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Serotonergic psychedelics, such as psilocybin and LSD, have garnered significant attention in recent years for their potential therapeutic effects and unique mechanisms of action. These compounds exert their primary effects through activating serotonin 5-HT2A receptors, found predominantly in cortical regions. By interacting with these receptors, serotonergic psychedelics induce alterations in perception, cognition, and emotions, leading to the characteristic psychedelic experience. One of the most crucial aspects of serotonergic psychedelics is their ability to promote neuroplasticity, the formation of new neural connections, and rewire neuronal networks. This neuroplasticity is believed to underlie their therapeutic potential for various mental health conditions, including depression, anxiety, and substance use disorders. In this mini-review, we will discuss how the 5-HT2A receptor activation is just one facet of the complex mechanisms of action of serotonergic psychedelics. They also interact with other serotonin receptor subtypes, such as 5-HT1A and 5-HT2C receptors, and with neurotrophin receptors (e.g., tropomyosin receptor kinase B). These interactions contribute to the complexity of their effects on perception, mood, and cognition. Moreover, as psychedelic research advances, there is an increasing interest in developing nonhallucinogenic derivatives of these drugs to create safer and more targeted medications for psychiatric disorders by removing the hallucinogenic properties while retaining the potential therapeutic benefits. These nonhallucinogenic derivatives would offer patients therapeutic advantages without the intense psychedelic experience, potentially reducing the risks of adverse reactions. Finally, we discuss the potential of psychedelics as substrates for post-translational modification of proteins as part of their mechanism of action. [ABSTRACT FROM AUTHOR]

Psychedelic research across different disciplines and biological levels is growing at a remarkably fast pace. In the prospect of a psychedelic drug becoming again an approved treatment, much of these efforts have been oriented toward exploring the relationship between the actual psychedelic effects and those manifestations of therapeutic interest. Considering the central role of the serotonin 5‐HT2A receptor in the distinct effects of psychedelics in human psyche, neuropharmacology sits at the center of this debate and exploratory continuum. Here we discuss some of the most recent findings in human studies and contextualize them considering previous preclinical models studying phenomena related to synaptic plasticity. A special emphasis is placed on knowledge gaps, challenges, and limitations to evaluate the underpinnings of psychedelics' potential antidepressant action. [ABSTRACT FROM AUTHOR]

Background: A high proportion of opioid drug deaths involve concurrent benzodiazepine use. To reduce the risk of drug overdose, various prescription drug monitoring programs have been implemented. This study examined the impact of concurrent benzodiazepine use on opioid-related deaths, and the utility of the Michigan Automated Prescription System (MAPS) in predicting risk of opioid death.Methods: Wayne County Medical Examiner's Office cases from 2018 were examined in terms of MAPS data and MAPS-derived drug risk scores, as well as postmortem toxicology. Opioid death cases with concurrent benzodiazepine use were compared to non-drug deaths.Results: For cases with a MAPS history for 6 months preceding death, the incidence of opioid prescriptions filled did not differ between groups. In contrast, significantly more opioid death cases had filled a benzodiazepine prescription; alprazolam prescription was the single best predictor of opioid drug death. Groups differed in MAPS-calculated drug risk scores, though these were less predictive of opioid death than some individual measures of prescription drug use. In terms of postmortem toxicology, fentanyl was the best discriminator between cohorts, with significant associations seen for morphine, benzodiazepine, or cocaine use. Similar results were obtained in the subset of subjects filling a prescription within a month of death, except that MAPS risk scores no longer predicted drug deaths.Conclusion: MAPS scores did not adequately predict risk of opioid-related death. Contrary to expectations, prescription opioid use was not correlated with opioid-related death, whereas concurrent use of opioids and benzodiazepines represented a highly significant risk factor. [ABSTRACT FROM AUTHOR]