Xylazine does not enhance fentanyl reinforcement in rats: A behavioral economic analysis.

The adulteration of illicit fentanyl with the alpha-2 agonist xylazine has been designated an emerging public health threat. The clinical rationale for combining fentanyl with xylazine is currently unclear, and the inability to study fentanyl/xylazine interactions in humans warrants the need for preclinical research. We studied fentanyl and xylazine pharmacodynamic and pharmacokinetic interactions in male and female rats using drug self-administration behavioral economic methods. Fentanyl, but not xylazine, functioned as a reinforcer under both fixed-ratio and progressive-ratio drug self-administration procedures. Xylazine combined with fentanyl at three fixed dose-proportion mixtures did not significantly alter fentanyl reinforcement as measured using behavioral economic analyses. Xylazine produced a proportion-dependent decrease in the behavioral economic Q0 endpoint compared to fentanyl alone. However, xylazine did not significantly alter fentanyl self-administration at FR1. Fentanyl and xylazine co-administration did not result in changes to pharmacokinetic endpoints. The present results demonstrate that xylazine does not enhance the addictive effects of fentanyl or alter fentanyl plasma concentrations. The premise for why illicitly manufacture fentanyl has been adulterated with xylazine remains to be determined.

Vaccine microarray patch self-administration: An innovative approach to improve pandemic and routine vaccination rates.

The high-density microprojection array patch (HD-MAP) is a novel vaccine delivery system with potential for self-administered vaccination. HD-MAPs provide an alternative to needle and syringe (N&S) vaccination. Additional advantages could include reduced cold-chain requirements, reduced vaccine dose, reduced vaccine wastage, an alternative for needle phobic patients and elimination of needlestick injuries. The drivers and potential benefits of vaccination by self-administering HD-MAPs are high patient acceptance and preference, higher vaccination rates, speed of roll-out, cost-savings, and reduced sharps and environmental waste. The HD-MAP presents a unique approach in pandemic preparedness and routine vaccination of adults. It could alleviate strain on the healthcare workforce and allows vaccine administration by minimally-trained workers, guardian or subjects themselves. Self-vaccination using HD-MAPs could occur in vaccination hubs with supervision, at home after purchasing at the pharmacy, or direct distribution to in-home settings. As a result, it has the potential to increase vaccine coverage and expand the reach of vaccines, while also reducing labor costs associated with vaccination. Key challenges remain around shifting the paradigm from medical professionals administrating vaccines using N&S to a future of self-administration using HD-MAPs. Greater awareness of HD-MAP technology and improving our understanding of the implementation processes required for adopting this technology, are critical factors underpinning HD-MAP uptake by the public.

Prefilled Syringe Injection Force Impact Assessment from Back Pressure: An Approach for Testing Syringe Injectability In Situ vs. In Vitro.

Prefilled syringes are commonly used combination products for parenteral drug and vaccine administration. The characterization of these devices is through functionality testing, such as injection and extrusion force performance. This testing is typically completed by measuring these forces in a nonrepresentative environment (i.e., dispensed in-air) or route of administration conditions. Although injection tissue may not always be feasible or accessible for use, questions from the health authorities make it increasingly important to understand the impact of tissue back pressure on device functionality. Particularly for injectables containing larger volumes and higher viscosities, which can widely impact injection and user experience. This work evaluates a comprehensive, safe, and cost-effective in situ testing model to characterize extrusion force while accounting for the variable range of opposing forces (i.e., back pressure) experienced by the user during injection into live tissue with a novel test configuration. Due to the variability of back pressure presented by human tissue for both subcutaneous and intramuscular injections, tissue back pressure was simulated (0 psi-13.1 psi) using a controlled, pressurized injection system. Testing was conducted across different syringe sizes (2.25 mL, 1.5 mL, and 1.0 mL) and types (Luer lock and stake needle) with two simulated drug product viscosities product (1 cP and 20 cP). Extrusion force was measured using a Texture Analyzer mechanical testing instrument with crosshead speeds of 100 mm/min and 200 mm/min. The results demonstrated that there is a contribution of increasing back pressure on extrusion force across all syringe types, viscosities, and injection speeds that can be predicted using the proposed empirical model. Moreover, this work demonstrated that the factors that largely influence the average and maximum extrusion force during injection are syringe and needle geometries, viscosity, and back pressure. This understanding of the device usability may aid in the development of more robust prefilled syringe designs to minimize use-related risks.

Demand and cross-price elasticity of cocaine and social contact in a free-operant procedure of nonexclusive choice.

Research examining the social determinants of addiction has advanced significantly with the recent development of preclinical models of drug use and the social environment. These models reveal that drug use and social contact compete with one another for behavioral expression in discrete-trial choice procedures using concurrent schedules of reinforcement. The purpose of this study was to determine how concurrent access to cocaine and a social partner influences the demand for each alternative under free-operant conditions in which responding maintained by each reinforcer is independent and nonexclusive of the other. To this end, male rats were trained under a free-operant, concurrent schedule of reinforcement in which responding maintained by cocaine and access to a social partner operated independently of one another. Measures of economic demand (e.g., intensity, Omax, cross-price elasticity) were determined by manipulating the response requirement (i.e., fixed ratio value) across sessions. Tests were conducted in which the social partner was either treated or not treated with cocaine to determine whether the intoxication state of the partner influenced demand. The principal findings of this study are (1) demand for a cocaine-treated partner is greater than demand for a cocaine-free partner, (2) demand for cocaine is greater in the presence of a cocaine-treated partner than a cocaine-free partner, and (3) concurrent access to cocaine decreases demand for social contact. Notably, measures of cross-price elasticity indicated that social contact is a robust economic substitute for cocaine.

Hierarchical cue control of cocaine seeking in the face of cost.

RATIONALE: Addiction is characterized by intermittent drug seeking despite rising costs. This behavior is heavily influenced by environmental stimuli that signal drug availability and reinforce drug seeking. OBJECTIVE: To establish the relationship between three key aspects of human drug use in rats: the intermittent, binge nature of drug intake, the motivational conflict of drug seeking in the face of escalating negative costs, and the ability of different drug cues to interact to modulate relapse. METHODS: Male and female rats were trained to self-administer cocaine on an intermittent access schedule, where brief drug-availability states were signaled by a shift in the ambient lighting of the environment, and cocaine infusions were signaled by a separate proximal discrete cue. Rats then went through a conflict procedure, where foot shock intensity associated with cocaine seeking was escalated until intake was suppressed. We then completed relapse tests where the drug-delivery cue was noncontingently presented alone, or in the context of dynamic drug-availability state transitions. RESULTS: Intermittent access spurred psychomotor sensitization and binge-like cocaine intake. The intensity of binge-like drug taking during training was predictive of later drug seeking despite escalating costs during conflict. In relapse tests, the ability of a proximal discrete drug cue to trigger relapse was gated by the presence of a global cue signaling drug-availability state transitions. CONCLUSIONS: Our results suggest that the pattern of drug intake plays a role in many features of addiction, including modifying an individual's willingness to endure high costs associated with drug seeking. Furthermore, our studies indicate that drug-related sensory information can be hierarchically organized to exert a dynamic modulating influence on drug-seeking motivation.

Relative reinforcing effects of dibutylone, ethylone, and N-ethylpentylone: self-administration and behavioral economics analysis in rats.

RATIONALE: Following the emergence of methylone as one of the most popular synthetic cathinones, this group of novel psychoactive substance with names ending in "-lone," such as dibutylone, ethylone, and N-ethylpentylone, appeared on the recreational drug market. The pharmacological mechanisms of dibutylone, ethylone, and N-ethylpentylone are well understood; however, to date, the reinforcing effects of dibutylone, ethylone, and N-ethylpentylone are still unclear. OBJECTIVES: This study aimed to examine the self-administration of dibutylone, ethylone, and N-ethylpentylone relative to methamphetamine (METH) and to quantify their relative reinforcing effectiveness using behavioral economic analysis. METHODS: Male Sprague-Dawley rats were trained to self-administer METH (0.05 mg/kg) under a fixed-ratio 1 (FR1) schedule. Following the training, dose substitution was used to generate full dose-response curves for METH and the three synthetic cathinones. According to the first doses on the descending limb of the dose-response curves, rats were trained to self-administer METH (0.05 mg/kg), dibutylone (0.1 mg·kg-1·infusion-1), ethylone (0.4 mg·kg-1·infusion-1), or N-ethylpentylone (0.1 mg·kg-1·infusion-1) under an FR1 schedule, and a behavioral economic evaluation of their reinforcing effectiveness was then performed. RESULTS: Dibutylone, ethylone, and N-ethylpentylone functioned as reinforcers, and the inverted U-shaped dose-response curves were obtained. The rank order of reinforcing potency in this procedure was METH > N-ethylpentylone ≈ dibutylone > ethylone. In the economic analysis, the comparisons of the essential value (EV) transformed from demand elasticity (α) indicated that the rank order of efficacy as reinforcers was METH (EV = 7.93) ≈ dibutylone (EV = 7.81) > N-ethylpentylone (EV = 5.21) ≈ ethylone (EV = 4.19). CONCLUSIONS: These findings demonstrated that dibutylone, ethylone, and N-ethylpentylone function as reinforcers and have addictive potential, suggesting that the modification of α-alkyl and N-alkyl side chains may affect their reinforcing efficacy.

Preclinical Assessment of the Abuse Potential of Purified Botanical Cannabidiol: Self-Administration, Drug Discrimination, and Physical Dependence.

Cannabidiol (CBD) is a constituent of the cannabis plant with a diverse array of pharmacological activities as well as potential therapeutic uses. An oral formulation of CBD (Epidiolex in the US; Epidyolex in Europe) is approved for treating seizures associated with rare and severe forms of epilepsy. These studies, which supported the approval of the medication, investigated abuse-related effects of CBD in rats and nonhuman primates (NHPs) using drug self-administration, drug discrimination, and physical dependence procedures and characterized its pharmacokinetics. In NHPs (n = 5) that self-administered midazolam (0.01 or 0.032 mg/kg/infusion), CBD (0.1-3.2 mg/kg/infusion) failed to maintain responding above vehicle levels. CBD maintained very modest levels of self-administration in rats (n = 7-8) that self-administered heroin (0.015 mg/kg/infusion) and did not increase drug-lever responding, up to a dose of 150 mg/kg (by mouth), in rats (n = 6) trained to discriminate 0.5 mg/kg (i.p.) midazolam. In juvenile (5-6 weeks old) and adult (10-11 weeks old) male and female rats, discontinuation of chronic treatment (twice daily for 20 days) with an oral formulation of CBD (20 or 100 mg/kg, by mouth) did not reliably produce signs of withdrawal. Pharmacokinetic studies confirmed that the dosing regimens used in these studies resulted in therapeutically relevant plasma levels. Taken together, the lack of reliable self-administration, the failure to increase drug-lever responding in rats trained to discriminate midazolam, and the absence of withdrawal signs upon discontinuation of chronic treatment indicate that CBD has very low abuse potential and is unlikely to produce physical dependence. SIGNIFICANCE STATEMENT: Legalization of cannabis across the United States and elsewhere has led to intense investigation into the safety and therapeutic potential of cannabis and its constituent materials, including cannabidiol (CBD). Results of these preclinical abuse potential studies on CBD indicate no rewarding properties, physical dependence potential, or similarity to a benzodiazepine. Together with data from in vitro pharmacology and human abuse potential studies, the abuse potential of Epidiolex in humans is likely to be negligible.

Hormonal milieu drives economic demand for cocaine in female rats.

There are substantial sex differences in drug abuse, and a key feature of cocaine addiction is pathologically high motivation for drug. We investigated the role of ovarian hormones on cocaine demand in female rats using a within-session threshold behavioral economics (BE) procedure, which allows us to compare motivation for drug across hormonal states and sex while controlling for differences in dose and intake. This approach quantifies demand elasticity (α) and free consumption (Q0, consumption at null effort) to determine motivation for cocaine. Overall, female rats showed greater motivation for cocaine compared to males. However, this difference was cycle phase-dependent - motivation for cocaine when females were in proestrus was lower compared to the same animals across cycle phases, and overall similar to that of males. Hormonal cycle phase accounted for 70% of the within-subject variance in demand elasticity, obscuring other individual differences in female demand. High serum progesterone (P4; e.g., in proestrus) predicted decreased cocaine motivation (high demand elasticity), whereas serum estradiol (E2) correlated to greater intake at null effort (Q0). However, individual differences were revealed across OVX females, who displayed a range of demand elasticity, as seen in males. E2 replacement in OVX females increased motivation for cocaine, whereas P4 replacement decreased motivation. We also found that as few as 4 weeks of cocaine self-administration accelerated estropause in female rats as young as 12 weeks old. By 13 weeks of self-administration, proestrus epochs were no longer observed, and cocaine demand was potentiated by persistent estrus in all females. Thus, P4 signaling is a key modulator of cocaine demand in females that may underlie previously observed sex differences in addiction phenotypes.

Effects of NMDA receptor antagonists on behavioral economic indices of cocaine self-administration.

BACKGROUND: Currently, there are no FDA-approved medications for the treatment of psychostimulant (e.g., cocaine) use disorders. Because the GluN2B subunit of the glutamate N-methyl-D-aspartate (NMDA) receptor is an important mediator of addiction-like behaviors, the goal of the current study was to determine if the GluN2B-selective antagonist Ro 63-1908 is efficacious in attenuating cocaine self-administration. METHODS: Adult Sprague Dawley rats (24 males and 11 females) were implanted with indwelling catheters and were trained to self-administer cocaine (0.75 mg/kg/inf). Rats were then trained in a threshold procedure, in which the dose of cocaine decreased across six 6-min blocks (0.75, 0.27, 0.08, 0.03, 0.01, 0.003 mg/kg/inf). This procedure allowed for the quantification of behavioral economic indices of drug self-administration. Following training in the threshold procedure, rats were treated with the GluN2B-selective antagonist Ro 63-1908 (0, 0.1, 0.3, 1.0 mg/kg; s.c.). Rats also received treatments of the NMDA receptor channel blocker MK-801 (0, 0.01, 0.03, 0.06 mg/kg; s.c.). RESULTS: Blocking NMDA receptors decreased initial intake (i.e., consumption during the first block), although Ro 63-1908 and MK-801 increased area under the curve (global measure of demand) and decreased demand elasticity, an effect observed primarily in males. Neither drug affected demand intensity (i.e., consumption of cocaine at a minimally constrained price). CONCLUSIONS: While blocking the NMDA receptor decreases initial intake of cocaine, NMDA receptor antagonists make cocaine more inelastic with increasing price. These results suggest that NMDA receptor antagonists can exacerbate addiction-like behaviors during self-administration during extinction-like conditions that are observed in later blocks of the threshold procedure.

Assessment of safety of self-controlled repetitive trans-vertebral magnetic stimulation.

OBJECTIVE: The aim of this study was to assess safety issues of self-controlled repetitive trans-vertebral magnetic stimulation (rTVMS) in humans. METHODS: We investigated effects of self-controlled rTVMS (≤20 Hz, ≤90% intensity) on vital signs and subjective sensations in 1690 trials of 30 healthy volunteers and 12 patients with spinal cord disorders. RESULTS: Healthy volunteers and the patients received 4595 ± 2345, and 4450 ± 2304 pulses in one day, respectively. No serious adverse events were observed in any participants, and only minor events were seen as follows. While blood pressure was unaffected in the patients, the diastolic blood pressure increased slightly after rTVMS in healthy volunteers. The peripheral capillary oxygen saturation increased after rTVMS in healthy volunteers. "Pain" or "Discomfort" was reported in approximately 10% of trials in both participants groups. Degree of the evoked sensation positively correlated with stimulus intensity and was affected by the site of stimulation. CONCLUSION: Self-controlled rTVMS (≤20 Hz and ≤90% intensity) did not induce any serious adverse effects in healthy volunteers and patients with spinal cord disorders. SIGNIFICANCE: Our results indicate that rTVMS can be used safely in physiological investigations in healthy volunteers and also as treatment for neurological disorders.

The Role of Subcutaneous Depot Medroxyprogesterone Acetate in Equitable Contraceptive Care: A Lesson From the Coronavirus Disease 2019 (COVID-19) Pandemic.

Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, health care professionals have made swift accommodations to provide consistent and safe care, including emphasizing remote access to allow physical distancing. Depot medroxyprogesterone acetate intramuscular injection (DMPA-IM) prescription is typically administered by a health care professional, whereas DMPA-subcutaneous has the potential to be safely self-injected by patients, avoiding contact with a health care professional. However, DMPA-subcutaneous is rarely prescribed despite its U.S. Food and Drug Administration approval in 2004 and widespread coverage by both state Medicaid providers and many private insurers. Depot medroxyprogesterone acetate users are disproportionately non-White, and thus the restriction in DMPA-subcutaneous prescribing may both stem from and contribute to systemic racial health disparities. We review evidence on acceptability, safety, and continuation rates of DMPA-subcutaneous, consider sources of implicit bias that may impede prescription of this contraceptive method, and provide recommendations for implementing DMPA-subcutaneous prescribing.

Why do patients struggle with their medicines?-A phenomenological hermeneutical study of how patients experience medicines in their everyday lives.

Why do so many people struggle with their medicines despite decades of research on medicines taking? Research into how people experience medicines in their everyday life remains scarce with the majority of research in this area of focusing on whether or not people take their medicines as prescribed. Hence, this study used a phenomenological hermeneutical qualitative design to gain a deeper understanding of individuals' perspectives on the lived experience of medicine-taking. Findings from this study highlight five main themes where participants experience medicines as: 1) life-saving and indispensable, 2) normal and a daily routine, 3) confusing and concerning, 4) unsuitable without adjustment, and 5) intrusive and unwelcome. These results can be the basis for mutually agreed prescribing through a co-creative approach that aims at enhancing open and honest dialogues between patients and healthcare professionals in partnership about medicines.

Women's experiences of a telemedicine abortion service (up to 12 weeks) implemented during the coronavirus (COVID-19) pandemic: a qualitative evaluation.

OBJECTIVE: To explore the experiences of women in Scotland who accessed medical abortion at home up to 12 weeks' gestation, delivered via a telemedicine abortion service implemented in response to the coronavirus (COVID-19) pandemic, to identify areas for improvement and inform service provision. DESIGN: Qualitative interview study. SETTING: Abortion service in one National Health Service health board in Scotland. POPULATION OR SAMPLE: Twenty women who accessed telemedicine abortion services and self-administered mifepristone and misoprostol at home up to 12 weeks' gestation. METHODS: Thematic analysis of semi-structured qualitative interviews, informed by the Framework analytic approach. MAIN OUTCOME MEASURES: Women's experiences of accessing telemedicine for medical abortion at home, specifically: acceptability of the telephone consultation and remote support; views on no pre-abortion ultrasound scan; and self-administration of abortion medications at home. RESULTS: Novel study findings were three-fold: (1) participants valued the option of accessing abortion care via telemedicine and emphasised the benefits of providing a choice of telephone and in-person consultation to suit those with different life circumstances; (2) the quality of abortion care was enhanced by the telemedicine service in relation to access, comfort and flexibility, and ongoing telephone support; (3) participants described being comfortable with, and in some cases a preference for, not having an ultrasound scan. CONCLUSIONS: This research demonstrates support for the continuation of telemedicine abortion services beyond the temporary arrangements in place during COVID-19, and lends weight to the argument that offering the option of telemedicine abortion care can enable women to access this essential health service. TWEETABLE ABSTRACT: #Telemedicine provision of medical #abortion at home up to 12 weeks' gestation is acceptable and highly valued by #women #Research #SRHR @nbw80 @doctorjjrw @jeniharden @cameronsharon @mrc_crh @edinuniusher.

Greasing the wheels: The impact of COVID-19 on US physician attitudes and practices regarding medication abortion.

OBJECTIVE: To explore US provider perspectives about self-sourced medication abortion and how their attitudes and clinic practices changed in the context of the COVID-19 pandemic. STUDY DESIGN: We conducted a multi-method study of survey and interview data. We performed 40 baseline interviews and surveys in spring 2019 and 36 follow-up surveys and ten interviews one year later. We compared pre- and post-Likert scale responses of provider views on the importance of different aspects of standard medication abortion assessment and evaluation (e.g., related to ultrasounds and blood-typing). We performed content analysis of the follow-up interviews using deductive-inductive analysis. RESULTS: Survey results revealed that clinics substantially changed their medication abortion protocols in response to COVID-19, with more than half increasing their gestational age limits and introducing telemedicine for follow-up of a medication abortion. Interview analysis suggested that physicians were more supportive of self-sourced medication abortion in response to changing clinic protocols that decreased in-clinic assessment and evaluation for medication abortion, and as a result of physicians' altered assessments of risk in the context of COVID-19. Having evidence already in place that supported these practice changes made the implementation of new protocols more efficient, while working in a state with restrictive abortion policies thwarted the flexibility of clinics to adapt to changes in standards of care. CONCLUSION: This exploratory study reveals that the COVID-19 pandemic has altered clinical assessment of risk and has shifted practice towards a less medicalized model. Further work to facilitate person-centered abortion information and care can build on initial modifications in response to the pandemic. IMPLICATIONS: COVID-19 has shifted clinician perception of risk and has catalyzed a change in clinical protocols for medication abortion. However, state laws and policies that regulate medication abortion limit physician ability to respond to changes in risk assessment.

Assessment of the abuse potential of methamnetamine in rodents: a behavioral pharmacology study.

RATIONALE: Methamnetamine (MNA; PAL-1046) is a new psychoactive substance that acts as a full biogenic amine transporter (BAT) substrate. BAT substrates promote neurotransmitter release from the nerve terminal and can be abused as stimulants. However, scientific information on the abuse potential of methamnetamine is lacking. OBJECTIVE: We evaluated the abuse liability of methamnetamine. METHODS: The effective dose range of methamnetamine was determined using a climbing behavior test. The rewarding effect and reinforcing effect of the test compound were evaluated in mice by conditioned place preference (CPP) testing and self-administration (SA) testing at the selected doses. Dopamine level changes were analyzed using synaptosomes and in vivo microdialysis to investigate the effects of methamnetamine on the central nervous system. Drug discrimination experiments were used to examine the potential similarity of the interoceptive effects of methamnetamine and cocaine. RESULTS: A significant response was observed in the climbing behavior test with 10 and 40 mg/kg intraperitoneally administered methamnetamine. In the CPP test, mice intraperitoneally administered methamnetamine (10 and 20 mg/kg) showed a significant preference for the drug-paired compartment. In the SA test, mice that intravenously received 1 mg/kg/infusion showed significant active-lever responses. Dopamine was significantly increased in synaptosomes and in in vivo microdialysis tests. Furthermore, methamnetamine showed cross-generalization with cocaine in a dose-dependent manner. CONCLUSIONS: Methamnetamine exhibits interceptive stimulus properties similar to those of cocaine and induces rewarding and reinforcing effects, suggesting its dependence liability potential.

Assessment of medication self-administration using artificial intelligence.

Errors in medication self-administration (MSA) lead to poor treatment adherence, increased hospitalizations and higher healthcare costs. These errors are particularly common when medication delivery involves devices such as inhalers or insulin pens. We present a contactless and unobtrusive artificial intelligence (AI) framework that can detect and monitor MSA errors by analyzing the wireless signals in the patient's home, without the need for physical contact. The system was developed by observing self-administration conducted by volunteers and evaluated by comparing its prediction with human annotations. Findings from this study demonstrate that our approach can automatically detect when patients use their inhalers (area under the curve (AUC) = 0.992) or insulin pens (AUC = 0.967), and assess whether patients follow the appropriate steps for using these devices (AUC = 0.952). The work shows the potential of leveraging AI-based solutions to improve medication safety with minimal overhead for patients and health professionals.

Addressing contraceptive needs exacerbated by COVID-19: A call for increasing choice and access to self-managed methods.

The COVID-19 pandemic has exposed the vulnerability of global contraception provision, exacerbating the barriers to access reproductive health services, leading to suspension of clinical services and disruption of supply chains. Critical to combatting this crisis is the expansion of healthcare to include self-care approaches to de-medicalize contraception and increase an individual's agency in determining what method they use, when they use it, and where they obtain it. Expanding the mix of self-administered contraceptives is essential for ensuring choice, access, and availability. We highlight advances in the self-care movement and actions needed to strengthen self-management approaches to maximize our chances of preventing a reproductive health crisis.