High Abuse Potential Research Articles

Smoking: Pathogenetic Mechanisms, Possibilities of Medical Correction (Literature Review)

The smoking epidemic is one of the greatest threats to human health, as it is the leading cause of death worldwide, as well as many preventable diseases. Diseases associated with smoking include cardiovascular disease, atherosclerosis, type 2 diabetes, chronic pancreatitis, chronic obstructive pulmonary disease, cancer, osteoporosis and others. The aim is to analyze information on the pathogenetic mechanisms of tobacco exposure and methods of its drug correction. Among the 4,000 chemicals identified in tobacco smoke, nicotine is the main active ingredient in tobacco products. It is highly toxic and potentially lethal. Nicotine affects many systems, including the neurological, neuromuscular, cardiovascular, respiratory, immunological and gastrointestinal systems. Therefore, nicotine-containing drugs reduce the symptoms of nicotine withdrawal in regular smokers who abstain from smoking. The presence of different types of nicotinic acetylcholine receptors, their regulation and desensitization affect these complex physiological effects. Nicotine replacement drugs contain pure nicotine, in order to reduce the patient’s propensity to use tobacco, physiological and psychomotor withdrawal symptoms. They increase the level of nicotine in the blood, thus facilitating the transition from cigarette smoking to complete abstinence. Smokers can quit without using nicotine-containing drugs, but most those who try do not succeed on the first try. Nicotine replacement drugs only affect physical dependence. Nicotine is the main factor responsible for dependence on cigarette smoking, and its rate of absorption and entry into the brain are considered key factors responsible for the high potential for abuse of this drug. The advantage of nicotine-containing drugs is the patient’s independence from the method of administration, determination of abstinence, duration of treatment, level of supportive counseling, place of treatment (hospital, clinic or support group), as well as fixed, variable or reduced doses. There are a number of nicotine-containing drugs in various forms that effectively promote smoking cessation in adults.

Drug-drug interaction between diclofenac and gamma-hydroxybutyric acid.

Gamma hydroxybutyric acid (GHB) has been approved clinically to treat excessive daytime sleepiness and cataplexy in patients with narcolepsy, alcohol and opioid withdrawal, and as an anesthetic. The use of GHB clinically is limited due to its high abuse potential. The absorption, clearance and tissue uptake of GHB is mediated by proton-dependent and sodium-coupled monocarboxylate transporters (MCTs and SMCTs) and inhibition of these transporters may result in a change in GHB pharmacokinetics and pharmacodynamics. Previous studies have reported that non-steroidal anti-inflammatory drugs (NSAIDs) may inhibit these monocarboxylate transporters. Therefore, the purpose of this work was to analyze the interaction between GHB (at a dose of 600 mg/kg i. v.) and the NSAID, diclofenac, by examining the effects of this drug on the in vivo pharmacokinetics and pharmacodynamics in rat studies. The pharmacodynamic effect evaluated was respiratory depression, a measure of toxicity observed by GHB at this dose. There was an improvement in the respiratory rate with diclofenac administration suggesting an effect of diclofenac on GHB toxicity. In vitro studies with rat blood brain endothelial cells (RBE4) that express MCT1 indicated that diclofenac can inhibit GHB transport with an IC50 of 10.6 μM at pH 7.4. In vivo studies found a decrease in brain GHB concentrations and a decrease in the brain-to-plasma concentration ratio following diclofenac treatment. With this study we can conclude that diclofenac and potentially other NSAIDs can inhibit the transport of GHB into the brain, therefore decreasing GHB's pharmacodynamic effects and toxicity.

Dual-action ADHD drug provides both early- and late-onset symptom relief

Dual-action ADHD drug provides both early- and late-onset symptom relief

Med Check: Naloxone and Opioid Overdose; Evekeo ODT and ADHD in Children; Theta Burst Protocol and Depressive Disorder; Brilaroxazine Phase 2 Trials

Back to table of contents Previous article Next article Med CheckFull AccessMed Check: Naloxone and Opioid Overdose; Evekeo ODT and ADHD in Children; Theta Burst Protocol and Depressive Disorder; Brilaroxazine Phase 2 TrialsTerri D’ArrigoTerri D’ArrigoSearch for more papers by this authorPublished Online:28 May 2021https://doi.org/10.1176/appi.pn.2021.6.14Higher Naloxone Dose Approved for Opioid OverdoseIn April the Food and Drug Administration (FDA) approved Kloxxado, a higher dosage of naloxone nasal spray for the emergency treatment of known or suspected opioid overdose. The newly approved product, developed by Hikma Pharmaceuticals, delivers 8 mg of naloxone into the nasal cavity. The FDA had previously approved 2 mg and 4 mg naloxone nasal spray products.The FDA approved Kloxxado based on previous findings about the safety and effectiveness of Narcan injection (naloxone hydrochloride) for treating opioid overdose. Hikma Pharmaceuticals also submitted its own safety and effectiveness data.“Over the last several years, the FDA has taken a number of steps to improve availability of naloxone products, including encouraging manufacturers to pursue approval of over-the-counter naloxone products; requiring drug manufacturers for all opioid pain relievers and medicines to treat opioid use disorder to add new recommendations about naloxone to the prescribing information; and extending the shelf life of naloxone nasal spray from 24 months to 36 months,” the agency said in a statement.Evekeo ODT Approved for ADHD in Young ChildrenIn April the FDA approved Evekeo ODT (amphetamine sulfate) by Arbor Pharmaceuticals for treating attention-deficit/hyperactivity disorder (ADHD) in patients aged 3 to 5 years. Evekeo ODT, a mixture of dextroamphetamine sulfate and levoamphetamine sulfate, was previously approved for treating ADHD in patients aged 5 to 17 years, with tablets ranging in dose from 5 mg to 20 mg. Evekeo ODT will be available in a new 2.5 mg orally disintegrating tablet for patients 3 to 5 years old. The recommended starting dose for patients in this age group is 2.5 mg daily, and a second dose may be administered after 4 to 6 hours.Evekeo ODT is a Schedule II controlled substance and comes with a boxed warning noting that central nervous systems stimulants have a high potential for abuse and dependence. The boxed warning advises health professionals to assess their patients’ risk of abuse and dependence before prescribing the drug, and to monitor patients for signs of abuse and dependence as therapy continues.Theta Burst Protocol Cleared for Treating Major Depressive DisorderBrainsWay announced in April that its Theta Burst protocol has been approved by the FDA for treating major depressive disorder. Theta Burst is a three-minute protocol that uses the company’s Deep Transcranial Magnetic Stimulation (Deep TMS) system. TMS uses magnetic fields to stimulate parts of the brain and activate neural pathways to improve symptoms of depression.In a study of 146 patients with major depressive disorder, patients treated with the three-minute protocol experienced reductions in depression scores similar to those who received the standard 20-minute sessions, the company said in a statement. The standard treatment protocol consists of 20-minute sessions five times a week for four to six weeks, followed by treatment twice a week for up to 12 weeks as needed for maintenance.Brilaroxazine Promising in Phase 2 TrialsReviva Pharmaceuticals’ investigational drug brilaroxazine appeared to be safe and effective for treating schizophrenia and schizoaffective disorder in a phase 2 clinical trial, the company announced in April.In the trial, 234 adults who had acute exacerbation of schizophrenia or schizoaffective disorder were randomized to receive either treatment with brilaroxazine or placebo for four weeks. The primary endpoint was reduction in total Positive and Negative Syndrome Scale (PANSS) from baseline to the end of the treatment. At the end of four weeks, the PANSS total score was reduced by 20 points in patients who took brilaroxazine, which the company said in a statement is a “statistically significant treatment difference from the placebo.” ■ ISSUES NewArchived

Early Chronic Methamphetamine Exposure Induces Cognitive Impairments and Oxidative Damage in Adult Mice

Prescription stimulant misuse among young adults has gained popularity in the United States over the last decade, with amphetamine compounds becoming the second most common illicit drug used in college students. Misuse of these drugs can pose serious risks due to their high potential for abuse that can lead to dependency and neurotoxicity. Furthermore, there are prominent sex differences in psychostimulant use: men use more frequently and women have higher success rates in treatment but are more vulnerable to dependence and adverse effects. Psychostimulants, even at moderate doses, have been shown to promote oxidative stress, via auto-oxidation or metabolism of accumulated redox active dopamine. Oxidative stress has also been implicated in neurobehavioral impairments. Therefore, exposure to psychostimulants as a consequence of abuse would provide a second hit predicted to increase brain impairments. Moreover, the mesocorticolimbic pathway, a critical dopaminergic pathway, is particularly vulnerable to oxidative insults, and reveals sex-dependent differences in dopamine dynamics. We hypothesized that oxidative stress may act as a prominent cellular mechanism in mediating psychostimulant-induced neurotoxicity and neurobehavioral deficits. The purpose of this pilot study was to determine the short-term consequences of chronic, low toxic dosing of the prototypical psychostimulant, methamphetamine (METH), on cognition and markers of oxidative stress and dopaminergic function. Groups of young male and female (4-month-old) C57BL/6J mice received non-contingent intraperitoneal injections of either saline or methamphetamine (1.4 mg/kg) twice a day for 4 weeks. Two weeks following the last injection, animals were tested for cognitive function using 3 different tests: Morris water maze, active avoidance, and fear conditioning. After the completion of behavioral testing, brain regions were dissected and markers of oxidative stress and dopaminergic function were assayed. METH administration appeared to induce deficits in spatial learning and memory in both males and females, and in active avoidance and fear conditioning response in female mice only. Markers of dopaminergic function do not seem to be majorly affected by METH administration, while markers of lipid peroxidation were increased in the cortex and hippocampus of METH-treated females. These preliminary results suggest that chronic administration of METH induced impairments in cognitive function and changes in oxidative stress. These data indicate functional and biochemical changes that may have long-term consequences on brain function which will be the focus of future studies.

Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline.

This guideline establishes clinical practice recommendations for the treatment of central disorders of hypersomnolence in adults and children. The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to develop recommendations and assign strengths to each recommendation, based on a systematic review of the literature and an assessment of the evidence using the GRADE process. The task force provided a summary of the relevant literature and the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations that support the recommendations. The AASM Board of Directors approved the final recommendations. The following recommendations are intended to guide clinicians in choosing a specific treatment for central disorders of hypersomnolence in adults and children. Each recommendation statement is assigned a strength ("strong" or "conditional"). A "strong" recommendation (ie, "We recommend…") is one that clinicians should follow under most circumstances. A "conditional" recommendation (ie, "We suggest…") is one that requires that the clinician use clinical knowledge and experience and strongly consider the individual patient's values and preferences to determine the best course of action. Under each disorder, strong recommendations are listed in alphabetical order followed by the conditional recommendations in alphabetical order. The section on adult patients with hypersomnia because of medical conditions is categorized based on the clinical and pathological subtypes identified in ICSD-3. The interventions in all the recommendation statements were compared to no treatment. We recommend that clinicians use modafinil for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use pitolisant for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use sodium oxybate for the treatment of narcolepsy in adults. (STRONG). We recommend that clinicians use solriamfetol for the treatment of narcolepsy in adults. (STRONG). We suggest that clinicians use armodafinil for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use dextroamphetamine for the treatment of narcolepsy in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of narcolepsy in adults. (CONDITIONAL). We recommend that clinicians use modafinil for the treatment of idiopathic hypersomnia in adults. (STRONG). We suggest that clinicians use clarithromycin for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use methylphenidate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use pitolisant for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL). We suggest that clinicians use lithium for the treatment of Kleine-Levin syndrome in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to dementia with Lewy bodies in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of hypersomnia secondary to Parkinson's disease in adults. (CONDITIONAL). We suggest that clinicians use armodafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to traumatic brain injury in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to myotonic dystrophy in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of hypersomnia secondary to multiple sclerosis in adults. (CONDITIONAL). We suggest that clinicians use modafinil for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). We suggest that clinicians use sodium oxybate for the treatment of narcolepsy in pediatric patients. (CONDITIONAL). Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(9):1881-1893.

Kratom: The safe legal high?

Illicit drugs are used to produce a sense of euphoria in the user. Like marijuana, kratom is a plant-based substance. The leaves of the Mitragyna speciosa tree were used to treat mild medical conditions in Thailand and Malaysia as a stimulant in low doses, and sedative and analgesic at high doses. Over recent years, kratom gained popularity as a recreational drug among younger individuals in Southeast Asia due to its availability as a cheap and easily assessable substance with euphoric effects. This trend has rapidly made its way to the West. Unlike marijuana, in the United States kratom’s use as an inexpensive herbal recreational “supplement” is poorly popularized. However, emerging reports garnished from use as a recreational drug reveals a potential health hazard. Seizures and neurological consequences have been reported from kratom abuse. Complex pharmacokinetics place patients at further risk of side effects and drug interactions. Still, individuals can legally purchase kratom at stores and through online distributers in capsule form or as teas, powders, and extracts under the veil of a harmless herbal remedy. Without United States Food and Drug Administration oversight, kratom has a high potential for abuse and without regulatory control threatens public safety.

Determination of Fentanyl, Alpha-Methylfentanyl, Beta-Hydroxyfentanyl and the Metabolite Norfentanyl in Rat Urine by LC-MS-MS.

Fentanyl and its analogs are potent synthetic opioids with a high potential for abuse and dependence. They have become major contributors to opioid deaths. This study aimed to determine whether the metabolites of fentanyl, alpha-methylfentanyl and beta-hydroxyfentanyl, excreted in the urine, can demonstrate historical drug exposure. Fentanyl is primarily metabolized via CYP3A4 into norfentanyl, although there is little research on its metabolization into alpha-methylfentanyl and beta-hydroxyfentanyl. We conducted in vitro experiments with human liver microsomes (HLMs) and rat liver microsomes (RLMs) to elucidate the major metabolic pathways of alpha-methylfentanyl and beta-hydroxyfentanyl using ultra-high-performance liquid chromatography coupled with mass spectrometry. The results showed that both alpha-methylfentanyl and beta-hydroxyfentanyl were predominantly metabolized into norfentanyl in HLM and RLM. Urine samples were collected at different intervals from 0 h to 72 h after intravenous administration of alpha-methylfentanyl and beta-hydroxyfentanyl (20 μg/kg) to Sprague-Dawley rats. We prepared the samples by liquid-liquid extraction, and the internal standard (IS) was cariprazine. A sensitive, rapid liquid chromatography-tandem mass spectrometry method was developed and validated to determine four analytes in the urine. The lower limit of qualification in urine was 2 pg/mL for fentanyl, 5 pg/mL for alpha-methylfentanyl, 10 pg/mL for beta-hydroxyfentanyl and 40 pg/mL for norfentanyl. The analytical range was 0.002-2 ng/mL for fentanyl, 0.005-5 ng/mL for alpha-methylfentanyl, 0.01-10 ng/mL for beta-hydroxyfentanyl and 0.04-40 ng/mL for norfentanyl. All analytes demonstrated good linearity (R2 > 0.99). The extraction recoveries were in the 67.8%-92.1% range, and the IS-normalized matrix effects were between 55.5% and 74.0% (coefficient of variance < 15%). Our data indicated that norfentanyl has a higher concentration in rat urine and was detectable for at least 3days after exposure to these compounds. This developed method may be useful in various fields, including forensic analysis, workplace drug testing and monitoring drug abuse.

Behavioral Effects of 4-CMC and 4-MeO-PVP in DBA/2J Mice After Acute and Intermittent Administration and Following Withdrawal from Intermittent 14-Day Treatment

Synthetic cathinones appeared on the market in the 2000s as new psychoactive substances and gained significant prevalence among drug abusers. Cathinones produce psychostimulant and empathogenic effects by enhancing dopaminergic, noradrenergic, and serotoninergic neurotransmission in the brain, and those which potently and selectively enhance dopaminergic transmission are considered to have higher abuse potential. The present study examines the behavioral effects related to psychostimulant properties, abuse potential, and addiction in DBA/2J mice of two cathinones with different profile of action on monoamine system, 4-chloromethcathinone (4-CMC), and 4-methoxy-pyrrolidinopentiophenone (4-MeO-PVP). 4-CMC and 4-MeO-PVP increase spontaneous locomotor activity after acute treatment and produce behavioral sensitization after 7-day intermittent treatment, which is a common feature of drugs of abuse. 4-MeO-PVP, but not 4-CMC, produces conditioned place preference after 4 days, indicating its rewarding properties. Finally, the ability of 4-CMC and 4-MeO-PVP to induce withdrawal symptoms after discontinuation from 14-day treatment was assessed using a battery of tests for behavioral markers of depression in mice: a tail suspension test, a forced swim test, measuring despair, and a sucrose preference test, measuring anhedonia. None of the three tests revealed increased depressive symptoms. Moreover, neither spontaneous locomotor activity nor motor performance on a rotarod was impaired after 14-day treatment with the tested compounds. These results indicate that 14-day treatment of mice with 4-CMC or 4-MeO-PVP does not induce significant withdrawal symptoms after cessation, nor significant impairment of dopaminergic circuitry resulting in motor impairment. The current study shows that 4-CMC and 4-MeO-PVP produce abuse-related behavioral changes in mice, which are more pronounced after more dopamine-selective 4-MeO-PVP.

A strategy to prioritize emerging drugs of abuse for analysis: Abuse liability testing using intracranial self-stimulation (ICSS) in rats and validation with α-pyrrolidinohexanophenone (α-PHP)

Novel psychoactive substances (NPS) threaten public health and safety while also straining the limited resources of forensic laboratories. To efficiently allocate the finite resources available, we propose a new strategy for prioritizing NPS with abuse liability testing using a preclinical behavioral procedure in rats known as intracranial self-stimulation (ICSS). To validate this assay, the recently-scheduled synthetic cathinone α-PHP was compared to cocaine, a mechanistically similar drug of abuse, as a positive control and saline as a negative control. Male Sprague-Dawley rats (n=6) were implanted with electrodes targeting the medial forebrain bundle and trained to respond by lever-press for electrical brain stimulation. The rats were tested with doses of 0.32, 1.0, and 3.2 mg/kg α-PHP as well as 10 mg/kg of cocaine and saline administered by intraperitoneal injection. Neither saline nor 0.32 mg/kg α-PHP altered ICSS response rates compared to baseline levels of responding; however, doses of 1.0 and 3.2 mg/kg α-PHP and 10 mg/kg cocaine facilitated ICSS responding. This ICSS profile suggests that α-PHP has high abuse potential, with a rapid onset of effects and a long duration of action, and supports the decision to schedule this compound. This study demonstrates the ability of ICSS to distinguish between compounds of low and high potential for abuse. A strategy is proposed here to screen NPS using ICSS and classify emerging drugs into four priority categories for further analysis.

Comparison of Opioids Prescribed for Patients at Risk for Opioid Misuse Before and After Publication of the Centers for Disease Control and Prevention’s Opioid Prescribing Guidelines

It is not known whether decreases in Schedule II (high abuse potential) vs Schedule IV (lower abuse potential) opioid prescriptions overall and among high-risk patients followed publication of the Centers for Disease Control and Prevention (CDC) opioid prescribing guideline on March 15, 2016. To compare the odds of new Schedule II opioid (codeine, hydrocodone, oxycodone) prescriptions vs Schedule IV opioid (tramadol) prescriptions in the 18-month periods before and after the CDC guideline release to determine whether new prescriptions for Schedule II opioids decreased relative to new prescriptions for tramadol and to assess whether patients with benzodiazepine prescriptions or those with depression, anxiety, or substance use disorders had a greater decrease in receipt of Schedule II vs Schedule IV opioids. Cross-sectional study of Optum's deidentified Integrated Claims-Clinical data set for 5 million US adults 18 months before and 18 months after March 15, 2016. Eligible patients were 18 years or older, free of HIV and cancer diagnoses, and had a noncancer painful condition. Patients received new prescriptions for codeine, hydrocodone, oxycodone, or tramadol. Data were analyzed from September 5, 2014, to September 14, 2017. The CDC opioid prescribing guideline published on March 15, 2016. The odds of prescriptions for each Schedule II opioid vs tramadol after guideline publication. Data from 279 435 patients were included in the study. The mean (SD) age of patients was 52.9 (16.5) years; 61% were female and 79.4% were White. The prevalence of new prescriptions for each drug before and after guideline publication was as follows: codeine, 7.1% vs 7.0%; hydrocodone, 47.4% vs 45.6%; oxycodone, 22.4% vs 24.0%; and tramadol, 23.0% vs 23.4%. Overall, the odds of being prescribed hydrocodone or oxycodone vs tramadol significantly decreased after guideline publication (odds ratios, 0.95; 95% CI, 0.91-0.98 and 0.86; 95% CI, 0.82-0.90, respectively). Odds of being prescribed a Schedule II opioid vs tramadol after vs before guideline publication were similar in patients with and without benzodiazepine comedication or psychiatric disorders. In the 18 months after compared with the 18 months before publication of the CDC prescribing guideline, a 14% decrease in oxycodone prescriptions was observed relative to tramadol. Little change in prescriptions of other Schedule II opioids was observed. Schedule II opioids continue to be prescribed to high-risk patients 18 months after publication of the CDC guideline.

The Consequences of Fickle Federal Policy: Administrative Hurdles for State Cannabis Policies

Under the Controlled Substances Act (1970), the federal government classifies cannabis as a Schedule I drug with high potential for abuse and no accepted medical use. Meanwhile, thirty-five states have defied federal prohibition and approved cannabis use for either medical or medical and recreational purposes. States are chipping away at War on Drugs policies with little clear guidance from the federal government. The starkly divergent approaches to cannabis regulation lead to administrative challenges for adopting states and the budding industry. We examine how the federal government’s rhetorical and regulatory fickleness on cannabis policy has led to several downstream administrative consequences in banking, taxes, social equity, and bankruptcy protections. We also discuss whether recent events like the coronavirus pandemic and more state adoptions can accelerate change at the federal level. Finally, we argue for additional research attention to cannabis policy by federalism and public administration scholars.

Psychopharmacological characterization of an emerging drug of abuse, a synthetic opioid U-47700, in adult zebrafish

3,4-Dichloro-N-[2-(dimethylamino)cyclohexyl]-N-methylbenzamide (U-47700) is a selective μ–opioid receptor agonist originally synthesized as a prospective analgesic drug. Several times more potent than morphine, U-47700 has high abuse potential and may cause clinical neurotoxicity, euphoria, respiratory depression and occasional mortality. U-47700 also evokes analgesia, sedation and euphoria-like states in both humans and rodents. Despite the growing use and abuse of U-47700, its psychopharmacological and toxicological profiles in vivo remain poorly understood. The zebrafish (Danio rerio) is rapidly becoming a popular aquatic model organism for central nervous system (CNS) disease modeling and drug discovery. Here, we examine acute (1, 5, 10, 25 and 50 mg/L for 20-min) and chronic (0.1, 0.5 and 1 mg/L for 14 days) effects of U-47700 in adult zebrafish. Overall, we found overt sedation evoked in fish by acute, and hyperlocomotion with an anxiolytic-like action by chronic, drug treatments. Acute treatment with 1 and 10 mg/L U-47700 also resulted in detectable amounts of this drug in the brain samples, supporting its permeability through the blood-brain barrier. Collectively, these findings emphasize complex dose- and treatment-dependent CNS effects of U-47700 following its acute and chronic administration. Our study also supports high sensitivity of zebrafish to U-47700, and suggests these aquatic models as promising in-vivo screens for probing potential CNS effects evoked by novel synthetic opioid drugs.

Bariatric Enhanced Recovery Protocol: a Community Quality Perspective.

Bariatric enhanced recovery protocols can decrease length of stay (LOS) and hospital costs without compromising patient safety. Increased data is needed to compare patient outcomes before and after application of enhanced recovery pathways. We present a bariatric enhanced recovery protocol (BERP) at a community hospital. The objectives were to decrease hospital LOS and reduce schedule II substance use (medications with a high potential for abuse, potentially resulting in psychological or physical dependence), without compromising patient safety. This was a combined retrospective and prospective analysis of all patients undergoing bariatric surgery by two surgeons from September 2016 to April 2018. Mann-Whitney U, Pearson chi-square, and Fisher's exact tests were used to compare demographics, comorbidities, and outcomes. Two hundred patients were evaluated. Overall median (interquartile range) age was 43.0 (36.0-54.0) years and body mass index (BMI) was 45.0 (40.6-50.3) kg/m2. Pre-protocol mean hospital LOS was 2.3days while enhanced recovery protocol patients mean LOS was 1.4days (p < 0.001). Sixty-five percent of BERP patients were discharged on hospital day 1, while no patients prior to the protocol were discharged before hospital day 2. Only 9% of BERP patients were discharged with schedule II medications, compared to 100% of the pre-protocol patients (p < 0.001). Intraoperative, in-hospital, and 30-day complication rates were not statistically significant between the two groups. Community hospitals can reduce length of stay and narcotic prescribing without compromising safety-related outcomes. Significant reductions in the amount of schedule II medications can be achieved when using multimodal enhanced recovery protocol approaches.

Workplace Cannabis Policies: A Moving Target.

Introduction: This article proposes a workplace cannabis policy paradigm that encompasses rapidly changing laws and regulations, legally defensible drug testing policies, and the needs of particular workplaces. Numerous states have now decriminalized medical or recreational use of cannabis, although U.S. federal law still defines cannabis as a Schedule I substance with no currently accepted medical use and a high potential for abuse. For employers and employees, the confusion generated by this contradiction is exacerbated by the widely varying effects of the available cannabis delivery systems, the primitive and cumbersome drug testing protocols often used in workplace settings, difficulties in measuring cannabis-related workplace impairment, and a rapidly changing cultural ethos regarding cannabis. Although other articles have addressed many of the broad theoretical constructs, there exists little practical guidance on how workplace drug programs should address cannabis use by employees, both on the job and during off-hours. Materials and Methods: Research for this review was performed in the PubMed/National Library of Medicine database. Discussion: Cannabis use is associated with cognitive deficits, motivation problems, and perceptual distortions, so employers have a legitimate interest in preventing on-the-job impairment related to cannabis use. Similarly, employees have a legitimate interest in behaving as they wish outside of the workplace, as long as that behavior does not affect their job performance. Relevant statues and case law on the subject of cannabis in the workplace reflect different legal models across jurisdictions, in addition to legislators and judges' attempts to manage this tension between employer and employees. Conclusion: An effective workplace cannabis policy must fit into a larger workplace drug and alcohol policy. It should be constructed with a collaborative effort of addiction professionals, labor attorneys, and human resource professionals. Only then can the ultimate workplace cannabis policy comply with relevant laws, protect workplace safety and productivity, and support employees while remaining flexible enough to adapt to changes in the legal environment.

A Piriform-Orbitofrontal Cortex Pathway Drives Relapse to Fentanyl-Seeking after Voluntary Abstinence

Fentanyl is a synthetic opioid commonly prescribed to treat severe pain, but its illicit use has contributed to the global opioid epidemic, largely because clandestinely manufactured fentanyl is sold as an alternative to heroin. Furthermore, fentanyl has a high abuse potential and risk of overdose

Neutropenia in Incarcerated Adolescents Secondary to Intranasal Quetiapine Misuse.

Objective: Between April 2015 and May 2016, a number of young males incarcerated at a Youth Justice center in New South Wales, Australia, were noted to have unexplained and significant neutropenia. None of the adolescents were prescribed quetiapine; however, it was prescribed for other young people in the center for this time period. The authors undertook a case series review to investigate the cause of this neutropenia. Methods: Case series review, including review of all pathology, electrocardiograms, medication charts, and medical file notes. Results: Quetiapine was used in the center; however, none of the young people with neutropenia were prescribed quetiapine (or any other medication causing neutropenia). During the assessments of these young people, it was found that the administration of quetiapine had changed during this time period to using pulverized quetiapine powder, administered after hours to young people when there were no health center staff available to supervise. On questioning, two neutropenic young people admitted to "snorting" diverted quetiapine powder. All instances of neutropenia resolved once the medication was removed from the center. Conclusions: Quetiapine has a high potential for abuse, especially in custodial settings. Quetiapine should never be crushed as this increases the potential for diversion, misuse, and serious side effects. Quetiapine misuse should be considered part of the differential diagnosis of unexplained neutropenia, especially in a setting where the drug is available.

Characteristics of online pharmacies selling Adderall

ObjectivesAdderall (amphetamine-dextroamphetamine) is a controlled substance with harmful adverse effects if abused or misused. We assessed the availability of Adderall from common search engines, and evaluated the safety and marketing characteristics of online pharmacies selling Adderall. DesignCross-sectional study. Setting and participantsFrom December 2019 to February 2020, the phrase “buy Adderall online” was queried in four search engines: Google (N = 100), Bing (N = 100), Yahoo (N = 50) and DuckDuckGo (N = 50). Online pharmacies that claimed to sell Adderall and had unique Uniform Resource Locators, were active, free-access, and in English language were included. Outcome measuresOnline pharmacies were categorized as rogue, unclassified, or legitimate on the basis of LegitScript classifications. Safety and marketing characteristics, and costs were collected. ResultsOf the 62 online pharmacies found to sell Adderall, 61 were rogue or unclassified. Across all rogue and unclassified online pharmacies, prescriptions were not required (100%), pharmacist services were not offered (100%), and quantity limits were not placed on the number of Adderall purchases (100%). Rogue and unclassified online pharmacies appealed to cost, offering price discounts (61%), bulk discounts (67%), and coupon codes (70%). Contrary to their claims, cheaper prices were available for all formulations and dosages of Adderall from GoodRx than from these online pharmacies. Rogue and unclassified online pharmacies promoted and enabled the illicit purchase of Adderall, appealing to privacy (74%), offering purchase through cryptocurrency (74%), and claiming registration or accreditation of their sites (33%). ConclusionRogue online pharmacies are pervasive in search engine results, enabling the illicit purchase of Adderall without a prescription. Consumers are at risk of purchasing Adderall, a medication with high abuse potential, from unsafe sources. Law enforcement, regulatory agencies, and search engines should work to further protect consumers from unregistered and illegitimate online pharmacies selling Adderall.

To CBD or not to CBD?: What pharmacists need to know

To CBD or not to CBD?: What pharmacists need to know

Metabolism of a Kratom Alkaloid Metabolite in Human Plasma Increases Its Opioid Potency and Efficacy.

Kratom is widely consumed in the United States for self-treatment of pain and opioid withdrawal symptoms. Mitragynine is the most abundant alkaloid in kratom and is a μ-opioid receptor agonist. 7-Hydroxymitragynine (7-HMG) is a mitragynine metabolite that is a more potent and efficacious opioid than its parent mitragynine. 7-HMG contributes to mitragynine's antinociceptive effects in mice, but evidence suggests it may also have a higher abuse potential. This in vitro study demonstrates that 7-HMG is stable in rodent and monkey plasma but is unstable in human plasma. Surprisingly, in human plasma 7-HMG is converted to mitragynine pseudoindoxyl, an opioid that is even more potent than either mitragynine or 7-HMG. This novel metabolite is formed in human plasma to a much greater extent than in the preclinical species tested (mouse, rat, dog, and cynomolgus monkey) and due to its μ-opioid potency may substantially contribute to the pharmacology of kratom in humans to a greater extent than in other tested species.