Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.

BACKGROUND: Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC. METHODS: Twenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30mg THC+15mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations. RESULTS: When d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15mg and 30mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30mg THC+15mg d-limonene significantly reduced ratings of "anxious/nervous" and "paranoid" compared with 30mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics. CONCLUSIONS: D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

Codeine and promethazine: Exploratory study on "lean" or "sizzurp" using national survey data and an online forum.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Effects of kratom on driving: Results from a cross-sectional survey, ecological momentary assessment, and pilot simulated driving Study.

OBJECTIVES: Despite widespread kratom use, there is a lack of knowledge regarding its effects on driving. We evaluated the self-reported driving behaviors of kratom consumers and assessed their simulated-driving performance after self-administering kratom products. METHODS: We present results from: 1) a remote, national study of US adults who regularly use kratom, and 2) an in-person substudy from which we re-recruited participants. In the national study (N = 357), participants completed a detailed survey and a 15-day ecological momentary assessment (EMA) that monitored naturalistic kratom use. For the remote study, outcomes were self-reported general and risky driving behaviors, perceived impairment, and driving confidence following kratom administration. For the in-person substudy, 10 adults consumed their typical kratom products and their driving performance on a high-fidelity driving simulator pre- and post-kratom administration was evaluated. RESULTS: Over 90% of participants surveyed self-reported driving under the influence of kratom. Most reported low rates of risky driving behavior and expressed high confidence in their driving ability after taking kratom. This was consistent with EMA findings: participants reported feeling confident in their driving ability and perceived little impairment within 15-180 min after using kratom. In the in-person substudy, there were no significant changes in simulated driving performance after taking kratom. CONCLUSIONS: Using kratom before driving appears routine, however, self-reported and simulated driving findings suggest kratom effects at self-selected doses among regular kratom consumers do not produce significant changes in subjective and objective measures of driving impairment. Research is needed to objectively characterize kratom's impact on driving in regular and infrequent consumers.

Pharmacokinetics and pharmacodynamics of five distinct commercially available hemp-derived topical cannabidiol products.

Products containing cannabidiol (CBD) have proliferated after the 2018 Farm Bill legalized hemp (cannabis with ≤0.3% delta-9-tetrahydrocannabinol (Δ9-THC)). CBD-containing topical products have surged in popularity, but controlled clinical studies on them are limited. This study characterized the effects of five commercially available hemp-derived high CBD/low Δ9-THC topical products. Healthy adults (N = 46) received one of six study drugs: a CBD-containing cream (N = 8), lotion (N = 8), patch (N = 7), balm (N = 8), gel (N = 6) or placebo (N = 9; matched to an active formulation). The protocol included three phases conducted over 17 days: (i) an acute drug application laboratory session, (ii) a 9-day outpatient phase with twice daily product application (visits occurred on Days 2, 3, 7 and 10) (iii) a 1-week washout phase. In each phase, whole blood, oral fluid and urine specimens were collected and analyzed via liquid chromatography with tandem mass spectrometry (LC-MS-MS) for CBD, Δ9-THC and primary metabolites of each and pharmacodynamic outcomes (subjective, cognitive/psychomotor and physiological effects) were assessed. Transdermal absorption of CBD was observed for three active products. On average, CBD/metabolite concentrations peaked after 7-10 days of product use and were highest for the lotion, which contained the most CBD and a permeation enhancer (vitamin E). Δ9-THC/metabolites were below the limit of detection in blood for all products, and no urine samples tested "positive" for cannabis using current US federal workplace drug testing criteria (immunoassay cut-off of 50 ng/mL and confirmatory LC-MS-MS cut-off of 15 ng/mL). Unexpectedly, nine participants (seven lotions, one patch and one gel) exhibited Δ9-THC oral fluid concentrations ≥2 ng/mL (current US federal workplace threshold for a "positive" test). Products did not produce discernable pharmacodynamic effects and were well-tolerated. This study provides important initial data on the acute/chronic effects of hemp-derived topical CBD products, but more research is needed given the diversity of products in this market.

Contingent administration of typical and biased kappa opioid agonists reduces cocaine and oxycodone choice in a drug vs. food choice procedure in male rhesus monkeys.

RATIONALE: Combinations 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. OBJECTIVE: The 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. METHODS: Adult 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. RESULTS: Cocaine 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. CONCLUSIONS: These 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.

A preliminary investigation of the simultaneous effects of cannabidiol and caffeine.

Caffeine and cannabidiol (CBD) are commonly consumed by the general population, particularly among young adults; however, there is little research on the simultaneous effects of caffeine and CBD. The present study aimed to examine the simultaneous self-reported effects of caffeine and CBD in young healthy adults. Participants (N = 54) who reported daily caffeine use (> 200 mg) attended one experimental session via Zoom and were assigned randomly to receive caffeine (200 mg) combined with either a placebo or CBD (25, 50, 80, 160, or 240 mg). Participants completed subjective drug effects measures at baseline and then ingested caffeine and their assigned CBD dose. Throughout the 140-min session, participants completed self-report measures. The primary outcomes of this study were measures of general drug effects and anxiety. After caffeine and CBD administration, few effects were observed in self-reported measures of general drug effects. No negative effects emerged as a result of combined caffeine and CBD administration. These results should be interpreted cautiously given the preliminary nature and variability in outcomes. The present study findings suggest that combinations of the tested doses of caffeine and CBD do not alter subjective drug effects; further, no negative effects emerged, providing preliminary safety evidence for using these products simultaneously. Further research is needed to examine the simultaneous and/or interactive nature of caffeine and CBD on other caffeine-induced outcomes (e.g., cognition and physiological effects) and will be critical for informing future regulatory decisions regarding caffeine: CBD mixtures. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Quantification of observable behaviors following oral administration of oxycodone and nalfurafine in male rhesus monkeys.

BACKGROUND: Recent preclinical studies have investigated the atypical kappa-opioid receptor (KOR) agonist, nalfurafine, as a co-formulary with mu-opioid receptor (MOR) agonists as a potential deterrent for misuse. However, no study has investigated effects of nalfurafine combined with a MOR agonist using an oral route of administration. The objective of the current study was to measure behavioral effects of orally administered oxycodone and nalfurafine, alone and combined, in rhesus monkeys using a quantitative behavioral observation procedure. METHODS: Adult male rhesus monkeys (N=5) were orally administered vehicle, oxycodone (0.56-1.8mg/kg), nalfurafine (0.001-0.0056mg/kg), or mixtures (1.0mg/kg oxycodone/0.001-0.0056mg/kg nalfurafine) in a Jell-O vehicle at multiple timepoints (10-320min). Species-typical and drug-induced behaviors were recorded by observers blinded to conditions. RESULTS: Oxycodone alone significantly increased scratch and face-rub behaviors without affecting other behaviors. Nalfurafine decreased baseline levels of scratch without affecting other behaviors, and oxycodone-nalfurafine combinations resulted in reduced oxycodone-induced scratching at a dose (0.001mg/kg) that did not produce sedation-like effects. Oxycodone combined with larger nalfurafine doses (0.0032-0.0056mg/kg) also reduced oxycodone induced scratch that were accompanied with sedation-like effects (i.e., increased lip droop). CONCLUSIONS: Nalfurafine was orally active in rhesus monkeys, and it reduced oxycodone-induced pruritus at a dose that did not produce sedation-like effects that are commonly observed with prototypical KOR agonists. Combinations of low doses of nalfurafine with MOR agonists such as oxycodone may be well-tolerated by humans who are prescribed MOR agonists for the treatment of pain.

Evaluation of Cytochrome P450-Mediated Cannabinoid-Drug Interactions in Healthy Adult Participants.

Understanding cannabis-drug interactions is critical given regulatory changes that have increased access to and use of cannabis. Cannabidiol (CBD) and Δ-9-tetrahydrocannabinol (Δ9-THC), the most abundant phytocannabinoids, are in vitro reversible and time-dependent (CBD only) inhibitors of several cytochrome P450 (CYP) enzymes. Cannabis extracts were used to evaluate quantitatively potential pharmacokinetic cannabinoid-drug interactions in 18 healthy adults. Participant received, in a randomized cross-over manner (separated by ≥ 1 week), a brownie containing (i) no cannabis extract (ethanol/placebo), (ii) CBD-dominant cannabis extract (640 mg CBD + 20 mg Δ9-THC), or (iii) Δ9-THC-dominant cannabis extract (20 mg Δ9-THC and no CBD). After 30 minutes, participants consumed a cytochrome P450 (CYP) drug cocktail consisting of caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A). Plasma and urine samples were collected (0-24 hours). The CBD + Δ9-THC brownie inhibited CYP2C19 > CYP2C9 > CYP3A > CYP1A2 (but not CYP2D6) activity, as evidenced by an increase in the geometric mean ratio of probe drug area under the plasma concentration-time curve (AUC) relative to placebo (AUCGMR ) of omeprazole, losartan, midazolam, and caffeine by 207%, 77%, 56%, and 39%, respectively. In contrast, the Δ9-THC brownie did not inhibit any of the CYPs. The CBD + Δ9-THC brownie increased Δ9-THC AUCGMR by 161%, consistent with CBD inhibiting CYP2C9-mediated oral Δ9-THC clearance. Except for caffeine, these interactions were well-predicted by our physiologically-based pharmacokinetic model (within 26% of observed interactions). Results can be used to help guide dose adjustment of drugs co-consumed with cannabis products and the dose of CBD in cannabis products to reduce interaction risk with Δ9-THC.

Oral Cannabidiol does not alter Alcohol Seeking and Self-Administration in Baboons.

BACKGROUND: The cannabinoid cannabidiol (CBD) is currently under investigation as a pharmacotherapy for alcohol use disorder. The aim of the present study was to examine whether acute and chronic treatment with pure CBD would decrease alcohol seeking and consumption behaviors or alter drinking patterns in male baboons with extensive histories of daily alcohol intake (1 g/kg/day). METHODS: Seven male baboons self-administered oral alcohol (4% w/v) in a validated chained schedule of reinforcement (CSR) procedure that modeled periods of anticipation, seeking, and consumption. In Experiment 1, CBD (5-40 mg/kg) or vehicle (peanut oil, USP) was administered orally 15- or 90-minutes prior to the start of the session. In Experiment 2, oral doses of CBD (10-40 mg/kg) or vehicle were administered for 5 consecutive days during ongoing alcohol access under the CSR. In addition, behavioral observations were conducted to assess potential drug side effects (e.g., sedation, motor incoordination) following chronic CBD treatment immediately after the session and 24-hours after drug administration. RESULTS: Across both experiments, baboons self-administered an average of 1 g/kg/day of alcohol under baseline conditions. Administration of acute or chronic CBD (150-1200 mg total CBD dose/day) that encompassed the purported therapeutic dose range did not significantly reduce alcohol seeking, self-administration or intake (g/kg). Drinking patterns (i.e., number of drinks/bouts, bout duration, nor interdrink interval) also were not altered. There were no observable behavioral disruptions following CBD treatment. CONCLUSIONS: In sum, the current data do not support use of pure CBD as an effective pharmacotherapy to reduce ongoing excessive drinking.

A cross-sectional survey on cannabis: Characterizing motives, opinions, and subjective experiences associated with the use of various oral cannabis products.

BACKGROUND: Cannabis-infused products available for oral consumption include food and drink items (i.e., edibles) (e.g., baked goods, gummy-, chocolate-, and hard-candies, beverages/drinks) as well as non-food formulations (e.g., oils/tinctures, pills/capsules). This study characterized the motives, opinions, and subjective experiences associated with the use of these seven subtypes of oral cannabis products. METHODS: This web-based survey collected cross-sectional, self-report data from a convenience sample of 370 adults regarding various use-motives, self-reported cannabinoid content, subjective experiences, and opinions related to ingesting oral cannabis products with alcohol and/or food. Advice participants had received about modifying oral cannabis product effects, in general, was also collected. RESULTS: Participants reported consuming cannabis baked goods and gummy candies most frequently over the past year (68% and 63%, respectively). Participants were less likely to use oils/tinctures for enjoyment/desire relative to other product types and more likely to use oils/tinctures for therapeutic purposes (e.g., medication-replacement). Self-reported cannabinoid content was highly variable across participants and within product subtype. Participants reported feeling stronger and longer-lasting effects when consuming oral cannabis products on an empty stomach and 43% received advice to "eat a snack or meal" to mitigate effects that are too strong, which contrasts with controlled studies. Finally, 43% of participants reported modifying their experiences with alcohol at least some of time. CONCLUSIONS: These findings underscore the need to further evaluate use-motives as well as the interaction between dietary factors, cannabinoid pharmacokinetics, and subjective drug effects and the interactive effects of oral cannabis products and alcohol in a controlled laboratory setting.

Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial.

Importance: Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations. Objective: To compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg). Design, Setting, and Participants: This randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week. Interventions: Brownies containing (1) no cannabis extract (ie, placebo); (2) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD); and (3) CBD-dominant extract (20 mg Δ9-THC + 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. Main Outcomes and Measures: Change-from-baseline plasma concentrations for Δ9-THC or Δ9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were determined. Results: The participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + Δ9-THC, CYP cocktail + Δ9-THC + CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail + Δ9-THC + CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail + Δ9-THC and CYP cocktail + placebo. Conclusions and Relevance: In this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC-dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid-cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision-making regarding the therapeutic and nontherapeutic use of cannabis products. Trial Registration: clinicaltrials.gov Identifier: NCT04201197.

Choice between food and cocaine reinforcers under fixed and variable schedules in female and male rhesus monkeys.

Illicit drugs like cocaine may be uncertain in terms of the time and effort required to obtain them. Behavior maintained by variable schedules resembles excessive drug-taking compared with fixed schedules. However, no prior research has examined fixed versus variable schedules in drug versus nondrug choice. The present study evaluated cocaine versus food choice under fixed- (FR) and variable-ratio (VR) schedules. The simpler food versus food and cocaine versus cocaine arrangements also were included. Adult female (n = 6) and male (n = 7) rhesus monkeys chose between cocaine (0.01-0.18 mg/kg/injection) and food (4 pellets/delivery), food and food (4 pellets/delivery), or cocaine and cocaine (0.018-0.03 mg/kg/injection) under FR and VR 100 and 200 schedules. In cocaine versus food choice, cocaine's potency to maintain choice was greatest when available under a VR 100 or 200 schedule and food under an FR schedule and was lowest when cocaine was available under an FR 200 schedule and food was available under a VR 200 schedule. In food versus food choice, males chose food associated with a VR schedule more than food associated with an FR schedule. In cocaine versus cocaine choice, females and males chose cocaine associated with a VR schedule more than cocaine associated with an FR schedule, particularly under VR 200. These findings suggest that uncertainty in terms of time and effort required to obtain cocaine, or perhaps the occasional low-cost access that results from VR schedules, results in greater allocation of behavior toward drug reinforcers at the expense of more certain, nondrug alternatives. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Self-Administration of Fentanyl-Alprazolam Combinations by Rhesus Monkeys Responding under a Progressive-Ratio Schedule.

This study evaluated the reinforcing effects of fentanyl, alone or in combination with the benzodiazepine alprazolam, in rhesus monkeys (3 females, 3 males). Subjects were trained to self-administer the opioid remifentanil (0.3 µg/kg/injection) under a progressive-ratio schedule of reinforcement. The reinforcing effects of fentanyl (0.1-10 µg/kg/injection) or alprazolam (1.0-100 µg/kg/injection) alone, or in combinations of fixed proportions (1:1, 1:3, and 3:1 fentanyl:alprazolam, with 1:1 based on the potencies of drugs alone) were evaluated in single-day test sessions (with double determinations). Dose-equivalence analysis was used to determine the extent to which fentanyl and alprazolam combinations differed from additivity. Fentanyl functioned as a positive reinforcer in all monkeys, while alprazolam was a reinforcer in 3 of 6 monkeys only. Therefore, drug combination data were grouped as "alprazolam-taking" and "non-alprazolam-taking" monkeys. For alprazolam-taking monkeys, we observed additive effects for the 3:1 and 1:3 combinations, and a significant supra-additive interaction for the 1:1 combination of fentanyl and alprazolam. For 2 of the 3 non-alprazolam-taking monkeys, the combination of fentanyl and alprazolam resulted in enhanced reinforcing effects relative to either drug alone. However, the one monkey showed primarily inhibitory, or suppressive effects, with the 3:1 dose combination resulting in a relatively modest rightward shift in the fentanyl dose-response function. In summary, our findings show that combining fentanyl and alprazolam generally result in proportion-dependent additive or supra-additive enhancements. These data raise the possibility that the prevalence of opioid-benzodiazepine polydrug abuse may reflect a unique enhancement of these drugs' reinforcing effects, although individual differences may exist. SIGNIFICANCE STATEMENT: Addressing the critical question of the degree to which benzodiazepines can modulate the abuse-related effects of opioids may provide improved pathways to treatment of this common form of polydrug addiction. In the present study, we show that combinations of the opioid fentanyl and the benzodiazepine alprazolam can be more reinforcing than either drug alone in a rhesus monkey model, suggesting that enhancement of reinforcement processes may underlie this prevalent form of polydrug use disorder.

The effects of oral and vaporized cannabis alone, and in combination with alcohol, on driving performance using the STISIM driving simulator: A two-part, double-blind, double-dummy, placebo-controlled, randomized crossover clinical laboratory protocol.

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.

Effects of methadone, buprenorphine, and naltrexone on actigraphy-based sleep-like parameters in male rhesus monkeys.

Opioid use disorder (OUD) has been associated with the emergence of sleep disturbances. Although effective treatments for OUD exist, evidence suggests that these treatments also may be associated with sleep impairment. The extent to which these effects are an effect of OUD treatment or a result of chronic opioid use remains unknown. We investigated the acute effects of methadone, buprenorphine, and naltrexone on actigraphy-based sleep-like parameters in non-opioid-dependent male rhesus monkeys (Macaca mulatta, n = 5). Subjects were fitted with actigraphy monitors attached to primate collars to measure sleep-like parameters. Actigraphy recordings were conducted under baseline conditions, or 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 (4 h after "lights on") or in the evening (1.5 h before "lights off"). Morning and evening treatments with methadone or buprenorphine significantly increased sleep latency and decreased sleep efficiency. The effects of buprenorphine on sleep-like measures resulted in a biphasic dose-response function, with the highest doses not disrupting actigraphy-based sleep. Buprenorphine induced a much more robust increase in sleep latency and decrease in sleep efficiency compared to methadone, particularly with evening administration, and detrimental effects of buprenorphine on sleep-like measures were observed up to 25.5 h after drug injection. Treatment with naltrexone, on the other hand, significantly improved sleep-like measures, with evening treatments improving both sleep latency and sleep efficiency. The currently available pharmacotherapies for OUD significantly alter sleep-like parameters in non-opioid-dependent monkeys, and opioid-dependent mechanisms may play a significant role in sleep-wake regulation.

Urinary Excretion Profile of Cannabinoid Analytes Following Acute Administration of Oral and Vaporized Cannabis in Infrequent Cannabis Users.

Traditionally, smoking has been the predominant method for administering cannabis, but alternative routes of administration have become more prevalent. Additionally, research examining urinary cannabinoid excretion profiles has primarily focused on 11-nor-9-carboxy-∆9-tetrahydrocannabinol (∆9-THC-COOH), a metabolite of ∆9-tetrahydrocannabinol (∆9-THC), as the primary analyte. The aim of the current study was to characterize the urinary excretion profile of ∆9-THC-COOH, ∆9-THC, ∆8-tetrahydrocannabinol (∆8-THC), 11-hydroxy-∆9-tetrahydrocannabinol (11-OH-∆9-THC), ∆9-tetrahydrocannabivarin (THCV), 11-nor-∆9-tetrahydrocannabivarin-9-carboxlic acid (THCV-COOH), cannabidiol (CBD), cannabinol (CBN) and 8,11-dihydroxytetrahydrocannabinol (8,11-diOH-∆9-THC) following controlled administration of both oral and vaporized cannabis. Participants (n = 21, 11 men/10 women) who were infrequent cannabis users ingested cannabis-containing brownies (0, 10 and 25 mg ∆9-THC) and inhaled vaporized cannabis (0, 5 and 20 mg ∆9-THC) across six double-blind outpatient sessions. Urinary concentrations of ∆9-THC analytes were measured at baseline and for 8 h after cannabis administration. Sensitivity, specificity and agreement between the three immunoassays (IAs) for ∆9-THC-COOH (cutoffs of 20, 50 and 100 ng/mL) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) analyses (confirmatory cutoff concentrations of 15 ng/mL) were assessed. Urinary concentrations for ∆9-THC-COOH, ∆9-THC, 11-OH-∆9-THC, THCV, CBN and 8,11-diOH-∆9-THC all peaked at 5-6 h and 4 h following oral and vaporized cannabis administration, respectively. At each active dose, median maximum concentrations (Cmax) for detected analytes were quantitatively higher after oral cannabis administration compared to vaporized. Using current recommended federal workplace drug-testing criteria (screening via IA with a cutoff of ≥50 ng/mL and confirmation via LC-MS-MS at a cutoff of ≥15 ng/mL), urine specimens tested positive for ∆9-THC-COOH in 97.6% of oral sessions and 59.5% of vaporized sessions with active ∆9-THC doses. These data indicate that while ∆9-THC-COOH may serve as the most consistent confirmatory analyte under the current drug-testing guidelines, future work examining 11-OH-∆9-THC under similar parameters could yield an alternative analyte that may be helpful in distinguishing between licit and illicit cannabis products.

The G-protein biased kappa opioid agonists, triazole 1.1 and nalfurafine, produce non-uniform behavioral effects in male rhesus monkeys.

Kappa-opioid receptor (KOR) agonists have been studied as potential treatments for pain, pruritus, and substance-use disorders, but prototypical KOR agonists produce side-effects like dysphoria and sedation. Atypical KOR agonists that exhibit G-protein biased signaling at the KOR have been reported to produce therapeutic-like effects with fewer or reduced side effects relative to prototypical KOR agonists. In the current report, behavioral profiles were determined using a behavioral scoring system that was modified to quantify drug-induced behaviors in nonhuman primates (NHPs). Profiles were determined for a prototypical and two biased KOR agonists, alone and combined with the mu-opioid receptor (MOR) agonist, oxycodone. Five adult male rhesus monkeys implanted with intravenous catheters were administered a range of doses of the KOR agonist, U50-488H (0.01-0.1 mg/kg) and the biased KOR agonists, nalfurafine (0.0001-0.001 mg/kg) and triazole 1.1 (0.32-1.0 mg/kg), alone and combined with the MOR agonist, oxycodone (0.01-0.32 mg/kg). In addition, the largest triazole 1.1 dose tested (1.0 mg/kg) was administered in time-course determinations (0-56 min), alone and combined with oxycodone (0.1 mg/kg). U50-488H and nalfurafine produced sedative-like and motor-impairing effects. Triazole 1.1 had a milder side-effect profile, in some instances producing sedative-like effects but to a lesser degree compared with the other KOR agonists, particularly for lip droop and rest/sleep posture. All KOR agonists reduced oxycodone-induced scratch, but nalfurafine produced behavior-disrupting and sedative-like effects when combined with oxycodone that were not observed with triazole 1.1. The duration of triazole 1.1's behavioral effects was relatively short, dissipating entirely by 56 min. Our results suggest that KOR agonists with comparable pharmacology to triazole 1.1 may be useful therapeutics with reduced side-effect profiles, and the mechanisms conferring these benefits may be attributed to factors other than G-protein bias.

The kappa-opioid receptor agonist, triazole 1.1, reduces oxycodone self-administration and enhances oxycodone-induced thermal antinociception in male rats.

RATIONALE: Triazole 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. OBJECTIVES: The 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. METHODS: In 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. RESULTS: All 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. CONCLUSION: This 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.

The kappa-opioid receptor agonist, nalfurafine, blocks acquisition of oxycodone self-administration and oxycodone's conditioned rewarding effects in male rats.

Mu-opioid receptor (MOR) agonists are highly efficacious for the treatment of pain but have significant abuse liability. Recently, we reported that nalfurafine, when combined with oxycodone at a certain ratio, reduced the reinforcing effects of oxycodone in rats while producing additive antinociceptive effects. Questions remain, however, including if the combination will function as a reinforcer in drug-naïve rats, and if the combination produces aversive effects that could explain nalfurafine's ability to reduce oxycodone self-administration? In the present study, we investigated nalfurafine's ability to reduce acquisition of oxycodone self-administration when the two were self-administered as a mixture in drug-naïve rats and nalfurafine's ability to attenuate a conditioned place preference (CPP) induced by oxycodone. In the self-administration study, male Sprague-Dawley rats self-administered intravenous injections of oxycodone (0.056 mg/kg/injection), an oxycodone/nalfurafine combination (0.056/0.0032 mg/kg/injection), or saline under fixed-ratio schedules of reinforcement for 20 days to compare rates of acquisition of drug taking. In the CPP assay, male Sprague-Dawley rats received subcutaneous injections of either saline, oxycodone (3.2 mg/kg), nalfurafine (0.18 mg/kg), or an oxycodone/nalfurafine combination at the same ratio used in the self-administration study (3.2 mg/kg/0.18 mg/kg). All subjects self-administering oxycodone alone met acquisition criteria. However, only 13% of subjects self-administering oxycodone/nalfurafine met criteria, and no subjects acquired self-administration of saline. Oxycodone, but not nalfurafine alone or the oxycodone/nalfurafine combination, produced rewarding effects in rats in the CPP test. These findings suggest that the combination of oxycodone and nalfurafine will be less habit forming in opioid-naïve patients than oxycodone alone.