Introduction: Serotonergic psychedelics and ketamine produce rapid and long-lasting symptomatic relief in multiple psychiatric disorders. Evidence suggests that despite having distinct molecular targets, both drugs may exert therapeutic benefit via their pro-neuroplastic effects. Following treatment with ketamine or serotonergic psychedelics, patients are reported to be more open to behavioral change, which is leveraged for psychotherapy-assisted reframing of narratives of the self.
View Article and Find Full Text PDFAspects of the acute experience induced by the serotonergic psychedelic psilocybin predict symptomatic relief in multiple psychiatric disorders and improved well-being in healthy participants, but whether these therapeutic effects are immediate or are based on memories of the experience is unclear. To examine this, we co-administered psilocybin (25 mg) with the amnestic benzodiazepine midazolam in 8 healthy participants and assayed the subjective quality of, and memory for, the dosing-day experience. We identified a midazolam dose that allowed a conscious psychedelic experience to occur while partially impairing memory for the experience.
View Article and Find Full Text PDFAntibiotic-resistant bacteria are a global health concern, necessitating the development of antibiotics working through new or underutilized mechanisms. Functionalized amino dihydropyrimidines have previously demonstrated potential as antibacterial agents, but they had limited potency, and their biological mechanism was not understood. To further evaluate their potential, focused libraries were prepared and screened for bacterial growth inhibition, and these compounds provided additional insights into the structure-activity relationships, allowing for the preparation of compounds that inhibited all strains of with an MIC of 2 μg/mL.
View Article and Find Full Text PDFThere is considerable evidence from the literature that psychedelics, such as N,N-dimethyltryptamine (DMT), are safe and effective treatments for depression. However, clinical administration to induce psychedelic effects and expensive psychotherapy-assisted treatments likely limit accessibility to the average patient. There is emerging evidence that DMT promotes positive behavioral changes in vivo at sub-hallucinogenic dosages, and depending on the target indication, subjecting patients to high, bolus dosages may not be necessary.
View Article and Find Full Text PDFIntroduction: The use of the psychedelic compound psilocybin in conjunction with psychotherapy has shown promising results in the treatment of psychiatric disorders, though the underlying mechanisms supporting these effects remain unclear. Psilocybin is a Schedule I substance that is dephosphorylated to form an active metabolite, psilocin. Psilacetin, also known as O-acetylpsilocin or 4-acetoxy-N,N-dimethyltryptamine (4-AcO-DMT), is an unscheduled compound that has long been suggested as an alternative psilocin prodrug, though direct support for this hypothesis has thus far been lacking.
View Article and Find Full Text PDFWhile correlations between drug-induced cortisol elevation, self-reported anxiety, and treatment outcomes have been reported for human studies during psilocybin-assisted psychotherapy, the mechanistic relationship between psychedelic-associated alterations in plasma glucocorticoid responses and the time course of anxious responsiveness remains unclear. Using rodents, both time-bound manipulation of glucocorticoid concentrations and assessment of anxiety-like behaviors can be achieved. Here, 3 mg/kg IP psilocybin was found to have anxiolytic-like effects in C57BL/6 male mice at 4 h after treatment.
View Article and Find Full Text PDFSynthetic cannabinoid receptor agonists (SCRAs) are compounds that mimic the pharmacology of the psychoactive components in cannabis. These compounds are structurally diverse, inexpensive, commercially available, and difficult to identify with modern analytical methods, making them highly accessible for recreational use. Suspected SCRA toxicity, which can present with a breadth of cardiovascular, gastrointestinal, and neurological disturbances, is currently addressed through symptom management followed by a toxicological screening that often occurs long after patient discharge.
View Article and Find Full Text PDFCentral nervous system (CNS) exposure to blood-borne biotherapeutics is limited by the restrictive nature of the brain vasculature. In particular, tightly sealed endothelial cells of the blood-brain barrier (BBB) prevent the uptake of protein and gene medicines. An approach to increase the bioavailability of such therapeutics is harnessing the BBB endothelial cells' own receptor-mediated transcytosis (RMT) mechanisms.
View Article and Find Full Text PDFThe dissociative-hypnotic compound ketamine is being used in an increasingly wide range of therapeutic contexts, including anesthesia, adjunctive analgesia, treatment-resistant depression, but it also continues to be a notable substance of abuse. No specific antidotes exist for ketamine intoxication or overdose. Immunopharmacotherapy has demonstrated the ability to offer overdose protection through production of highly specific antibodies that prevent psychoactive drug penetration across the blood-brain barrier, although antiketamine antibodies have not yet been assessed or optimized for use in this approach.
View Article and Find Full Text PDFThe resurgence of interest in the therapeutic potential of psychedelics for treating psychiatric disorders has rekindled efforts to elucidate their mechanism of action. In this Perspective, we focus on the ability of psychedelics to promote , postulated to be central to their therapeutic activity. We begin with a brief overview of the history and behavioral effects of the classical psychedelics.
View Article and Find Full Text PDFACS Pharmacol Transl Sci
October 2020
In addition to the risk of developing opioid use disorder (OUD), known side-effects of long-term opioid use include chronic inflammation and hyperalgesia, which may arise from immune responses induced following chronic opioid use. To investigate this hypothesis, blood samples were obtained from individuals with chronic back pain who were either chronically taking prescription opioids or had minimal recent opioid exposure. Patient samples were analyzed using an enzyme-linked immunosorbent assay (ELISA) against hydrocodone- or oxycodone-hapten conjugates to assess the levels of antibodies present in the samples.
View Article and Find Full Text PDFRes Social Adm Pharm
May 2021
Background: Opioid overdose is a major public health concern in the United States. Naloxone education and distribution can decrease the risk of overdose deaths. A previous study showed that a longitudinal, multi-attempt telephone intervention by a single pharmacy resident was effective for distributing naloxone to a high-risk veteran population.
View Article and Find Full Text PDFBuprenorphine has not only had an interdisciplinary impact on our understanding of key neuroscience topics like opioid pharmacology, pain signaling, and reward processing but has also been a key influence in changing the way that substance use disorders are approached in modern medical systems. From its leading role in expanding outpatient treatment of opioid use disorders to its continued influence on research into next-generation analgesics, buprenorphine has been a continuous player in the ever-evolving societal perception of opioids and substance use disorder. To provide a multifaceted account on the enormous diversity of areas where this molecule has made an impact, this article discusses buprenorphine's chemical properties, synthesis and development, pharmacology, adverse effects, manufacturing information, and historical place in the field of chemical neuroscience.
View Article and Find Full Text PDFAnti-drug vaccines have potential as new interventions against substance use disorder (SUD). However, given the challenges seen with inter-individual variability in SUD vaccine trials to date, new interventions should ensure a robust immune response and safety profile among a diverse population. This requires accounting for sex and heritable genetic differences in response to both abused substances as well as the vaccination itself.
View Article and Find Full Text PDFThe peptide hormone acyl-ghrelin and its receptor, GHSR, represent intriguing therapeutic targets due to their actions in metabolic homeostasis and reward activity. However, this pleotropic activity makes it difficult to intervene in this system without inducing unwanted effects. Thus, it is desirable to identify passive and active regulatory mechanisms that allow differentiation between functional domains.
View Article and Find Full Text PDFIn recent years, drug conjugate vaccines have shown promise as therapeutics for substance use disorder. As a means to improve the efficacy of a heroin conjugate vaccine, we systematically explored 20 vaccine formulations with varying combinations of carrier proteins and adjuvants. In regard to adjuvants, we explored a Toll-like receptor 9 (TLR9) agonist and a TLR3 agonist in the presence of alum.
View Article and Find Full Text PDFFenethylline, also known by the trade name Captagon, is a synthetic psychoactive stimulant that has recently been linked to a substance-use disorder and 'pharmacoterrorism' in the Middle East. Although fenethylline shares a common phenethylamine core with other amphetamine-type stimulants, it also incorporates a covalently linked xanthine moiety into its parent structure. These independently active pharmacophores are liberated during metabolism, resulting in the release of a structurally diverse chemical mixture into the central nervous system.
View Article and Find Full Text PDFGiven the need for further improvements in anti-cocaine vaccination strategies, a chimeric hapten (GNET) was developed that combines chemically-stable structural features from steady-state haptens with the hydrolytic functionality present in transition-state mimetic haptens. Additionally, as a further investigation into the generation of an improved bifunctional antibody pool, sequential vaccination with steady-state and transition-state mimetic haptens was undertaken. While GNET induced the formation of catalytically-active antibodies, it did not improve overall behavioral efficacy.
View Article and Find Full Text PDFPrescription opioids (POs) such as oxycodone and hydrocodone are highly effective medications for pain management, yet they also present a substantial risk for abuse and addiction. The consumption of POs has been escalating worldwide, resulting in tens of thousands of deaths due to overdose each year. Pharmacokinetic strategies based upon vaccination present an attractive avenue to suppress PO abuse.
View Article and Find Full Text PDFActive vaccination examining a single hapten engendered with a series of peptidic linkers has resulted in the production of antimethamphetamine antibodies. Given the limited chemical complexity of methamphetamine, the structure of the linker species embedded within the hapten could have a substantial effect on the ultimate efficacy of the resulting vaccines. Herein, we investigate linker effects by generating a series of methamphetamine haptens that harbor a linker with varying amino acid identity, peptide length, and associated carrier protein.
View Article and Find Full Text PDFAlthough cocaine abuse and addiction continue to cause serious health and societal problems, an FDA-approved medication to treat cocaine addiction has yet to be developed. Employing a pharmacokinetic strategy, an anticocaine vaccine provides an attractive avenue to address these issues; however, current vaccines have shown varying degrees of efficacy, indicating that further formulation is necessary. As a means to improve vaccine efficacy, we examined the effects of varying anticocaine vaccine formulations by combining a Toll-like receptor 9 (TLR9) agonist with a TLR5 agonist in the presence of alum.
View Article and Find Full Text PDFAs the first drug to see widespread use for the treatment of attention deficit hyperactivity disorder (ADHD), methylphenidate was the forerunner and catalyst to the modern era of rapidly increasing diagnosis, treatment, and medication development for this condition. During its often controversial history, it has variously elucidated the importance of dopamine signaling in memory and attention, provoked concerns about pharmaceutical cognitive enhancement, driven innovation in controlled-release technologies and enantiospecific therapeutics, and stimulated debate about the impact of pharmaceutical sales techniques on the practice of medicine. In this Review, we will illustrate the history and importance of methylphenidate to ADHD treatment and neuroscience in general, as well as provide key information about its synthesis, structure-activity relationship, pharmacological activity, metabolism, manufacturing, FDA-approved indications, and adverse effects.
View Article and Find Full Text PDFClinical studies have revealed that genetic variations in metabotropic glutamate receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro.
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