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The concoction known as \"lean\" containing codeine and promethazine, holds a prominent cultural presence and is often referenced in mass media platforms (e.g., music and social media). Surprisingly, there's a scarcity of national data characterizing the use of lean. Therefore, the current study investigated the use of lean using national survey data and online forum participant input, and focused on identifying concurrent substance use, exploring co-administration with other substances (e.g., alcohol, cannabis), and determining lean-related experiences. We analyzed data from the National Survey on Drug Use and Health (NSDUH) spanning 2007-2019, identifying persons who used lean (weighted N = 42,275). Additionally, we conducted a Reddit-based study to gather insights about lean consumtion (N = 192). The NSDUH data indicated that lean use was most prevalent among teenagers and young adults (ages 13-21), accounting for 66% of the sample. This trend was more pronounced in male respondents (75%) compared to females. Additionally, the use was predominantly observed among Black/African American (29%), Hispanic (28%), and White (33%) populations, with these groups also reporting higher levels of concurrent alcohol and cannabis use. Similarly, findings from Reddit showed that individuals who used lean were predominantly male (67%) and exhibited elevated concurrent rates of alcohol (83%) and cannabis (46%) use in the past 30 days. Moreover, approximately 66% of respondents met criteria for severe lean use disorder, and 37% acknowledged driving under its influence. The NSDUH data found that mostly young adult males reported consuming lean in the past twelve months, though the racial/ethnic breakdown of persons who used lean was diverse. The Reddit data found that most individuals in the sample met the criteria for a substance use disorder pertaining to their lean consumption. These findings underscore the clinical significance and necessity for further controlled research on lean.

RationaleTriazole 1.1 is a novel kappa-opioid receptor (KOR) agonist reported to produce antinociception without KOR-typical adverse effects. When combined with the mu-opioid receptor (MOR) agonist, oxycodone, triazole 1.1 blocks oxycodone-induced pruritis without producing sedation-like effects in nonhuman primates. However, it is unknown if triazole 1.1 can reduce the abuse-related effects or enhance the antinociceptive effects of oxycodone similarly to other KOR agonists.ObjectivesThe aim of the present study was to quantitatively compare the behavioral effects of triazole 1.1 to the KOR agonists, U50,488h and nalfurafine, on oxycodone self-administration and oxycodone-induced thermal antinociception when administered as mixtures with oxycodone.MethodsIn the self-administration study, male Sprague–Dawley (SD) rats (n = 6) self-administered intravenous (i.v.) oxycodone alone (0.056 mg/kg/inj) or combined with U50,488 h (0.032-0.32 mg/kg/inj), nalfurafine (0.00032–0.0032 mg/kg/inj), or triazole 1.1 (0.32–1.8 mg/kg/inj) under a progressive-ratio schedule of reinforcement. In a hot plate assay, male SD rats (n = 6) received i.v. injections of oxycodone (1.0-5.6 mg/kg), U50,488h (1.0-18.0 mg/kg), nalfurafine (0.01-1.0 mg/kg), or triazole 1.1 (3.2-32.0 mg/kg) alone or in combinations of fixed proportion with oxycodone based on the relative potencies of the single drugs. Each study concluded with administration of the KOR antagonist nor-BNI and some degree of retesting of the previous conditions to verify that the behavioral effects were mediated by KOR activation.ResultsAll KOR agonists reduced oxycodone self-administration in a dose-dependent manner. Moreover, all single drugs and drug combinations produced dose-dependent, fully efficacious thermal antinociception. All KOR agonist:oxycodone combinations produced either additive or super-additive thermal antinociception. Finally, each KOR agonist was blocked in effect by nor-BNI in both behavioral measures.ConclusionThis study demonstrates that triazole 1.1 reduces oxycodone’s reinforcing effects and enhances oxycodone-induced antinociception to degrees that are comparable to typical KOR agonists. Given triazole 1.1’s mild adverse-effect profile, developing MOR-KOR agonist combinations from the triazole 1.1 series may render new pain therapeutics with reduced abuse liability.

RationaleCombinations of mu and kappa opioid receptor (KOR) agonists have been proposed as potential analgesic formulations with reduced abuse liability. The current studies extend previous work by investigating the typical KOR agonist, salvinorin A, and the atypical KOR agonist, nalfurafine, as deterrents of oxycodone self-administration using a progressive ratio (PR) schedule of reinforcement.MethodsIn separate experiments, adult male rhesus monkeys (N = 4/experiment) were trained under a PR schedule of reinforcement to self-administer cocaine (0.1 mg/kg/injection) and saline on alternating days. Oxycodone (0.01–0.1 mg/kg/injection) alone and combined with salvinorin A (experiment 1; 0.006, 0.012 mg/kg/injection) or nalfurafine (experiment 2; 0.0001–0.00032 mg/kg/injection) were tested within the alternating cocaine and saline baseline. The mechanism of nalfurafine’s effects on oxycodone self-administration was investigated via pretreatment with the KOR antagonist, nor-binaltorphimine (nor-BNI; 10 mg/kg; i.m.).ResultsAll subjects self-administered oxycodone alone above saline levels at sufficiently large doses, and combining salvinorin A or nalfurafine with oxycodone reduced the mean number of injections per session to saline levels (experiment 1) or to levels that were significantly lower than oxycodone alone (experiment 2). The ability of nalfurafine to reduce oxycodone self-administration was reversed by pretreatment with nor-BNI.ConclusionsThese results demonstrate that KOR agonists, including the clinically used KOR agonist, nalfurafine, can punish self-administration of a prescription opioid analgesic, oxycodone, in rhesus monkeys and that nalfurafine’s punishing effect is KOR-dependent. Combinations of KOR agonists with prescription opioids may have reduced abuse liability.

Context-induced relapse is a major barrier to recovery from alcohol use disorder (AUD). Identifying molecular targets involved in contextual memories associated with alcohol use may serve as novel pharmacotherapies. Our RNAseq profiling study of the hippocampus from rhesus monkeys with chronic alcohol use identified the voltage-gated calcium channel CACNA1C as a promising therapeutic target. However, data regarding CACNA1C expression in AUD and whether inhibition of CACNA1C can attenuate ethanol contextual memories remains limited. We tested the hypothesis that hippocampal CACNA1C expression is increased in human and nonhuman primates (NHPs) with chronic alcohol use. Further, we used a mouse conditioned place preference (CPP) paradigm to test the hypothesis that Nifedipine, a CACNA1C-selective L-type calcium channel antagonist, can attenuate ethanol-induced CPP. CACNA1C mRNA expression was increased in the hippocampus of subjects with AUD ( p  < 0.03). Increased densities of CACNA1C neurons ( p  < 0.01) and glia ( p  < 0.02) were observed in rhesus monkeys with chronic alcohol use. Ethanol-treated mice spent more time in the ethanol-paired chamber compared to the vehicle animals ( p  < 0.04), demonstrating ethanol-induced CPP. This effect was attenuated by Nifedipine, as time spent in the ethanol-paired chamber in the ethanol + Nifedipine group was not significantly different from the vehicle group. These findings demonstrate that chronic alcohol use increases CACNA1C expression in the hippocampus across species and that a CACNA1C subtype-selective antagonist reduces ethanol-induced CPP. Together, these results support CACNA1C as a promising therapeutic target for memory dysfunction in AUD.

The legalization of cannabis for medicinal and non-medicinal purposes, and the corresponding increase in diversity of cannabis products, has resulted an urgent need for cannabis regulatory science. Among the most pressing needs is research related to impairment due to cannabis exposure, especially on driving performance. The present project was designed to evaluate the impact of oral and vaporized cannabis, when administered alone or in combination with alcohol, on simulated driving performance (STISIM driving simulator), cognitive/psychomotor ability, and field sobriety performance. Healthy adults will complete two, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory studies, one with oral cannabis (16 men/16 women) and the second with vaporized cannabis (16 men/16 women). In each study, participants will complete seven experimental sessions during which acute doses of placebo or high Δ9-THC cannabis containing 0, 10, or 25 mg Δ9-THC will be administered both alone and in combination with placebo or alcohol-containing beverages (target breath alcohol concentrations, BAC, of 0.0% or 0.05%). A positive control session (i.e., alcohol at target BAC of 0.08% with placebo cannabis) will also be completed. Simulated driving performance tests (available for download; see Methods), field sobriety assessments, subjective drug effect questionnaires, a mobile device impairment test (DRUID app), and collection of whole blood specimens will be completed repeatedly during each session. Linear mixed models will be used to test for differences across experimental conditions and a priori planned comparisons will be used to determine differences between conditions of interest (e.g., cannabis alone vs cannabis with alcohol). This research is designed to extend prior studies of cannabis and alcohol on driving performance by using oral and vaporized routes of cannabis administration. By increasing understanding of impairment associated with co-use of alcohol and these novel forms of cannabis, this research could inform impairment detection standards for cannabis and alcohol and have important implications for law enforcement, public policy decisions regarding accessibility of these substances, and education of the general population who may use cannabis and/or alcohol. Lastly, this manuscript provides interested researchers with access to the simulated driving scenarios and data extraction tools developed for this study as a means of facilitating future cross-study comparisons, which is important given the heterogeneity in methods used across laboratories in prior research.

Introduction Opioid use disorder (OUD) is a significant public health problem, and it has been associated with the emergence of sleep disturbances. Effective treatment options for OUD exist, including medication-assisted therapy with methadone or buprenorphine. However, emerging evidence suggests that these treatments also may be associated with significant sleep impairment. The extent to which these effects are a result of the medication or an effect of chronic opioid use remains unknown. In the present study, we investigated the acute effects of methadone, buprenorphine or naltrexone in male rhesus monkeys in order to understand whether pharmacological treatment with these drugs per se would have deleterious effects on sleep. Methods Adult naïve male rhesus macaques (Macaca mulatta, n=5) maintained on a 12h/12h light/dark cycle were fitted with primate collars to which actigraphy monitors were attached. Actigraphy recording was conducted during baseline conditions and following acute injections of vehicle, methadone (0.03 – 1.0 mg/kg, i.m.), buprenorphine (0.01 – 1.0 mg/kg, i.m.) or naltrexone (0.03 – 1.0 mg/kg, i.m.) in the morning (10h, 4h after “lights on”) or in the evening (16:30h, 1.5h before “lights off”). Results Morning treatment with methadone or buprenorphine dose-dependently impaired sleep in rhesus monkeys, with at least one dose significantly increasing sleep latency and decreasing sleep efficiency. Evening treatment with methadone or buprenorphine also impaired sleep, with lower doses significantly inducing sleep alterations compared to morning treatments. The effects of buprenorphine on sleep was a biphasic function, with the highest doses not disrupting sleep. Treatment with naltrexone significantly improved sleep-like measures in rhesus monkeys, with evening treatments improving measures of both sleep latency and sleep efficiency. Conclusion Acute administration of methadone and buprenorphine induced marked sleep impairment in rhesus monkeys, even when the drugs were administered in the morning. Unexpectedly, acute administration of the opioid antagonist naltrexone significantly improved sleep-like measures. Our findings show that the currently available pharmacotherapies for OUD significantly affect sleep in naïve monkeys, and that opioid mechanisms yet to be determined may play a significant role in sleep-wake regulation. Support (if any) Supported by NIH grants DA049886 to L.F.B.; DA048586 to C.A.Z.; DA039167 to K.B.F.; DA011792, DA043204 and DA046778 to J.K.R..

RationaleCombinations of mu and kappa-opioid receptor (KOR) agonists have been proposed as analgesic formulations with reduced abuse potential. The feasibility of this approach has been increased by the development of KOR agonists with biased signaling profiles that produce KOR-typical antinociception with fewer KOR-typical side effects.ObjectiveThe present study determined if the biased KOR agonists, nalfurafine and triazole 1.1, could reduce choice for oxycodone in rhesus monkeys as effectively as the typical KOR agonist, salvinorin A.MethodsAdult male rhesus monkeys (N = 5) responded under a concurrent schedule of food delivery and intravenous cocaine injections (0.018 mg/kg/injection). Once trained, cocaine (0.018 mg/kg/injection) or oxycodone (0.0056 mg/kg/injection) was tested alone or in combination with contingent injections of salvinorin A (0.1–3.2 µg/kg/injection), nalfurafine (0.0032–0.1 µg/kg/injection), triazole 1.1 (3.2–100.0 µg/kg/injection), or vehicle. In each condition, the cocaine or oxycodone dose, as well as the food amount, was held constant across choice components, while the dose of the KOR agonist was increased across choice components.ResultsCocaine and oxycodone were chosen over food on more than 80% of trials when administered alone or contingently with vehicle. When KOR agonists were administered contingently with either cocaine or oxycodone, drug choice decreased in a dose-dependent manner. Salvinorin A and triazole 1.1 decreased drug-reinforcer choice without altering total trials completed (i.e., choice allocation shifted to food), while nalfurafine dose dependently decreased total trials completed.ConclusionsThese results demonstrate that salvinorin A and triazole 1.1, but not nalfurafine, selectively reduce cocaine and oxycodone self-administration independent of nonspecific effects on behavior, suggesting that G-protein bias does not appear to be a moderating factor in this outcome. Triazole 1.1 represents an important prototypical compound for developing novel KOR agonists as deterrents for prescription opioid abuse.

RationaleG-protein biased mu-opioid receptor (MOR) agonists have been reported to exhibit superior therapeutic windows compared to prototypical MOR agonists when relating antinociception to respiratory depression. However, there is relatively little research on the abuse potential of G-protein biased MOR agonists in relation to other behavioral endpoints.ObjectivesThe aim of the present study was to quantitatively compare the reinforcing, antinociceptive, and respiratory-depressant effects of the prototypical MOR agonists, fentanyl and oxycodone, to the G-protein biased MOR agonists, SR14968 and SR17018, in male and female rats.MethodsIn the self-administration study, four separate groups of Sprague–Dawley (SD) rats self-administered intravenous (i.v.) fentanyl, oxycodone, SR14968, and SR17018 under a progressive-ratio schedule of reinforcement. Using a within-subjects design, separate cohorts of SD rats were tested with i.v. fentanyl, oxycodone, SR14968, and SR17018 using a hot-plate assay, assays of neuropathic and inflammatory antinociception, and whole-body plethysmography.ResultsAll MOR agonists functioned as reinforcers, but SR14968 and SR17018 were less efficacious relative to oxycodone and fentanyl. Moreover, all MOR agonists produced dose-dependent and fully efficacious antinociception across all nociception modalities. Oxycodone and fentanyl, but not SR14968 or SR17018, produced respiratory depression in a dose-dependent manner.ConclusionThe present results indicate that the G-protein biased MOR agonists tested herein produce MOR-typical antinociception, exhibit reduced but apparent abuse potential, and do not produce respiratory effects at doses that are above the antinociceptive range. Atypical MOR agonists within the SR series should be further studied as foundational molecules for the development of safter analgesics.

Purpose of Review With cannabis legalization expanding throughout the world, an unprecedented number of people now have access to legal cannabis. This expanded legalization has also created an extensive retail market that includes a litany of cannabis products, which vary on factors such as chemical profile (i.e., chemotype), formulation, and intended route of administration. Despite increases in cannabis access and product variety, research on the effects of product and user characteristics on drug effect profiles is limited. Recent Findings Controlled laboratory studies are important because they can reveal what factors influence the pharmacokinetic (PK) and pharmacodynamic (PD; e.g., subjective, cognitive, psychological) effects of cannabis and its principal constituents D-9-tetrahydrocannbinol (D-9-THC) and cannabidiol (CBD). In this review, we describe the various product (e.g., chemotype, route of administration) and user factors (e.g., frequency of use, sex, and age) that influence the PK and PD effects of cannabis. Summary Understanding the factors that impact the PK/PD profile of cannabis could be used to promote more consistency in drug effects, as well as cannabinoid delivery for medical purposes. Furthermore, such knowledge is key to informing eventual regulatory actions and dosing guidelines for cannabis products.

Cannabis is among the most widely consumed psychoactive substances, with increasing consumption due to growing legalization for medical and non-medical use. As access expands, healthcare providers are faced with clinical challenges, despite variability in knowledge and attitudes on cannabis use in clinical practice. We conducted an anonymous, cross-sectional web-based survey of U.S. healthcare professionals to assess knowledge and attitudes regarding cannabis use in clinical settings. Participants completed demographic items, self-report measures of cannabis-related beliefs and attitudes, and an objective knowledge assessment covering cannabis therapeutic indications, risks, and mechanisms of action. Descriptive analyses were conducted, followed by multivariable linear regression models examining whether demographic characteristics, knowledge, or concerns predicted openness to the clinical use of cannabis. Among 879 respondents (71% female; 86% White; mean age = 46 years), 89% reported having patients who use cannabis. The sample included mental health professionals (29%), registered nurses (25%), physicians (18%), and advanced practice providers (15%). Participants rated their self-reported knowledge highest for cannabis's risks (mean = 4.1/5), followed by therapeutic indications (mean = 4.0/5), and mechanisms of action (mean = 3.5/5). In contrast, objective knowledge check scores were generally low across these domains (13-64% correct). Personal experience (76%) and popular media (73%) were the most endorsed sources of cannabis-related knowledge. Overall, most respondents (87%) endorsed the therapeutic promise of cannabis, 74% reported openness to recommending medical cannabis, and 95% supported its legal medical use. Commonly cited concerns regarding clinical use of cannabis included lack of trained providers (35%), possible patient exploitation (22%), recreational misuse (21%), and risk of psychosis (20%). Greater openness to clinical use was associated with higher self-rated knowledge, younger age, professional role, and lower levels of concern. Although most respondents reported having patients who use cannabis and were largely supportive of medical cannabis use, objective knowledge gaps and limited formal training were evident. These findings suggest a need for structured clinical training on cannabis pharmacology, dosing, contraindications, and legal and ethical frameworks, as well as better monitoring of cannabis use to support safe and informed patient care.