyle interventions that mitigate them, remain critical knowledge gaps. No aging study, from rodent to human, has reported loss of any dopamine (DA) signaling marker near the magnitude associated with onset of parkinsonian signs in Parkinson's disease (PD). However, in substantia nigra (SN), similar loss of DA signaling markers in PD or aging coincide with parkinsonian signs. Alleviation of these parkinsonian signs may be possible by interventions such as calorie restriction (CR), which augment DA signaling markers like tyrosine hydroxylase (TH) expression in the SN, but not striatum. Here, we interrogated respective contributions of nigral and striatal DA mechanisms to aging-related parkinsonian signs in aging (18 months old) rats in two studies: by the imposition of CR for 6 months, and inhibition of DA uptake within the SN or striatum by cannula-directed infusion of nomifensine. Parkinsonian signs were mitigated within 12 weeks after CR and maintained until 24 months old, commensurate with increased D1 receptor expression in the SN alone, and increased GDNF family receptor, GFR-α1, in the striatum, suggesting increased GDNF signaling. Nomifensine infusion into the SN or striatum selectively increased extracellular DA. However, only nigral infusion increased locomotor activity. These results indicate mechanisms that increase components of DA signaling in the SN alone mitigate parkinsonian signs in aging, and are modifiable by interventions, like CR, to offset parkinsonian signs, even at advanced age. Moreover, these results give evidence that changes in nigral DA signaling may modulate some parameters of locomotor activity autonomously from striatal DA signaling.

Labelfree mapping and profiling of altered lipid homeostasis in the rat hippocampus after traumatic stress: Role of oxidative homeostasis.

Oxidative and lipid homeostasis are altered by stress and trauma and post-traumatic stress disorder (PTSD) is associated with alterations to lipid species in plasma. Stress-induced alterations to lipid oxidative and homeostasis may exacerbate PTSD pathology, but few preclinical investigations of stress-induced lipidomic changes in the brain exist. Currently available techniques for the quantification of lipid species in biological samples require tissue extraction and are limited in their ability to retrieve spatial information. Raman imaging can overcome this limitation through the quantification of lipid species in situ in minimally processed tissue slices. Here, we utilized a predator exposure and psychosocial stress (PE/PSS) model of traumatic stress to standardize Raman imaging of lipid species in the hippocampus using LC-MS based lipidomics and these data were confirmed with qRT-PCR measures of mRNA expression of relevant enzymes and transporters. Electron Paramagnetic Resonance Spectroscopy (EPR) was used to measure free radical production and an MDA assay to measure oxidized polyunsaturated fatty acids. We observed that PE/PSS is associated with increased cholesterol, altered lipid concentrations, increased free radical production and reduced oxidized polyunsaturated fats (PUFAs) in the hippocampus (HPC), indicating shifts in lipid and oxidative homeostasis in the HPC after traumatic stress.

Pharmahuasca and DMT Rescue ROS Production and Differentially Expressed Genes Observed after Predator and Psychosocial Stress: Relevance to Human PTSD.

Post-traumatic stress disorder (PTSD) is associated with cognitive deficits, oxidative stress, and inflammation. Animal models have recapitulated features of PTSD, but no comparative RNA sequencing analysis of differentially expressed genes (DEGs) in the brain between PTSD and animal models of traumatic stress has been carried out. We compared DEGs from the prefrontal cortex (PFC) of an established stress model to DEGs from the dorsolateral PFC (dlPFC) of humans. We observed a significant enrichment of rat DEGs in human PTSD and identified 20 overlapping DEGs, of which 17 (85%) are directionally concordant. N,N-dimethyltryptamine (DMT) is a known indirect antioxidant, anti-inflammatory, and neuroprotective compound with antidepressant and plasticity-facilitating effects. We tested the capacity of DMT, the monoamine oxidase inhibitor (MAOI) harmaline, and "pharmahuasca" (DMT + harmaline) to reduce reactive oxygen species (ROS) production and inflammatory gene expression and to modulate neuroplasticity-related gene expression in the model. We administered DMT (2 mg/kg IP), harmaline (1.5 mg/kg IP), pharmahuasca, or vehicle every other day for 5 days, following a 30 day stress regiment. We measured ROS production in the PFC and hippocampus (HC) by electron paramagnetic resonance spectroscopy and sequenced total mRNA in the PFC. We also performed in vitro assays to measure the affinity and efficacy of DMT and harmaline at 5HT2AR compared to 5-HT. DMT and pharmahuasca reduced ROS production in the PFC and HC, while harmaline had mixed effects. Treatments normalized 9, 12, and 14 overlapping DEGs, and pathway analysis implicated that genes were involved in ROS production, inflammation, growth factor signaling, neurotransmission, and neuroplasticity.

Current and future functional imaging techniques for post-traumatic stress disorder.

Posttraumatic stress disorder (PTSD) is a trauma and stressor related psychiatric disorder associated with structural, metabolic, and molecular alternations in several brain regions including diverse cortical areas, neuroendocrine regions, the striatum, dopaminergic, adrenergic and serotonergic pathways, and the limbic system. We are in critical need of novel therapeutics and biomarkers for PTSD and a deep understanding of cutting edge imaging and spectroscopy methods is necessary for the development of promising new approaches to better diagnose and treat the disorder. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-V) criterion, all forms of traumatic stress-induced disorder are considered acute stress disorder for the first month following the stressor. Only after symptoms do not remit for one month can the disorder be deemed PTSD. It would be particularly useful to differentiate between acute stress disorder and PTSD during the one month waiting period so that more intensive treatments can be applied early on to patients with a high likelihood of developing PTSD. This would potentially enhance treatment outcomes and/or prevent the development of PTSD. Comprehension of the qualities and limitations of currently applied methods as well as the novel emerging techniques provide invaluable knowledge for fast paced development. Conventional methods of studying PTSD have proven to be insufficient for diagnosis, measurement of treatment efficacy, and monitoring disease progression. As the field currently stands, there is no diagnostic biomarker available for any psychiatric disease, PTSD included. Currently, emerging and available technologies are not utilized to their full capacity and in appropriate experimental designs for the most fruitful possible studies in this area. Therefore, there is an apparent need for improved methods in PTSD research. This review demonstrates the current state of the literature in PTSD, including molecular, cellular, and behavioral indicators, possible biomarkers and clinical and pre-clinical imaging techniques relevant to PTSD, and through this, elucidate the void of current practical imaging and spectroscopy methods that provide true biomarkers for the disorder and the significance of devising new techniques for future investigations. We are unlikely to develop a single biomarker for any psychiatric disorder however. As psychiatric disorders are incomparably complex compared to other medical diagnoses, its most likely that transcriptomic, metabolomic and structural and connectomic imaging data will have to be analyzed in concert in order to produce a dependable non-behavioral marker of PTSD. This can explain the necessity of bridging conventional approaches to novel technologies in order to create a framework for further discoveries in the treatment of PTSD.