Society for Research on Nicotine and Tobacco as an Outgrowth of the 1988 Surgeon General's Report on Nicotine Addiction: Reflections of the Early Presidents.

INTRODUCTION: The Society for Research on Nicotine and Tobacco began in the United States as a scientific organization "to stimulate the generation and dissemination of new knowledge concerning nicotine and tobacco in all its manifestations." Now in its 30th year, the Society is taking on new challenges in tobacco control, nicotine vaping, product regulation, and public policy. AIMS AND METHODS: This Review describes the formative years of the Society from the perspective of researchers who were in leadership positions during that time, documenting how biobehavioral and clinical research in the first 10 years was a continuation of the scientific mission of the 1988 United States Surgeon General's Report on Nicotine Addiction and summarizing organizational innovations during each president's term of office. CONCLUSIONS: The Society's promotion of scientific research served as a catalyst for funding, policy, and regulation, setting the stage for its influence and credibility. IMPLICATIONS: This Commentary provides context and an overview of the scientific research and the organizational innovations that occurred during the early years of the Society for Research on Nicotine and Tobacco using publications and available documentation. The Society was able to thrive because biobehavioral research on nicotine addiction provided the scientific underpinnings for the tobacco control enterprise as a whole. The objective of this Commentary is to describe formative events in the Society's history based on the accomplishments of its early leaders.

Need for clarity and context in case reports on kratom use, assessment, and intervention.

This Letter to the Editor is a response to Broyan and colleagues who recently published a Case Report presenting data on 28 patients in the United States who identified kratom as their primary substance of use and who were subsequently induced on buprenorphine/naloxone for a reported diagnosis of kratom use disorder. We applaud the authors for helping to advance the science on kratom and recognize the difficulties in conducting kratom-related clinical assessment and research. However, a number of inconsistences and generalizations were identified in this Case Report, which also lacked some critical context. Importantly, such inconsistencies and generalizations can be observed throughout kratom-specific case reports. We feel this is now an important opportunity to highlight these issues that are present in the Broyan and colleagues Case report but emphasize that they are not unique to it. We do this with the hope that by acknowledging these issues it can help inform editors, clinicians, and researchers who may not be familiar with kratom and, as a result of this unfamiliarity, may inadvertently present findings in a manner that could confuse readers and even misinform clinical researchers and practitioners.

An Open-Label, Randomized, Controlled, Crossover Study to Assess Nicotine Pharmacokinetics and Subjective Effects of the JUUL System with Three Nicotine Concentrations Relative to Combustible Cigarettes in Adult Smokers.

INTRODUCTION: This randomized, open-label, crossover clinical study evaluated nicotine pharmacokinetics (PK) and subjective effects of the JUUL System (JS; Juul Labs, Inc.) with three nicotine concentrations compared to the usual brand (UB) cigarettes in 24 adult smokers. METHODS: At five study visits, subjects used either the JS in 59 mg/mL, JS 18 mg/mL (two visits), and JS 9 mg/mL (all tobacco-flavored) or smoked their UB cigarette first during a controlled puffing sequence (CPS) and then ad libitum (5 min) use sessions. Blood samples were taken at specified timepoints for 60 min in each session. The modified Product Evaluation Scale assessed subjective effects 30-min post-use in the CPS session. RESULTS: Maximum plasma nicotine concentration (Cmax-BL), total nicotine exposure (AUC0-60-BL), and rate of plasma nicotine rise were significantly lower for all JS products compared to subjects' UB cigarette in CPS and ad libitum use sessions. In both use sessions these PK parameters were significantly higher for JS 59 mg/mL compared to 18 and 9 mg/mL. Subjective measures of cigarette craving relief and "Enough Nicotine" for JS 59 mg/mL did not differ significantly from UB cigarettes, but JS 18 and 9 mg/mL were rated significantly lower than JS 59 mg/mL and UB cigarettes. CONCLUSIONS: Nicotine exposure and subjective relief were directly related to JS nicotine concentration: higher nicotine concentrations gave rise to significantly greater plasma nicotine levels and relief from craving. Heavier and more dependent smokers may require the greater nicotine delivery of JS 59 mg/mL to successfully transition away from cigarettes. IMPLICATIONS: It has been suggested that electronic nicotine delivery systems (ENDS) and other alternative nicotine delivery products that more closely mimic the nicotine pharmacokinetics (PK) of cigarettes may facilitate smokers transitioning away from cigarettes. We examined nicotine PK and subjective effects of JUUL System (JS) ENDS with three nicotine concentrations (59, 18 and 9 mg/mL) compared to combustible cigarettes. Nicotine delivery from JS ENDS was nicotine concentration dependent, with higher nicotine concentrations giving rise to higher nicotine exposure. These findings suggest that heavier and more dependent smokers may require ENDS with nicotine concentrations greater than 20 mg/mL to successfully transition away from cigarettes.

Measuring Opioid Withdrawal in a Phase 3 Study of a New Analgesic, NKTR-181 (Oxycodegol), in Patients with Moderate to Severe Chronic Low Back Pain.

OBJECTIVE: To evaluate the SUMMIT-07 trial opioid withdrawal results of NKTR-181 (oxycodegol), a new molecular entity mu-opioid receptor agonist. DESIGN: Phase 3, enriched-enrollment, double-blind, randomized-withdrawal study in patients with chronic low back pain (CLBP). SETTING: Conducted in the United States at multiple sites. METHODS: SUMMIT-07 was comprised of five periods: screening; NKTR-181 open-label titration (100 to 400 mg twice daily); 12-week randomized, double-blind study drug (NKTR-181 or placebo); one-week study drug taper; and two-week safety follow-up. Permitted rescue medication included hydrocodone 5 mg/acetaminophen 300 mg (two tablets daily) for two weeks after randomization, then acetaminophen 1.0 gm daily for the remainder of the trial. Signs and symptoms of drug withdrawal were evaluated using the Clinical Opiate Withdrawal Scale (COWS); Subjective Opiate Withdrawal Scale (SOWS); Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS); and withdrawal-related adverse events. RESULTS: Of 1,190 patients entering titration, one patient had moderate withdrawal (COWS score 13/48 maximum) three days after discontinuing NKTR-181. Of 610 patients randomized (N = 309, NKTR-181; N = 301, placebo), no COWS scores indicating withdrawal at a moderate level or greater (i.e., score ≥13) were observed at any time point. At day 8 after randomization, week 12, and the end of tapering, COWS scores indicating mild withdrawal (<13) were observed in seven (2.4%), one (0.4%), and one (0.5%) placebo patients, respectively, and three (1.0%), one (0.4%), and five (2.3%) NKTR-181 patients, respectively. Mean SOWS scores in both arms were ≤2.8 of 64 possible points at all time points. During the randomized period, of 35 events identified by MADDERS, adjudicators identified 20 possible "withdrawal" events (9 [2.9%] NKTR-181 and 11 [3.7%] placebo). CONCLUSIONS: NKTR-181 exhibited a low rate and severity of opioid withdrawal in SUMMIT-07 patients with CLBP.

Human Abuse Potential of Oral NKTR-181 in Recreational Opioid Users: A Randomized, Double-Blind, Crossover Study.

OBJECTIVE: To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone. DESIGN: This double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non-physically dependent recreational opioid users. SETTING: Inpatient clinical research site. SUBJECTS: Seventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years). METHODS: The primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking "at this moment" (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo. RESULTS: Compared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone. CONCLUSIONS: NKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone.

The nexus of opioids, pain, and addiction: Challenges and solutions.

Pain and addiction are complex disorders with many commonalities. Beneficial outcomes for both disorders can be achieved through similar principles such as individualized medication selection and dosing, comprehensive multi-modal therapies, and judicious modification of treatment as indicated by the patient's status. This is implicit in the term "medication assisted treatment" (MAT) for opioid use disorders (OUD), and is equally important in pain management; however, for many OUD and pain patients, medication is central to the treatment plan and should neither be denied nor withdrawn if critical to patient well-being. Most patients prescribed opioids for pain do not develop OUD, and most people with OUD do not develop it as a result of appropriately prescribed opioids. Nonetheless, concerns about undertreatment of pain in the late 20th century likely contributed to inappropriate prescribing of opioids. This, coupled with a shortfall in OUD treatment capacity and the unfettered flood of inexpensive heroin and fentanyl, behavioral economics and other factors facilitated the 21st century opioid epidemic. Presently, injudicious reductions in opioid prescriptions for pain are contributing to increased suffering and suicides by pain patients as well as worsening disparities in pain management for ethnic minority and low-income people. Many of these people are turning to illicit opioids, and no evidence shows that the reduction in opioid prescriptions is reducing OUD or overdose deaths. Comprehensive, science-based policies that increase access to addiction treatment for all in need and better serve people with pain are vital to addressing both pain and addiction.

Risk of death associated with kratom use compared to opioids.

Kratom use appears to be increasing across the United States, increasing attention to deaths in which kratom use was detected. Most such deaths have been ascribed to fentanyl, heroin, benzodiazepines, prescription opioids, cocaine and other causes (e.g., homicide, suicide and various preexisting diseases). Because kratom has certain opioid-like effects (e.g., pain relief), and is used by some people as a substitute for opioids for pain or addiction, kratom has been compared to "narcotic-like opioids" (e.g., morphine) with respect to risk of death despite evidence that its primary alkaloid, mitragynine, carries little of the signature respiratory depressing effects of morphine-like opioids. This commentary summarizes animal toxicology data, surveys and mortality data associated with opioids and kratom to provide a basis for estimating relative mortality risk. Population-level mortality estimates attributed to opioids as compared to kratom, and the per user mortality risks of opioids as compared to kratom are provided. By any of our assessments, it appears that the risk of overdose death is >1000 times greater for opioids than for kratom. The limitations of the mortality risk estimate warrants caution in individuals with unknown factors such as use of other substances and medications, or other preexisting conditions. More research on kratom safety and risks is needed, as is regulation of commercial kratom products to ensure that consumers are informed by FDA labeling and that kratom products are not contaminated or adulterated with other substances.

Nicotine Reduction Strategy: State of the science and challenges to tobacco control policy and FDA tobacco product regulation.

Nicotine addiction is the proximate cause of disease and death from cigarette smoking. In 1994, we proposed reducing the nicotine content of cigarettes to non-addicting levels to reduce the risk of youth becoming addicted smokers and promoting quitting in established smokers. In 2009, the Family Smoking Prevention and Tobacco Control Act provided the authority to FDA to reduce nicotine levels as appropriate to benefit public health. Over the past 15 years, considerable research has determined that nicotine reduction is feasible and safe, resulting in reduced nicotine dependence with little evidence of compensatory over-smoking. The availability of acceptable non-combusted form of nicotine would provide support and enhance acceptability of nicotine reduction in tobacco. Most recently, the FDA promulgated a nicotine-based regulatory framework, which includes nicotine reduction combined with ready availability of noncombustible nicotine products. Nicotine reduction could contribute to a virtual end to the use of cigarette smoking, with enormous benefits to public health.

Are we guilty of errors of omission on the potential role of electronic nicotine delivery systems as less harmful substitutes for combusted tobacco use?

Two of the more controversial tobacco control and regulatory strategies in recent years are the nicotine reduction and tobacco harm reduction (THR) strategies. They have become inextricably intertwined as a successful nicotine reduction policy might only be possible in an environment in which alternative, noncombusted forms of nicotine like electronic nicotine delivery systems (ENDS) are available to address the needs of those who were unable or unwilling to completely give up nicotine. Unfortunately, ENDS have emerged as particularly controversial, in part, because they are the first product to carry reduced risk potential while being broadly appealing to cigarette smokers across demographic groups and subpopulations, and to a much smaller extent nonsmokers including, and most controversial, adolescents. In an effort to better understand some of the reasons that make this a controversial topic, we review some of the relevant history and discuss a broader dilemma that faces practitioners and policy developers of medical and public health interventions, namely, weighing the potential consequences of errors of commission versus omission. Commission errors involve a salient, direct link between an action and associated adverse or unintended consequences while omission errors are typically less salient with a more indirect link between inaction and associated adverse consequences. Decision-making research demonstrates that humans have a bias towards avoidance of commission errors and insensitivity to omission errors. This bias may be contributing to some of the aforementioned difficulties in finding common ground regarding the potential contribution of ENDS to reducing the harm of combusted tobacco use.

Eluxadoline Demonstrates a Lack of Abuse Potential in Phase 2 and 3 Studies of Patients With Irritable Bowel Syndrome With Diarrhea.

BACKGROUND & AIMS: Eluxadoline is approved by the Food and Drug Administration for the treatment of adults with irritable bowel syndrome with diarrhea (IBS-D). Eluxadoline is a locally acting mixed µ-opiod and κ-opioid receptor agonist and δ-opioid receptor antagonist. The abuse potential of eluxadoline was evaluated as part of the Phase 2 and 3 clinical trials assessing the efficacy, safety, and tolerability of the drug. METHODS: One Phase 2 (IBS-2001) and two Phase 3 (IBS-3001 and IBS-3002) randomized controlled trials enrolled patients meeting Rome III criteria for IBS-D. Patients received oral twice-daily double-blind treatment with eluxadoline or placebo for 12, 26, or 52 weeks. The primary end point of these studies was the proportion of patients who had a composite response of decrease in abdominal pain and improvement in stool consistency on the same day for at least 50% of days. Safety data were pooled, and specific adverse event terms potentially related to abuse were assessed descriptively. Adverse events reported during a 2-week post-treatment period (IBS-3001) and a 4-week single-blind washout period (IBS-3002) were assessed for signs of opioid withdrawal. Potential withdrawal effects were assessed by using the Subjective Opiate Withdrawal Scale. RESULTS: Overall, 807 and 1032 patients received 1 or more doses of eluxadoline (75 or 100 mg, respectively), and 975 patients received placebo. The overall incidence of adverse events potentially related to abuse did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (2.8%, 2.7%, and 4.3%, respectively). The most common adverse events potentially related to abuse were anxiety and somnolence, which occurred in less than 2% of patients in each group. Median overall Subjective Opiate Withdrawal Scale scores did not differ significantly among the groups given placebo, eluxadoline 75 mg, or eluxadoline 100 mg (3.0, 2.0, and 3.0, respectively). CONCLUSIONS: In an analysis of data from Phase 2 and Phase 3 trials of eluxadoline (75 or 100 mg) for patients with IBS-D, data revealed no signs of abuse potential for eluxadoline. ClinicalTrials.gov numbers: NCT01130272, NCT01553591, NCT01553747.

A literature review on prevalence of gender differences and intersections with other vulnerabilities to tobacco use in the United States, 2004-2014.

This report describes results from a systematic literature review examining gender differences in U.S. prevalence rates of current use of tobacco and nicotine delivery products and how they intersect with other vulnerabilities to tobacco use. We searched PubMed on gender differences in tobacco use across the years 2004-2014. For inclusion, reports had to be in English, in a peer-reviewed journal or federal government report, report prevalence rates for current use of a tobacco product in males and females, and use a U.S. nationally representative sample. Prevalence rates were generally higher in males than in females across all products. This pattern remained stable despite changes over time in overall prevalence rates. Gender differences generally were robust when intersecting with other vulnerabilities, although decreases in the magnitude of gender differences were noted among younger and older users, and among educational levels and race/ethnic groups associated with the highest or lowest prevalence rates. Overall, these results document a pervasive association of gender with vulnerability to tobacco use that acts additively with other vulnerabilities. These vulnerabilities should be considered whenever formulating tobacco control and regulatory policies.

NIH electronic cigarette workshop: developing a research agenda.

BACKGROUND: Electronic cigarettes (e-cigarettes) represent an emerging public health issue. These devices deliver nicotine along with other constituents, including flavorants, via an inhalable aerosol. Their uptake is rapidly increasing in both adults and youths, primarily among current smokers. Public debate is increasing on how these devices should be regulated and used, yet only limited peer-reviewed research exists. To develop a informed policy for e-cigarettes, their effects on human behavior, physiology, and health need to be understood. PURPOSE: This paper describes proceedings from a National Institutes of Health-sponsored workshop, which was held in November 2013, to identify research needs related to the effects of e-cigarettes. Discussion topics included e-cigarette risks and abuse potential; the potential role for e-cigarettes in harm reduction and smoking cessation; unintended consequences of e-cigarette use, such as becoming a gateway to conventional cigarettes; and dual use of both e-cigarettes and conventional cigarettes. RESULTS AND CONCLUSIONS: The research needs identified by the workshop participants included the following: standards to measure the contents and emissions of e-cigarettes; biomarkers of exposure; physiological effects of e-cigarettes on tissues and organ systems, including pulmonary and cardiovascular; information on e-cigarette users, how the devices are used, and identification of the best tools to assess these measures; factors that drive use and influence patterns of use; and appropriate methods for evaluating a potential role for e-cigarettes in smoking or nicotine cessation. To understand fully the challenges and the opportunities that e-cigarettes represent, expertise will be needed in basic, behavioral, translational, and clinical sciences.

The tobacco endgame: it's all about behavior.

One of the ten great public health achievements in the 20th century was turning the tide on one of the greatest public health disasters of that century: the tobacco use and related disease epidemic. The premature death and disease caused by tobacco can be considered largely as a side-effect of tobacco use behavior and the disease of addiction. The spread of that disease was fostered by an industry that researched the behavioral and biological basis of tobacco use and addiction and applied its findings and knowledge to develop products and marketing approaches to increase the likelihood that people, especially young people, would try tobacco products and develop persistent use and addiction. Researchers outside of the tobacco industry also investigated the behavioral biology of tobacco use and their research has been critical in turning the tide of the tobacco and disease epidemic. The behavioral factors are considered vital to understand and address by United States Food and Drug Administration and Surgeon General, as well as the World Health Organization in their tobacco control efforts. This commentary discusses key behavioral factors in the rise and fall of the epidemic, as well as some of those increasingly discussed as potential contributors to the endgame.

Kratom safety and toxicology in the public health context: research needs to better inform regulation.

Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5 years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom's benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product.

Reducing the nicotine content to make cigarettes less addictive.

Nicotine is highly addictive and is primarily responsible for the maintenance of cigarette smoking. In 1994, Benowitz and Henningfield proposed the idea of federal regulation of the nicotine content of cigarettes such that the nicotine content of cigarettes would be reduced over time, resulting in lower intake of nicotine and a lower level of nicotine dependence. When nicotine levels get very low, cigarettes would be much less addictive. As a result, fewer young people who experiment with cigarettes would become addicted adult smokers and previously addicted smokers would find it easier to quit smoking when they attempt to do so. The regulatory authority to promulgate such a public health strategy was provided by the Family Smoking Prevention and Tobacco Control Act. Although it precludes 'reducing nicotine to zero', the act does not prohibit the Food and Drug Administration from setting standards for cigarette nicotine content that would prevent them from being capable of causing addiction. This paper reviews the assumptions implicit in a nicotine reduction strategy, examines the available data on the feasibility and safety of nicotine reduction, and discusses the public education, surveillance and support services that would be needed for the implementation of such a policy.

Psychedelic drug abuse potential assessment for new drug applications and controlled substance scheduling: A United States perspective.

BACKGROUND: Psychedelics are an increasingly active area of research and pharmaceutical development. This includes abuse potential assessment to better understand their pharmacological mechanisms and effects and guide controlled substance regulation. Psychedelics pose challenges to abuse assessments to ensure valid, reliable, and generalizable outcomes and safe study conduct. FINDINGS: Key nonclinical techniques, for example, receptor binding and functional assays in vitro, and nonclinical physical dependence determinations, are easily adaptable to psychedelics. However, the entactogens (weak reinforcers) and hallucinogens (non-reinforcers) require more flexible approaches than typically recommended by regulatory agencies. Phase 1 pharmacokinetic/pharmacodynamic safety studies and Phases 2/3 efficacy/safety trials with systematic monitoring of abuse-related adverse events are readily applicable to psychedelics. Human abuse trials require modification because supratherapeutic doses may not be safe and procedures, for example, personal monitors to manage serious adverse events, might bias outcomes. RECOMMENDATIONS: Abuse-related studies for psychedelics requiring approval by Food and Drug Administration and other agencies should take into consideration existing knowledge that will vary from extensive, for example, psilocybin, to zero for novel hallucinogens and entactogens. Many abuse assessments can be reasonably applied to animals and humans without compromising scientific integrity. Modification of existing techniques and incorporating a broader range of nonclinical tests should ensure generalizable outcomes. Human abuse studies merit reconsideration and possible modification to ensure safety and validity for psychedelic drug evaluation. Other nonclinical and clinical methods can provide evaluations of the pharmacological equivalence of test drugs to known drugs of abuse to provide context to the abuse assessment and guide drug scheduling.

The abuse potential of lemborexant, a dual orexin receptor antagonist, according to the 8 factors of the Controlled Substances Act.

RATIONALE: Lemborexant (LEM) is a dual orexin receptor antagonist (DORA) approved in multiple countries including the USA, Japan, Canada, Australia, and several Asian countries for the treatment of insomnia in adults. As a compound with central nervous system activity, it is important to understand the abuse potential of LEM with respect to public health. OBJECTIVES: This review discusses data for LEM relevant to each of the 8 factors of the United States Controlled Substances Act. RESULTS: LEM did not demonstrate abuse potential in nonclinical testing and was associated with a low incidence of abuse-related adverse events in clinical study participants with insomnia disorder. Similar to other DORAs that have been evaluated (eg., almorexant, suvorexant (SUV), and daridorexant), LEM and the positive controls (zolpidem and SUV) also showed drug liking in a phase 1 abuse potential study that enrolled subjects who used sedatives recreationally. However, internet surveillance of SUV and the FDA Adverse Events Reporting System suggests that drugs in the DORA class display very low abuse-related risks in the community. Additionally, as described in FDA-approved labeling, it does not carry physical dependence and withdrawal risks. CONCLUSIONS: LEM, similar to most other prescription insomnia medications, was placed into Schedule IV. However, LEM and other drugs in the DORA class may have a lower potential for abuse as suggested by real-world postmarketing data from federal surveys and internet surveillance, and thus may have lower risks to public health than Schedule IV benzodiazepines and nonbenzodiazepine hypnotics that potentiate GABA signaling.

Are psychedelic medicines the reset for chronic pain? Preliminary findings and research needs.

Chronic pain is a leading cause of disability, reduced productivity, healthcare seeking behavior, and a contributor to opioid overdose in the United States. For many people, pain can be satisfactorily managed by existing medicines and comprehensive psychosocial treatments. For others, available treatments are either ineffective or not acceptable, due to side effects and concerns about risks. Preliminary evidence suggests that some psychedelics may be effective for certain types of pain and/or improved quality of life with increased functionality and reduced disability and distress in people whose pain may never be completely relieved. Efficacy in these quality-of-life related outcomes would be consistent with the 'reset in thinking' about chronic pain management being increasingly called for as a more realistic goal for some people as compared to complete elimination of pain. This commentary summarizes the rationale for conducting more basic research and clinical trials to further explore the potential for psychedelics in chronic pain management. Additionally, if shown to be effective, to then determine whether the effects of psychedelics are primarily due to direct antinociceptive or anti-inflammatory mechanisms, or via increased tolerability, acceptance, and sense of spirituality, that appear to at least partially mediate the therapeutic effects of psychedelics observed in psychiatric disorders such as major depression. This commentary represents a collaboration of clinical and more basic scientists examining these issues and developing recommendations for research ranging from neuropharmacology to the biopsychosocial treatment factors that appear to be as important in pain management as in depression and other disorders in which psychedelic medicines are under development. This article is part of the Special Issue on "National Institutes of Health Psilocybin Research Speaker Series".

Psychedelic Science, Contemplative Practices, and Indigenous and Other Traditional Knowledge Systems: Towards Integrative Community-Based Approaches in Global Health.

As individuals and communities around the world confront mounting physical, psychological, and social threats, three complimentary mind-body-spirit pathways toward health, wellbeing, and human flourishing remain underappreciated within conventional practice among the biomedical, public health, and policy communities. This paper reviews literature on psychedelic science, contemplative practices, and Indigenous and other traditional knowledge systems to make the case that combining them in integrative models of care delivered through community-based approaches backed by strong and accountable health systems could prove transformative for global health. Both contemplative practices and certain psychedelic substances reliably induce self-transcendent experiences that can generate positive effects on health, well-being, and prosocial behavior, and combining them appears to have synergistic effects. Traditional knowledge systems can be rich sources of ethnobotanical expertise and repertoires of time-tested practices. A decolonized agenda for psychedelic research and practice involves engaging with the stewards of such traditional knowledges in collaborative ways to codevelop evidence-based models of integrative care accessible to the members of these very same communities. Going forward, health systems could consider Indigenous and other traditional healers or spiritual guides as stakeholders in the design, implementation, and evaluation of community-based approaches for safely scaling up access to effective psychedelic treatments.

The novel uncompetitive NMDA receptor antagonist esmethadone (REL-1017) has no meaningful abuse potential in recreational drug users.

Esmethadone (REL-1017) is the opioid-inactive dextro-isomer of methadone and a low-affinity, low-potency uncompetitive NMDA receptor antagonist. In a Phase 2, randomized, double-blind, placebo-controlled trial, esmethadone showed rapid, robust, and sustained antidepressant effects. Two studies were conducted to evaluate the abuse potential of esmethadone. Each study utilized a randomized, double-blind, active-, and placebo-controlled crossover design to assess esmethadone compared with oxycodone (Oxycodone Study) or ketamine (Ketamine Study) in healthy recreational drug users. Esmethadone 25 mg (proposed therapeutic daily dose), 75 mg (loading dose), and 150 mg (Maximum Tolerated Dose) were evaluated in each study. Positive controls were oral oxycodone 40 mg and intravenous ketamine 0.5 mg/kg infused over 40 min. The Ketamine study included oral dextromethorphan 300 mg as an exploratory comparator. The primary endpoint was maximum effect (Emax) for Drug Liking, assessed using a bipolar 100-point visual analog scale (VAS). A total of 47 and 51 participants completed the Oxycodone Study and the Ketamine Study, respectively (Completer Population). In both studies, esmethadone doses ranging from therapeutic (25 mg) to 6 times therapeutic (150 mg) had a meaningful and statistically significantly (p < 0.001) lower Drug Liking VAS Emax compared with the positive control. Results were consistent for all secondary endpoints in both studies. In both studies, all doses of esmethadone were statistically equivalent to placebo on Drug Liking VAS Emax (p < 0.05). In the Ketamine Study, Drug Liking VAS Emax scores for esmethadone at all tested doses were significantly lower vs. dextromethorphan (p < 0.05) (exploratory endpoint). These studies indicate no meaningful abuse potential for esmethadone at all tested doses.