5-HT2C Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology.

Drugs frequently require interactions with multiple targets-via a process known as polypharmacology-to achieve their therapeutic actions. Currently, drugs targeting several serotonin receptors, including the 5-HT2C receptor, are useful for treating obesity, drug abuse, and schizophrenia. The competing challenges of developing selective 5-HT2C receptor ligands or creating drugs with a defined polypharmacological profile, especially aimed at G protein-coupled receptors (GPCRs), remain extremely difficult. Here, we solved two structures of the 5-HT2C receptor in complex with the highly promiscuous agonist ergotamine and the 5-HT2A-C receptor-selective inverse agonist ritanserin at resolutions of 3.0 Å and 2.7 Å, respectively. We analyzed their respective binding poses to provide mechanistic insights into their receptor recognition and opposing pharmacological actions. This study investigates the structural basis of polypharmacology at canonical GPCRs and illustrates how understanding characteristic patterns of ligand-receptor interaction and activation may ultimately facilitate drug design at multiple GPCRs.

A non-hallucinogenic psychedelic analogue with therapeutic potential.

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.

Psychedelic therapy in depression and substance use disorders.

Psychoactive substances obtained from botanicals have been applied for a wide variety of purposes in the rituals of different cultures for thousands of years. Classical psychedelics from N,N'-dimethyltryptamine, psilocybin, mescaline and various lysergamides cause specific alterations in perception, emotion and cognition by acting through serotonin 5-HT2A receptor activation. Lysergic acid diethylamide, the first famous breakthrough in the field, was discovered by chance by Albert Hoffman in the Zurich Sandoz laboratory in 1943, and studies on its psychoactive effects began to take place in the literature. Studies in this area were blocked after the legislation controlling the use and research of psychedelic drugs came into force in 1967, but since the 1990s, it has started to be a matter of scientific curiosity again by various research groups. In particular, with the crucial reports of psychotherapy-assisted psilocybin applications for life-threatening cancer-related anxiety and depression, a new avenues have been opened in the treatment of psychiatric diseases such as treatment-resistant depression and substance addictions. An increasing number of studies show that psychedelics have a very promising potential in the treatment of neuropsychiatric diseases where the desired efficiency cannot be achieved with conventional treatment methods. In this context, we discuss psychedelic therapy, encompassing its historical development, therapeutic applications and potential treatment effects-especially in depression, trauma disorders and substance use disorders-within the framework of ethical considerations.

Examining Adult Patients' Success with Discontinuing Long-term Benzodiazepine Use: a Qualitative Study.

BACKGROUND: Little is known about patients' experiences with benzodiazepine (BZD) discontinuation, which is thought to be challenging given the physiological and psychological dependence and accompanying potential for significant withdrawal symptoms. The marked decline in BZD prescribing over the past decade in the US Department of Veterans Affairs healthcare system presents an important opportunity to examine the experience of BZD discontinuation among long-term users. OBJECTIVE: Examine the experience of BZD discontinuation among individuals prescribed long-term BZD treatment to identify factors that contributed to successful discontinuation. DESIGN: Descriptive qualitative analysis of semi-structured interviews conducted between April and December of 2020. PARTICIPANTS: A total of 21 Veterans who had been prescribed long-term BZD pharmacotherapy (i.e., > 120 days of exposure in a 12-month period) and had their BZD discontinued. APPROACH: We conducted semi-structured interviews with Veteran participants to learn about their BZD use and the process of discontinuation, with interviews recorded and transcribed verbatim. Data were deductively and inductively coded and coded text entered into a matrix to identify factors that contributed to successful BZD discontinuation. KEY RESULTS: The mean age of interview participants was 63.0 years (standard deviation 3.9); 94.2% were male and 76.2% were white. Of 21 participants, only 1 had resumed BZD treatment (prescribed by a non-VA clinician). Three main factors influenced success with discontinuation: (1) participants' attitudes toward BZDs (e.g., risks of long-term use, perceived lack of efficacy, potential for dependence); (2) limited withdrawal symptoms; and (3) effective alternatives, either from their clinician (e.g., medication, psychotherapy) or identified by participants. CONCLUSIONS: BZD discontinuation after long-term use is relatively well tolerated, and participants appreciated reducing their medication exposure, particularly to one associated with physical dependence. These findings may help reduce both patient and clinician anxiety related to BZD discontinuation.

Preventing incubation of drug craving to treat drug relapse: from bench to bedside.

In 1986, Gawin and Kleber reported a progressive increase in cue-induced drug craving in individuals with cocaine use disorders during prolonged abstinence. After years of controversy, as of 2001, this phenomenon was confirmed in rodent studies using self-administration model, and defined as the incubation of drug craving. The intensification of cue-induced drug craving after withdrawal exposes abstinent individuals to a high risk of relapse, which urged us to develop effective interventions to prevent incubated craving. Substantial achievements have been made in deciphering the neural mechanisms, with potential implications for reducing drug craving and preventing the relapse. The present review discusses promising drug targets that have been well investigated in animal studies, including some neurotransmitters, neuropeptides, neurotrophic factors, and epigenetic markers. We also discuss translational exploitation and challenges in the field of the incubation of drug craving, providing insights into future investigations and highlighting the potential of pharmacological interventions, environment-based interventions, and neuromodulation techniques.

Mechanisms and molecular targets surrounding the potential therapeutic effects of psychedelics.

Psychedelics, also known as classical hallucinogens, have been investigated for decades due to their potential therapeutic effects in the treatment of neuropsychiatric and substance use disorders. The results from clinical trials have shown promise for the use of psychedelics to alleviate symptoms of depression and anxiety, as well as to promote substantial decreases in the use of nicotine and alcohol. While these studies provide compelling evidence for the powerful subjective experience and prolonged therapeutic adaptations, the underlying molecular reasons for these robust and clinically meaningful improvements are still poorly understood. Preclinical studies assessing the targets and circuitry of the post-acute effects of classical psychedelics are ongoing. Current literature is split between a serotonin 5-HT2A receptor (5-HT2AR)-dependent or -independent signaling pathway, as researchers are attempting to harness the mechanisms behind the sustained post-acute therapeutically relevant effects. A combination of molecular, behavioral, and genetic techniques in neuropharmacology has begun to show promise for elucidating these mechanisms. As the field progresses, increasing evidence points towards the importance of the subjective experience induced by psychedelic-assisted therapy, but without further cross validation between clinical and preclinical research, the why behind the experience and its translational validity may be lost.

IUPHAR-review: The integration of classic psychedelics into current substance use disorder treatment models.

Substance use disorders (SUDs) have an enormous impact on public health. With classic psychedelic-assisted therapies showing initial promise in treating multiple SUDs, it is possible that these treatments will become legally available options for patients with SUDs in the future. This article highlights how classic psychedelic-assisted therapies might be integrated into current clinical practice. We first describe contemporary evidence-based treatments for SUDs and highlight how classic psychedelic-assisted therapies might fit within each treatment. We suggest that classic psychedelic-assisted therapies can be integrated into most mainstream evidence-based SUD treatments that are currently used in clinical settings, indicating broad compatibility of classic psychedelics with contemporary SUD treatment paradigms.

IUPHAR review - Glucagon-like peptide-1 (GLP-1) and substance use disorders: An emerging pharmacotherapeutic target.

Addiction is a chronic relapsing disease with high morbidity and mortality. Treatments for addiction include pharmacological and psychosocial interventions; however, currently available medications are limited in number and efficacy. The glucagon-like-peptide-1 (GLP-1) system is emerging as a potential novel pharmacotherapeutic target for alcohol and other substance use disorders (ASUDs). In this review, we summarize and discuss the wealth of available evidence from testing GLP-1 receptor (GLP-1R) agonist medications in preclinical models and humans with ASUDs, possible mechanisms underlying the impact of GLP-1R agonists on alcohol/substance use, gaps in knowledge, and future directions. Most of the research with GLP-1R agonists has been conducted in relation to alcohol use; psychostimulants, opioids, and nicotine have also been investigated. Preclinical evidence suggests that GLP-1R agonists reduce alcohol/substance use and other related outcomes. The main proposed mechanisms are related to reward processing, stress, and cognitive function, as well as broader mechanisms related to satiety, changes in gastric motility, and glucose homeostasis. More in-depth mechanistic studies are warranted. Clinical studies have been limited and their findings have been less conclusive; however, most support the safety and potential efficacy of GLP-1R agonists in ASUD treatment. Identifying preferred compounds, as well as possible subgroups who are most responsive to GLP-1R agonists are some of the key research questions to translate the promising preclinical data into clinical settings. Several clinical trials are underway to test GLP-1R agonists in people with ASUDs.

Targeting the cytoskeleton as a therapeutic approach to substance use disorders.

Substance use disorders (SUD) are chronic relapsing disorders governed by continually shifting cycles of positive drug reward experiences and drug withdrawal-induced negative experiences. A large body of research points to plasticity within systems regulating emotional, motivational, and cognitive processes as drivers of continued compulsive pursuit and consumption of substances despite negative consequences. This plasticity is observed at all levels of analysis from molecules to networks, providing multiple avenues for intervention in SUD. The cytoskeleton and its regulatory proteins within neurons and glia are fundamental to the structural and functional integrity of brain processes and are potentially the major drivers of the morphological and behavioral plasticity associated with substance use. In this review, we discuss preclinical studies that provide support for targeting the brain cytoskeleton as a therapeutic approach to SUD. We focus on the interplay between actin cytoskeleton dynamics and exposure to cocaine, methamphetamine, alcohol, opioids, and nicotine and highlight preclinical studies pointing to a wide range of potential therapeutic targets, such as nonmuscle myosin II, Rac1, cofilin, prosapip 1, and drebrin. These studies broaden our understanding of substance-induced plasticity driving behaviors associated with SUD and provide new research directions for the development of SUD therapeutics.

IUPHAR Review: New strategies for medications to treat substance use disorders.

Substance use disorders (SUDs) and drug overdose are a public health emergency and safe and effective treatments are urgently needed. Developing new medications to treat them is expensive, time-consuming, and the probability of a compound progressing to clinical trials and obtaining FDA-approval is low. The small number of FDA-approved medications for SUDs reflects the low interest of pharmaceutical companies to invest in this area due to market forces, characteristics of the population (e.g., stigma, and socio-economic and legal disadvantages), and the high bar regulatory agencies set for new medication approval. In consequence, most research on medications is funded by government agencies, such as the National Institute on Drug Abuse (NIDA). Multiple scientific opportunities are emerging that can accelerate the discovery and development of new medications for SUDs. These include fast and efficient tools to screen new molecules, discover new medication targets, use of big data to explore large clinical data sets and artificial intelligence (AI) applications to make predictions, and precision medicine tools to individualize and optimize treatments. This review provides a general description of these new research strategies for the development of medications to treat SUDs with emphasis on the gaps and scientific opportunities. It includes a brief overview of the rising public health toll of SUDs; the justification, challenges, and opportunities to develop new medications; and a discussion of medications and treatment endpoints that are being evaluated with support from NIDA.

Controversies in Assessment, Diagnosis, and Treatment of Kratom Use Disorder.

PURPOSE OF REVIEW: We apply the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5) criteria for substance use disorders (SUDs) to the herbal product kratom. Similarities and differences between kratom use disorder (KUD) and other SUDs are explored, along with assessment, diagnostic, and therapeutic recommendations for KUD. RECENT FINDINGS: Literature reports of "kratom addiction" or KUD rarely specify the criteria by which patients were diagnosed. Individuals meeting DSM-5 KUD criteria typically do so via tolerance and withdrawal, using more than intended, and craving, not functional or ​psychosocial disruption, which occur rarely. Most clinicians who use medication to treat patients with isolated KUD select buprenorphine formulations, although there are no controlled studies showing that buprenorphine is safe or efficacious in this patient population. Diagnosis and treatment decisions for KUD should be systematic. We propose an algorithm that takes into consideration whether KUD occurs with comorbid opioid use disorder.

The Effects of Substance Misuse on Auditory and Vestibular Function: A Systematic Review.

BACKGROUND: Chronic substance misuse is an ongoing and significant public health concern. Among a myriad of health complications that can occur, substance misuse potentially causes ototoxic effects. Case reports, retrospective chart data, and a few cohort studies suggest that certain prescription opioids and illicit drugs can have either temporary or permanent effects on auditory and/or vestibular function. Given the steady rise of people with a substance-use disorder (SUD), it is of growing importance that audiologists and otolaryngologists have an insight into the potential ototoxic effects of substance misuse. OBJECTIVES: A systematic review was conducted to (1) synthesize the literature on the illicit drugs, prescription opioids, and alcohol misuse on the auditory and vestibular systems, (2) highlight common hearing and vestibular impairments for each substance class, and (3) discuss the limitations of the literature, the potential mechanisms, and clinical implications for clinicians who may encounter patients with hearing or vestibular loss related to substance misuse, and describe opportunities for further study. DESIGN: Systematic searches were performed via PubMed, Scopus, and Google Scholar, and the final updated search was conducted through March 30, 2022. Inclusion criteria included peer-reviewed articles, regardless of study design, from inception until the present that included adults with chronic substance misuse and hearing and/or vestibular complaints. Articles that focused on the acute effects of substances in healthy people, ototoxicity from already known ototoxic medications, the relationship between hearing loss and development of a SUD, articles not available in English, animal work, and duplicates were excluded. Information on the population (adults), outcomes (hearing and/or vestibular data results), and study design (e.g., case report, cohort) were extracted. A meta-analysis could not be performed because more than 60% of the studies were single-case reports or small cohort. RESULTS: The full text of 67 studies that met the eligibility criteria were selected for the review. Overall, 21 studies reported associations between HL/VL related to illicit drug misuse, 28 studies reported HL/VL from prescription opioids, and 20 studies reported HL/VL related to chronic alcohol misuse (2 studies spanned more than one category). Synthesis of the findings suggested that the misuse and/or overdose of amphetamines and cocaine was associated with sudden, bilateral, and temporary HL, whereas HL from the combination of a stimulant and an opioid often presented with greater HL in the mid-frequency range. Reports of temporary vertigo or imbalance were mainly associated with illicit drugs. HL associated with misuse of prescription opioids was typically sudden or rapidly progressive, bilateral, moderately severe to profound, and in almost all cases permanent. The misuse of prescription opioids occasionally resulted in peripheral VL, especially when the opioid misuse was long term. Chronic alcohol misuse tended to associate with high-frequency sudden or progressive sensorineural hearing loss, or retrocochlear dysfunction, and a high occurrence of central vestibular dysfunction and imbalance. CONCLUSIONS: Overall, chronic substance misuse associates with potential ototoxic effects, resulting in temporary or permanent hearing and/or vestibular dysfunction. However, there are notable limitations to the evidence from the extant literature including a lack of objective test measures used to describe hearing or vestibular effects associated with substance misuse, small study sample sizes, reliance on case studies, lack of controlling for confounders related to health, age, sex, and other substance-use factors. Future large-scale studies with prospective study designs are needed to further ascertain the role and risk factors of substance misuse on auditory and vestibular function and to further clinical management practices.

Factors associated with daily use of benzodiazepines/tranquilizers and opioids among people who use drugs.

BACKGROUND: Co-use of benzodiazepines and opioids significantly increases fatal overdose risk, yet few studies have examined co-use of these drugs when obtained both with and without a prescription. We examined associations of daily co-use of prescribed benzodiazepines/tranquilizers (BZD/TRQ) and prescribed and nonprescribed opioids among people who use street opioids (PWUO). METHODS: PWUO (N = 417) were recruited from Baltimore City and neighboring Anne Arundel County, Maryland, and surveyed on sociodemographic characteristics, structural vulnerabilities, healthcare access and utilization, substance use, and overdose experiences. Multivariable logistic regression was used to identify factors associated with self-reported co-use. RESULTS: Participants were 46 years old on average, and predominantly Black (74%) males (62%). Daily co-use was reported by 22%. In multivariable analyses, odds of co-use were significantly higher among participants who did not have a high school degree/GED (adjusted odds ratio [aOR]: 1.71, 95% confidence interval [CI]: 1.02-2.88), endorsed receiving mental health treatment in the past 6 months (aOR: 2.13, 95% CI: 1.28-3.56), reported daily use of powdered cocaine (aOR: 3.57, 95% CI: 1.98-6.45), and synthetic cannabinoids (aOR: 3.11, 95% CI: 1.40-6.93). Odds of co-use were significantly lower among Black participants compared to white participants (aOR: 0.39, 95% CI: 0.19-0.82). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Clinicians working with PWUO or who prescribe BZDs or opioids should screen patients who use cocaine or synthetic cannabinoids, have low level of educational attainment, or recently accessed mental health services, as these patients may be at higher risk for daily co-use of BZD/TRQ and opioids, and therefore lethal overdose.

Psychedelics: From Cave Art to 21st-Century Medicine for Addiction.

BACKGROUND: Psychedelic substance use in ritualistic and ceremonial settings dates back as early as 8,500 BCE. Only in recent years, from the mid-20th century, we have seen the re-emergence of psychedelics in a therapeutic setting and more specifically for the treatment of addiction. This article aims to review research over the past 40 years using classic (psilocybin, lysergic acid diethylamide [LSD], dimethyltryptamine [DMT], mescaline) and atypical (ketamine, ibogaine, 5-MeO-DMT, 3,4-methylenedioxymethamphetamine) psychedelics for the treatment of addiction. SUMMARY: We will start with an overview of the pharmacology and physiological and psychological properties of psychedelic substances from pre-clinical and clinical research. We will then provide an overview of evidence gathered by studies conducted in controlled research environments and naturalistic and ceremonial settings, while we identify the proposed therapeutic mechanisms of each psychedelic substance. KEY MESSAGES: Classic and atypical psychedelics show promise as therapeutic alternatives for the treatment of addiction, through the improvement of psychological and physiological symptoms of dependence. A more comprehensive understanding of the ancient and present-day knowledge of the therapeutic potential of psychedelics can facilitate hope for psychedelic therapeutics in the treatment of addiction, especially for individuals who have failed other conventional treatment methods.

The Effect of Methylphenidate on Cognition in Patients with Comorbid Attention Deficit/Hyperactivity Disorder and Amphetamine Use Disorder: An Exploratory Single-Blinded within-Subject Study.

INTRODUCTION: Attention deficit/hyperactivity disorder (ADHD) with co-occurring substance use disorder (SUD) is associated with poor treatment outcomes. Two randomized controlled trials, utilizing robust doses of stimulants, demonstrated a significant effect on treatment outcomes in patients with ADHD/SUD. This study aimed to investigate differences in executive functioning and explore the dose-dependent effect of OROS-methylphenidate (MPH) in patients with comorbid ADHD and amphetamine use disorder (ADHD+AMPH) and patients with ADHD only. METHODS: Three groups (ADHD+AMPH, ADHD only, and healthy controls) were assessed repeatedly with a neuropsychological test battery. An exploratory within-subject single-blinded design was employed where the ADHD only group received a maximum dose of 72 mg OROS-MPH, the ADHD+AMPH group a maximum dose of 180 mg, whereas the healthy subjects did not receive any study medication. Both ADHD groups received the same dose titration up to 72 mg OROS-MPH. RESULTS: The ADHD+AMPH group demonstrated a significantly poorer motor inhibition and spatial working memory and reported more severe ADHD symptoms compared to the ADHD only group. 180 mg OROS-MPH was associated with a significant improvement in executive functioning in the dual diagnosis group. However, the exploratory study design and recruitment issues do not allow for any conclusion to be drawn regarding the effect of 180 mg OROS-MPH. CONCLUSION: Patients with ADHD+AMPH present with more severe neurocognitive deficits compared to ADHD only. The effect of 180 mg OROS-MPH on cognition in patients with ADHD+AMPH was inconclusive. Future studies should consider recruitment issues and high drop-out rates in this study population.

Feeling safer: effectiveness, feasibility, and acceptability of continuous pulse oximetry for people who smoke opioids at overdose prevention services in British Columbia, Canada.

BACKGROUND: Smoking is the most common mode of unregulated opioid consumption overall and implicated in fatal overdoses in British Columbia (BC). In part, perception of decreased risk (e.g., fewer who smoke carry naloxone kits) and limited smoking-specific harm reduction services contribute to overdose deaths. Overdose prevention services (OPS) offer supervised settings for drug use. Continuous pulse oximetry, common in acute care, allows real-time, remote oxygen monitoring. We evaluated the effectiveness of a novel continuous pulse oximetry protocol aimed at allowing physical distancing (as required by COVID-19, secluded spaces, and to avoid staff exposure to vaporized opioids), its feasibility, and acceptability at OPS for people who smoke opioids. METHODS: This was a mixed methods survey study. We developed a continuous pulse oximetry protocol in collaboration with clinical experts and people with lived/living experience of substance use. We implemented our protocol from March to August 2021 at four OPS in BC permitting smoking. We included adults (≥ 18 years) presenting to OPS to smoke opioids. Peer researchers collected demographic, health, and substance use information, and conducted structured observations. OPS clients participating in our study, OPS staff, and peer researchers completed post-monitoring surveys. We analyzed responses using a thematic inductive approach and validated themes with peer researchers. RESULTS: We included 599 smoking events. OPS clients participating in our study had a mean age of 38.5 years; 73% were male. Most (98%) reported using "down", heroin, or fentanyl; 48% concurrently used other substances (32% of whom reported stimulants); 76% reported smoking alone in the last 3 days; and 36% reported an overdose while smoking. Respondents reported that the protocol facilitated physical distancing, was easy to use, high satisfaction, improved confidence, improved sense of safety, and that they would use it again. CONCLUSIONS: Continuous pulse oximetry allowed safe physical distancing, was feasible, and acceptable in monitoring people who smoke opioids at OPS.

The Rising Use of LSD among Business Managers.

BACKGROUND: Although studies have demonstrated that the use of lysergic acid diethylamide (LSD) is on the rise in the United States, it remains unclear how this trend looks across the hierarchical ladder of the American workforce. This is relevant given that LSD is increasingly being touted as a means of boosting creativity and performance, with mounting anecdotal evidence that business managers in particular are turning to it for inspiration and insight. METHODS: Using pooled cross-sectional data from the National Survey on Drug Use and Health (2006-2014) on 168,920 adults in the United States employed full-time (weighted = 117,270,940), this study investigates how temporal trends in past year LSD use differ among business managers and non-managers. RESULTS: The results suggest that the prevalence of past year LSD use increased over time at a greater rate among business managers than non-managers and that this difference cannot be accounted for by changes in business managers' perceived risk of LSD use or general substance use relative to non-managers. CONCLUSIONS: The study's findings indicate that temporal trends in past year LSD use depend on employees' hierarchical rank in their organization and suggest that business managers, regardless of gender, are becomingly increasingly interested in the potential competitive advantages that LSD may offer.

Naloxone access in perinatal substance use disorder.

BACKGROUND: Risk of fatal drug overdose is higher in pregnant and postpartum people with substance use disorder (SUD) than for nonpregnant women of reproductive age. It is recommended that naloxone is prescribed for pregnancies complicated by opioid or stimulant use disorder. OBJECTIVE: The purpose of this study was to assess the rates of naloxone coprescribing with buprenorphine in a perinatal SUD (PSUD) specialty clinic and identify opportunities for pharmacist-led interventions to improve communication and documentation surrounding naloxone access to achieve a rate of 100% coprescribing of naloxone with buprenorphine. PRACTICE DESCRIPTION: A clinical pharmacist practitioner is embedded on the Project CARA (Care that Advocates Respect/Resilience/Recovery for All) team, which provides outpatient SUD care integrated with perinatal care in Western North Carolina. PRACTICE INNOVATION: The clinical pharmacist practitioner assessed baseline rates of naloxone coprescribing with medications for opioid use disorder. Interventions to improve rates of coprescribing include provider education, electronic health record (EHR) documentation templates, and direct patient outreach. EVALUATION METHODS: Baseline rates of naloxone coprescribing were assessed and then re-evaluated after different interventions to measure pharmacist impact. RESULTS: Each intervention improved rates of naloxone coprescribing in a PSUD clinic. EHR documentation templates had the largest impact on baseline efforts, although the long-term benefits derived from these efforts have not yet been demonstrated. Substantial time investment from the pharmacist was required to address patients' barriers to obtaining naloxone after their visits. CONCLUSION: Further process improvement should address barriers to naloxone access for both patients and providers. This may include proactive identification of patients in need of naloxone and a "meds-to-beds" pilot to assist patients in navigating logistical challenges.

Integrative Pharmacology in the Treatment of Substance Use Disorders.

The detrimental physical, mental, and socioeconomic effects of substance use disorders (SUDs) have been apparent to the medical community for decades. However, it has become increasingly urgent in recent years to develop novel pharmacotherapies to treat SUDs. Currently, practitioners typically rely on monotherapy. Monotherapy has been shown to be superior to no treatment at all for most substance classes. However, many randomized controlled trials (RCTs) have revealed that monotherapy leads to poorer outcomes when compared with combination treatment in all specialties of medicine. The results of RCTs suggest that monotherapy frequently fails since multiple dysregulated pathways, enzymes, neurotransmitters, and receptors are involved in the pathophysiology of SUDs. As such, research is urgently needed to determine how various neurobiological mechanisms can be targeted by novel combination treatments to create increasingly specific yet exceedingly comprehensive approaches to SUD treatment. This article aims to review the neurobiology that integrates many pathophysiologic mechanisms and discuss integrative pharmacology developments that may ultimately improve clinical outcomes for patients with SUDs. Many neurobiological mechanisms are known to be involved in SUDs including dopaminergic, nicotinic, N-methyl-D-aspartate (NMDA), and kynurenic acid (KYNA) mechanisms. Emerging evidence indicates that KYNA, a tryptophan metabolite, modulates all these major pathophysiologic mechanisms. Therefore, achieving KYNA homeostasis by harmonizing integrative pathophysiology and pharmacology could prove to be a better therapeutic approach for SUDs. We propose KYNA-NMDA-α7nAChRcentric pathophysiology, the "conductor of the orchestra," as a novel approach to treat many SUDs concurrently. KYNA-NMDA-α7nAChR pathophysiology may be the "command center" of neuropsychiatry. To date, extant RCTs have shown equivocal findings across comparison conditions, possibly because investigators targeted single pathophysiologic mechanisms, hit wrong targets in underlying pathophysiologic mechanisms, and tested inadequate monotherapy treatment. We provide examples of potential combination treatments that simultaneously target multiple pathophysiologic mechanisms in addition to KYNA. Kynurenine pathway metabolism demonstrates the greatest potential as a target for neuropsychiatric diseases. The investigational medications with the most evidence include memantine, galantamine, and N-acetylcysteine. Future RCTs are warranted with novel combination treatments for SUDs. Multicenter RCTs with integrative pharmacology offer a promising, potentially fruitful avenue to develop novel therapeutics for the treatment of SUDs.