High Abuse Potential Research Articles

Methylphenidate dose-response behavioral and neurophysiological study of the ventral tegmental area and nucleus accumbens in adolescent rats.

The psychostimulant methylphenidate (MPD) is the most common medication used in treating ADHD in children. Studies have shown an increasing prevalence among adolescents without ADHD to take MPD as a cognitive booster and recreational drug, even though it is a Schedule II drug and has a high potential for abuse. The objective of this study is to explore if there is an association between the animals' behavioral and neurophysiological responses to acute and/or chronic methylphenidate exposure within the ventral tegmental area and the nucleus accumbens, and to compare how these two brain structures fire in response to methylphenidate. Freely moving adolescent rats implanted with semimicroelectrodes within the VTA and NAc were divided into three MPD dosing groups: 0.6, 2.5, and 10mg/kg i.p., as well as a saline control group. The animals were divided into two groups based on their behavioral responses to chronic MPD, behavioral sensitization and tolerance, and the neuronal responses of the two groups were compared for each MPD dosing. Significant differences in the proportion of neuronal units in the VTA and NAc responding to MPD were observed at the 0.6 and 10.0mg/kg MPD dosing groups. Moreover, the same doses of 0.6, 2.5, and 10.0mg/kg MPD elicited behavioral sensitization in some animals and behavioral tolerance in others. This specific study shows that the VTA and NAc neurons respond differently to the same doses of MPD. MPD has different neuronal and behavioral effects depending on the individual, the dosage of MPD, and the brain structure studied.

Abuse Potential of Phendimetrazine and its Effects on Cocaine Self‐Administration in Rhesus Monkeys

Cocaine use disorder (CUD) continues to be a major public health and social problem with >1.5 million users resulting in 14,556 deaths in 2017 in the United States and with no FDA‐approved medications available (Volkow and Koob, 2016). Preclinical studies in nonhuman primates have shown that monoamine releasers such as amphetamine can reduce the reinforcing strength of cocaine under several schedules of cocaine self‐administration (SA; Czoty et al. 2010; Negus et al. 2003a, b). However, the high abuse potential of this category of drugs has hindered advancement of their clinical use for treatment of CUD. More recently, preclinical researchers have investigated phendimetrazine (PDM), an FDA‐approved Schedule III anorectic agent, with evidence of efficacy in animal models (Banks and Negus, 2013; Czoty et al. 2016). As a pro‐drug for the monoamine releaser phenmetrazine, PDM has a slow onset and long duration of action. Only two studies (Griffiths et al. 1976; Corwin et al. 1987) have evaluated the reinforcing effects of PDM, with opposite conclusions. The goal of the present study was to compare, in the same subjects, the efficacy of PDM to decrease cocaine SA and the reinforcing strength of PDM relative to cocaine. For 5 consecutive days, three adult male rhesus monkeys responded under a daily fixed‐ratio 20 schedule of food presentation, which, on the fifth day, was followed by a progressive‐ratio (PR) schedule of cocaine (0.003–0.3 mg/kg/injection) presentation (limited hold 30‐min, maximum 4‐hr). PDM was administered daily (1.0–6.0 mg/kg, PO, BID). The primary dependent variable under the PR schedule was the number of injections delivered. Under baseline conditions, monkeys typically earned 10 food reinforcers and the number of cocaine injections was characterized as an inverted U‐shaped function of dose. Under treatment conditions, in two subjects, food‐maintained responding was disrupted at higher PDM doses that also decreased cocaine SA. In the third subject, food reinforcement was not affected and PDM did not show efficacy in decreasing cocaine SA. When PDM (0.1–1.0 mg/kg/injection) was substituted for cocaine, it functioned as a reinforcer in all three subjects; the number of injections observed at peak doses of PDM (0.3 and 1.0 mg/kg/injection) were similar to those observed at the peak dose of cocaine (0.03 mg/kg/injection). These findings suggest that PDM has abuse liability and was ineffective in decreasing cocaine SA. These data do not support the use of PDM as a potential treatment for CUD.Support or Funding InformationP50 DA06634‐27This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Scheduling synthetic cathinone substances under the Controlled Substances Act.

Cathinones are amphetamine analogues that produce stimulant effects with rewarding properties. For many decades, synthetic cathinones have been used in the United States (USA) for abuse purposes, leading to concern about public safety by the federal government. Under the Controlled Substances Act (CSA), the federal government may place drugs with high abuse potential but no currently accepted medical use into Schedule I of the CSA. The process of scheduling an abusable drug involves both the Department of Health and Human Services (HHS), through the Food and Drug Administration (FDA) and the National Institute on Drug Abuse (NIDA), and the Department of Justice, through the Drug Enforcement Administration (DEA). This paper details how numerous synthetic cathinones were placed under CSA control between 1973 and 2018, with an emphasis on 10 cathinones that were placed into Schedule I in 2017 (butylone, naphyrone, pentylone, pentedrone, 3-fluoro-N-methylcathinone (FMC), 4-FMC, 4-methyl-N-ethylcathinone, 4-methyl-pyrrolidinopropiophenone, alpha-pyrrolidinobutiophenone, and α-pyrrolidinopentiophenone). A summary is provided of the scientific and medical analysis performed by HHS, in the form of an Eight-Factor Analysis (8FA), as prescribed by the CSA. This 8FA was then evaluated and signed by the Assistant Secretary for Health at HHS and transmitted to DEA, which permanently placed the 10 cathinones into Schedule I after public notices were published into the Federal Register. Understanding the scientific data, analysis, and complex process utilized by the US federal government in the CSA scheduling of cathinones with abuse potential and no accepted medical use is important for transparency in governmental decision-making.

Navigating Blind in the Green Rush: Clinical Considerations and Harm Reduction Practices for Cannabis.

The United States has recently experienced extensive changes in state policy regarding the use of cannabis for recreational and medicinal purposes. Despite its rapidly increasing accessibility and social acceptance, there is a striking dearth of research on cannabis as a treatment for medical and psychological conditions. Research on cannabis is difficult to conduct as it is classified as a schedule I drug with high potential for abuse and currently no accepted medical use in treatment. As a result, no standard dosing procedures exist and the lack of conclusive scientific evidence has left clinical providers without evidence-based guidelines about if, when, and how to guide clients on using cannabis safely. To (1) provide critical psychoeducational information about cannabis and cannabis problems to guide client-provider conversations about cannabis use and (2) describe common clinical concerns around cannabis use, highlight special considerations for vulnerable populations, and review harm reduction techniques and practical resources that may help clinicians and their clients navigate safer cannabis use. The removal of regulatory barriers would enable researchers to address key public health questions about the potential therapeutic and adverse effects of cannabis use. Additionally, funds for research, clinician education, and public health education initiatives are necessary to reduce risk around cannabis use in the United States.

When fish take a bath: Psychopharmacological characterization of the effects of a synthetic cathinone bath salt ‘flakka’ on adult zebrafish

Alpha-pyrrolidinopentiophenone (α-PVP) is a synthetic cathinone which exerts robust mental and physiological effects clinically, as well as causes aberrant stereotypic behaviors and altered locomotion in rodents. Given the rich spectrum of pharmacological activity of α-PVP in rodents and humans, as well as its high abuse potential, further studies are needed to better understand the pharmacology and toxicology of this drug. The zebrafish (Danio rerio) is a relatively novel model organism in neuropharmacology and toxicology research. Here, we characterize behavioral effects of α-PVP in adult zebrafish following its acute (1, 5, 25 and 50 mg/L for 20 min) and chronic (1, 5 and 10 mg/L for 7 days) treatments. Overall, acute exposure to α-PVP evoked psychostimulant (but not anxiolytic-like) effects in zebrafish novel tank test, with characteristic stereotypic ‘side-to-side’ bottom swimming at 5, 25 and 50 mg/L. The high-performance liquid chromatography/high-resolution mass spectrometry (HPLC/HRMS) analyses of zebrafish brains showed detectable levels of α-PVP following its acute administration, likely underlying the observed behavioral effects. Although acute 2-day discontinuation of chronic 7-day α-PVP at 1, 5 and 10 mg/L produced no effects, hypolocomotion occurred after a 7-day chronic treatment and repeated withdrawal, resembling rodent effects of some chronic psychostimulants. Collectively, these findings support zebrafish sensitivity to α-PVP and show some parallels with its effects in mammals and humans. This study also suggests that aquatic models based on zebrafish can help further examine the CNS effects evoked by α-PVP and screen for related synthetic new psychoactive drugs.

Associations between child physical abuse potential, observed maternal parenting, and young children's emotion regulation: Is participation in Early Head Start protective?

Clinicians working with Early Head Start (EHS) families consider family well-being and positive parent-child relationships as foundational to school readiness. Understanding the links between risk factors and these dimensions of family engagement can inform clinical decision-making, as risk assessments are used to tailoring program services. The current study examined the associations between high risk, or potential, for child physical abuse and both parenting quality and children's emotion regulation (ER) during toddlerhood; EHS participation was examined as a buffer. The sample included EHS-eligible mothers of infants (N = 80) drawn from one site of the EHS Research and Evaluation Project. Associations were tested between mothers' potential for child physical abuse, measured during infancy, and observed maternal sensitivity, positive regard, harshness, and children's ER skills at child ages 1 and 2 years. Results indicated that high potential for child physical abuse was associated with lower positive regard at age 1 and lower ER skills at age 2. EHS participation operated as a buffer on each of these associations. Implications for screening for child physical abuse potential and the constructs it represents in clinical settings as well as how EHS can promote family engagement are discussed.

Contribution of monoaminergic mechanisms to the discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) in Sprague-Dawley rats.

3,4-Methylenedioxypyrovalerone (MDPV) is a popular synthetic cathinone reported to have a high abuse potential. Recent preclinical research indicates the psychopharmacology of MDPV is comparable to cocaine. Despite a recent influx of research on the psychopharmacology of MDPV, few studies have employed preclinical drug discrimination methods to discern the neurochemical mechanisms involved in its interoceptive stimulus effects. The aim of this study was to evaluate a variety of monoaminergic agents for substitution, potentiation, or antagonism in rats trained to discriminate MDPV. Male Sprague-Dawley rats were trained to discriminate 0.5 (experiment 1) or 1mg/kg MDPV (experiment 2) from saline under an FR 20 schedule of food reinforcement. In experiment 1, MDMA, MDA, and their respective optical isomers (0.75-3mg/kg), cocaine (2.5-20mg/kg), GBR 12909 (5-40mg/kg), and desipramine (3.2-10mg/kg) were assessed for substitution. GBR 12909 (40mg/kg) and desipramine (3.2mg/kg) were subsequently assessed for potentiation of the MDPV cue. In experiment 2, stimulus antagonism tests were conducted with dopamine antagonists (Sch 23390, haloperidol) and serotonin antagonists (pirenperone, MDL100907, WAY 100635). The MDMA and MDA enantiomers produced divergent results, with virtually no substitution by (-)-MDMA or (-)-MDA, partial substitution with (+)-MDA, and full substitution with (+)-MDMA, as well as full substitution by the racemates, (±)-MDMA and (±)-MDA. Consistent with previous findings, cocaine fully substituted for MDPV. Although no dose of GBR 12909 or desipramine substituted for MDPV, these reuptake inhibitors enhanced the discriminative stimulus effects of lower MDPV doses. Both D1 (Sch 23390) and D2 (haloperidol) DA antagonists attenuated 1mg/kg MDPV discrimination, whereas none of the 5-HT antagonists assessed altered MDPV discrimination. These findings indicate MDPV's interoceptive stimulus effects are mediated predominantly by dopaminergic actions, although serotonergic and/or noradrenergic modulation of these effects cannot be ruled out. Further investigations into the neurochemical actions involved in the discriminative stimulus effects of MDPV may serve to inform medication discovery and development for the treatment of MDPV abuse.

The Misclassification of Medical Marijuana.

Marijuana has a complicated legal, social, and economic history in the United States, as well as an uncertain future. Marijuana has been consistently tied to racial minority groups since its arrival in the United States in the 1900s, and former Attorney General Jeff Sessions further propagated that notion. AG Sessions even recently wrote a memo that directly contradicted Obama-era policy, demonstrating that the current legal status of marijuana in both state and federal government is currently up for debate. While several states have legalized marijuana for medical or even recreational purposes, federal law still categorizes cannabis as a drug with no currently accepted medical use and a high potential for abuse. The comparison between marijuana, opioids, and ketamine in this article demonstrates that marijuana has been unnecessarily withheld and stigmatized by the federal government. Also reviewed is the impact of stringent marijuana-based legal policies upon the racial makeup of prison populations. The implications of current policy upon potential and future research are also discussed, with the determination that current policy has stymied research and prevented a more accurate determination of the risks and benefits of medical marijuana.

Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters.

New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling. The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. Affinities to displace the radioligand [125I]RTI-55 and potencies to inhibit [3H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83-360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters' binding pockets that influence drug affinities. The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.

Long-Term Systemic Treatment With Methamphetamine Causes Retinal Damage in CD1 Mice.

As a powerful psychostimulant with high potential for abuse, methamphetamine (Meth) could cause long-lasting abnormalities in retinas. The purpose of this study was to investigate the effects of systemic administration of Meth at low dose on retinal damage and understand the underlying mechanisms of pathology. CD1 mice were treated with 0.5 mg/kg or 1 mg/kg Meth by intraperitoneal injection daily for 2 months, mice treated with saline were used as negative control. Electroretinography (ERG) reflects the mass response of photoreceptor cells and was used to test the outer retinal function after Meth treatment. Toluidine blue staining was used to show the retinal morphology and evaluate the photoreceptor cell loss. Inflammatory factors were measured by enzyme-linked immunosorbent assay to show the inflammatory response. Terminal deoxynucleotidyl transferase dUTP Nick end labeling assay was used to detect the apoptosis-positive cells. Real-time polymerase chain reaction and Western blot were applied to measure the gene and protein change to explore the underlying mechanisms. Results demonstrated that retinal damage was caused by Meth treatment after 2 months, evidenced by loss of rod photoreceptor cells; decreased ERG amplitude; increased apoptotic photoreceptor cells, cytochrome-c release, caspase-3 activity, caspase-9 activity, and apoptosis-related protein expression; increased malondialdehyde level as well as nicotinamide adenine dinucleotide phosphate oxidase 4 protein expression; decreased anti-oxidative agents glutathione as well as superoxide dismutase levels; and increased production and gene expression of inflammatory factors. Our study indicated that systemic administration of Meth caused neurotoxic effects on CD1 mouse retinas, providing the potential mechanisms for the retina damage caused by Meth abuse.

Prophylactic Gabapentin Combined with Methadone Improves Overall Health in Patients Undergoing Chemoradiation for Head and Neck Cancer While Reducing Use of Opioids with High Abuse Potential: Early Results of a Prospective Randomized Trial

Oral mucositis occurs in the majority of patients (pts) undergoing chemoradiation therapy (CRT) for head and neck cancer (HNC). The Oral Mucositis Daily Questionnaire (OMDQ) is a validated survey for HNC patient pain. Gabapentin (GABA) has been used concurrently with opioids to improve pain control in pts with HNC. Methadone (MTD) is a low abuse potential opioid that is used for neuropathic pain. This single center prospective randomized study was undertaken to compare analgesia regimens for pts undergoing CRT. Hypothesis: We hypothesized pts treated with GABA would have improved pain control and delay the onset of narcotic requirement, and the addition of MTD would provide improved pain control. Pts with Stage II-IV HNC who were treated with definitive CRT were randomized to one of two pain regimens: 1) High-dose GABA (900mg TID) with hydrocodone-acetaminophen followed by transdermal fentanyl as needed (HD-HAF) or 2) Low-dose GABA (300mg TID) with methadone (5-15mg BID) and oxycodone as needed (LD-MTD). Pts were stratified by bilateral or unilateral radiation. At baseline and weekly on-treatment visits, clinical data including narcotic use was recorded and OMDQ was administered. Average daily narcotic use was converted to oral morphine milligram equivalents. Two sided T and Fischer exact tests were performed. A total of 60 pts were randomized; at the time of analysis not all patients had completed their scheduled evaluations. Median dose to the primary was 70 Gy. There were no attributable grade 3 adverse events. Approximately half of HD-HAF and three quarters of LD-MTD required a narcotic during CRT. The time to first narcotic was approximately 4.5 weeks for both groups. LD-MTD had better Overall Health at week 7 vs. HD-HAF (p<0.05). This study demonstrates that both pain regimens are safe and well tolerated. Methadone is associated with better overall health at the end of treatment for pts undergoing CRT. Our next study will utilize high dose GABA and methadone. Implications for practice or research: Methadone, as a low abuse potential narcotic, combined with prophylactic GABA can improve overall health at the end of CRT for HNC. Further escalating GABA dose may optimize the therapeutic benefit of MTD and will be tested in a future study.

Medical Marijuana: A Potpourri of the Evidence Base, Clinical, Neurodevelopmental, Legal, Ethical, and Research Issues

Medical marijuana policies currently exist in 29 states and the District of Columbia. Child and adolescent psychiatrists are faced with requests for medical marijuana by youth and parents. Federal law prohibits distribution or dispensing marijuana, whereas states are permissive in allowing physicians to certify or recommend its use. Marijuana is classified as a schedule 1 drug with high potential for abuse. The state-qualified conditions cover a range of conditions, some with a strong evidence base for benefit, such as chemotherapy-associated nausea and vomiting, whereas other conditions include ASD, PTSD, and Tourette’s disorder, which have poor-quality evidence. There is a gap between the evidence base for medical cannabinoids as treatment for pediatric conditions compared with increased access. There are adverse effects on mental illness and on neurodevelopment. There are ethical and legal questions on physician liability or legal consequences for those using recommended marijuana. There are barriers to research on cannabinoids and ethical issues from human research protections perspectives that are important for child and adolescent psychiatrists to understand.

Commentary on Liang et al. (2018): The potential impact of medical cannabis on public health with respect to reducing prescription opioid use and associated harm.

Substitution of prescription opioid use by medical cannabis is not public health relevant, as it is restricted to substitution of a small subset of less potent opioids such as codeine. In addition, it substitutes one substance with abuse potential by another, and there are better alternatives available. Liang and colleagues 1 have presented a time–series analysis based on 21 years of state-level data of Medicaid records, in which they found that medical cannabis legalization was associated with substantial reductions in the number of Schedule III opioid prescriptions in the United States (−30%), their dosage (30%) and related Medicaid spending (−29%). Prescription opioids in Schedule III are characterized by lower abuse potential compared to opioids in Schedule II, with abuse of these opioids potentially leading to moderate or low physical dependence and/or high psychological dependence 2. In the analyses of Liang and colleagues 1, the Schedule III prescriptions made up only approximately 5% of all opioid prescriptions for the last year of analysis (2014), with codeine prescriptions comprising 99% of all Schedule III prescriptions. Codeine is used in the United States to treat mild to moderate pain and as a cough suppressant. Cannabis has been in use for both of these indications, and thus a substitution effect may be plausible. What would be the public health implications of a partial substitution? First, the overall substitution was not found to be affecting a large portion of the overall opioid prescription use. Secondly, however, codeine has an abuse potential. Although this abuse potential was evaluated to be lower compared to Schedule II opioids, abuse has been documented with both prescribed and over-the-counter codeine 3. Furthermore, codeine use may contribute as a gateway to other opioids, both prescription and illicit opioids, with high overdose potential 4, 5. Overall, the United States has, by far, globally the highest prescription opioid use per capita 6, and probably also the highest overall opioid use per capita in the world (i.e. combining prescription and illicit use), at least if indirectly inferred by opioid use disorders 7. The overall culture of medically overusing opioids has contributed markedly to this situation 8. What about cannabis? Its scheduling currently seems to be in flux, with many US states starting medical marijuana programs 9. However, while its consequences are not as detrimental as those of other drugs, in particular in terms of mortality 10, they are far from benign 11. Finally, the effectiveness of both codeine and cannabis for relieving moderate chronic pain seems to be limited, with no Cochrane Reviews supporting such a claim as primary drug of choice (e.g. 12, 13). Perhaps this judgement about effectiveness is premature for cannabis, with research to collect better evidence only now commencing, but it reflects the current evidence base. However, from a public health point of view, given the abuse potentials of both drugs involved, perhaps solutions should be sought with non-pharmacological therapies or with medications with less abuse potential than opioids or cannabis. The history of opioids in pain medication in North America should be a lesson. Despite limited evidence for effectiveness, prescription opioids were seen as a wonder drug, especially for pain management, with rapidly accelerating use to the point where they contributed markedly to a high level of opioid addiction on the population level and a major public health crisis 14, and decreasing life expectancies 15, 16. As a result, new national guidelines for opioid pain prescription stress non-pharmacological therapies and non-opioid medication as first-line treatment 17. We should not repeat this history with yet another wonder drug installed before proper evidence for effectiveness and well-documented unintentional consequences. Given the current evidence, there is no good reason not to start pain management with non-pharmacological therapies, but there are good reasons to limit the use of drugs with high abuse potential to the highest degree possible. None. The author acknowledges funding from the Canadian Institutes of Health Research, Institute of Neurosciences, Mental Health and Addiction (CRISM Ontario Node grant no. SMN-13950).

Nicotine effects on associative learning in human non-smokers.

Tobacco smoking is the most common preventable cause of death in the US. Nicotine is considered the primary constituent responsible for tobacco addiction. Its paradoxically high abuse potential may reflect behavioral control by drug-associated stimuli, which appears to play a larger role for tobacco dependence than for other abused drugs. We tested a potential explanation, hypothesizing that nicotine enhances associative learning, the mechanism underlying the conditioning of drug-associated stimuli. Thirty-two non-smokers were exposed to transdermal nicotine (7 mg/24 h) and placebo in a double-blind cross-over study and tested with behavioral paradigms designed to isolate incidental stimulus-stimulus or stimulus-response learning. The stop signal task required speeded gender judgments of face stimuli. A tone signaled when to withhold the response. Unbeknownst to participants, some faces were always paired with stop trials. Nicotine enhanced the facilitation of stop-responses to these stimuli, and the slowing of go-responses when previously stop-associated stimuli were paired with go trials, indicating stronger associations between paired stimuli and the stop signal/stop response. Another task required feedback-based learning of associations between pairs of shape stimuli. Five pairs were made from either ten different stimuli, or from different combinations of two identical sets of five stimuli with correct associations depending on contextual information. Nicotine increased incorrect choices of stimuli that were associated in a different context, indicating stronger stimulus-stimulus associations at the expense of flexible context-adaptive behavior. The results indicate that nicotine can enhance incidental associative learning, a mechanism that may promote the formation of smoking-associated stimuli and cue-controlled drug-taking.

What happens when the insurer can say no? Assessing prior authorization as a tool to prevent high-risk prescriptions and to lower costs

Insurers are increasingly requiring physicians to obtain prior authorization before prescribing drugs that are costly or have high abuse potential. These prior authorization requirements have the potential to reduce risky prescriptions and to lower prescription drug costs, but little is known about their ability to do either. This study estimates the effect of a prior authorization requirement for certain costly and abuse-prone drugs on prescription drug use and costs for work-related injuries in Texas. The findings indicate that the prior authorization requirement reduces the likelihood that claimants receive non-preferred drugs as well as insurers' spending on non-preferred drugs. While there is some substitution to preferred drugs, I do not find evidence of large increases in spending on preferred drugs. The estimated effects on average total pharmacy spending are imprecise, though there is suggestive evidence that the prior authorization requirement reduces the likelihood that a claim has high prescription drug costs. The results provide strong evidence that the prior authorization requirement drastically reduces the likelihood that patients receive combinations of drugs that have contributed disproportionately to the rise in prescription drug overdoses. Despite the success of prior authorization in lowering spending on non-preferred drugs and in reducing high-risk prescriptions, I find little evidence that prior authorization has disproportionately large effects on the most dangerous prescription drug use and only weak, suggestive evidence that it has larger effects on prescription drug use that likely arises because physicians are not fully informed, suggesting that prior authorization requirements do not necessarily target the riskiest drug use.

Abuse liability and therapeutic potential of the Mitragyna speciosa (kratom) alkaloids mitragynine and 7-hydroxymitragynine.

Kratom, derived from the plant Mitragyna speciosa, is receiving increased attention as an alternative to traditional opiates and as a replacement therapy for opiate dependence. Mitragynine (MG) and 7-hydroxymitragynine (7-HMG) are major psychoactive constituents of kratom. While MG and 7-HMG share behavioral and analgesic properties with morphine, their reinforcing effects have not been examined to date. 7-HMG, but not MG, substituted for morphine self-administration in a dose-dependent manner in the rat self-administration paradigm. Following the substitution procedure, re-assessment of morphine self-administration revealed a significant increase following 7-HMG and a significant decrease following MG substitution. In a separate cohort, 7-HMG, but not MG, engendered and maintained intravenous self-administration in a dose-dependent manner. The effects of pretreatment with nalxonaxine (NLXZ), a μ1 opiate receptor antagonist, and naltrindole (NTI), a δ opiate receptor antagonist, on 7-HMG and morphine self-administration were also examined. Both NLXZ and NTI reduced 7-HMG self-administration, whereas only NLXZ decreased morphine intake. The present results are the first to demonstrate that 7-HMG is readily self-administered, and the reinforcing effects of 7-HMG are mediated in part by μ and δ opiate receptors. In addition, prior exposure to 7-HMG increased subsequent morphine intake whereas prior exposure to MG decreased morphine intake. The present findings indicate that MG does not have abuse potential and reduces morphine intake, desired characteristics of candidate pharmacotherapies for opiate addiction and withdrawal, whereas 7-HMG should be considered a kratom constituent with high abuse potential that may also increase the intake of other opiates.

Food and Drug Administration upscheduling of hydrocodone and the effects on nurse practitioner pain management practices.

In 2013, the Advisory Committee of the Food and Drug Administration determined hydrocodone combination medications (HCMs) needed tighter regulation due to high abuse potential; they recommended upscheduling HCMs from Schedule III to II. The purpose of this study was to examine the effect of upscheduling of HCMs on pain management practices of advanced practiced registered nurses (APRNs) in Oklahoma. In this qualitative study, 25 participants described their primary care experiences after the upscheduling. A thematic analysis was used to understand the effects on APRN pain management practices. The upscheduling of HCMs has greatly affected the pain management practices of APRNs in a state where Schedule II narcotic prescribing is forbidden. Findings will assist APRNs with improving patient access to care, implementing practice regulations, and exploring options for alternative pain therapies in primary care. Upscheduling of HCMs has had a severe impact on APRNs, affecting their prescribing practices and leading to increased referrals. They noted limited treatment options, increased health care costs, and decreased access to care. The APRNs understand the problem of prescription opioid abuse, diversion, and misuse. A consensus model could standardize the regulatory process for APRNs, increase interstate mobility for practice, and increase access to APRN care nationwide.

DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants.

Cathinone is a plant alkaloid found in khat leaves of perennial shrubs grown in East Africa. Similar to cocaine, cathinone elicits psychostimulant effects which are in part attributed to its amphetamine-like structure. Around 2010, home laboratories began altering the parent structure of cathinone to synthesize derivatives with mechanisms of action, potencies, and pharmacokinetics permitting high abuse potential and toxicity. These "synthetic cathinones" include 4-methylmethcathinone (mephedrone), 3,4-methylenedioxypyrovalerone (MDPV), and the empathogenic agent 3,4-methylenedioxymethcathinone (methylone) which collectively gained international popularity following aggressive online marketing as well as availability in various retail outlets. Case reports made clear the health risks associated with these agents and, in 2012, the Drug Enforcement Agency of the United States placed a series of synthetic cathinones on Schedule I under emergency order. Mechanistically, cathinone and synthetic derivatives work by augmenting monoamine transmission through release facilitation and/or presynaptic transport inhibition. Animal studies confirm the rewarding and reinforcing properties of synthetic cathinones by utilizing self-administration, place conditioning, and intracranial self-stimulation assays and additionally show persistent neuropathological features which demonstrate a clear need to better understand this class of drugs. This Review will thus detail (i) historical context of cathinone use and the rise of "dark" synthetic derivatives, (ii) structural features and mechanisms of synthetic cathinones, (iii) behavioral effects observed clinically and in animals under controlled laboratory conditions, and (iv) neurotransmitters and circuits that may be targeted to manage synthetic cathinone abuse in humans.

The Synergistic Effect of Dopamine and Norepinephrine Transporter Inhibition on Cognitive Enhancement

Psychostimulants such as amphetamine and methylphenidate are highly effective cognitive enhancing medications, yet have a high potential for abuse and addiction. Evidence suggests that both norepinephrine transporter (NET) and dopamine transporter (DAT) inhibition is required for the procognitive effects of psychostimulants. Although DAT inhibition is also responsible for the addictive potential of psychostimulants, drugs with low activity at DAT may not produce addiction. In the present study, we examined the cognitive and reinforcing effects of various DAT inhibitors (e.g., bupropion, GBR‐12909, GBR‐12935) and NET inhibitors (e.g., atomoxetine, nisoxetine) alone and in combination, using Pavlovian fear conditioning and conditioned place preference. We found that certain dose combinations of these DAT and NET inhibitors produced enhancements in immediate and/or long‐term fear memory acquisition, but did not produce reinforcement or behavioral sensitization. We propose that a pharmaceutical combination of DAT and NET inhibition could lead to the development of a non‐stimulating, non‐addictive, and non‐controlled, yet highly effective cognitive enhancer.Support or Funding InformationNIH DA020041 (SGA)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Impact of the U.S. Drug Enforcement Agency Schedule Changes for Hydrocodone and Tramadol on California Prescriptions Patterns

The Impact of the U.S. Drug Enforcement Agency Schedule Changes for Hydrocodone and Tramadol on California Prescriptions Patterns