Differences in withdrawal symptoms, microglia activity, and cognitive functioning in rats exposed to continuous low-dose heroin in-utero.

INTRODUCTION: Opioid use during pregnancy and subsequent neonatal opioid withdrawal syndrome (NOWS) have been associated with poor developmental outcomes including cognitive functioning. Less is known about the underlying molecular effects of prenatal opioid exposure and subsequent withdrawal; however, given the recent increase in NOWS cases, there is a pressing need to better understand these effects, which may partially explain cognitive deficits that have been observed in both preclinical NOWS models and patients with NOWS. This study evaluated the effects of prenatal heroin exposure and subsequent precipitated withdrawal symptoms on microglial reactivity in the nucleus accumbens (NAc), dorsal hippocampus (HC), and ventral tegmental area (VTA) in rat neonates, as well as cognitive functioning at three developmental time points using the Morris Water Maze (MWM) task. METHODS: Heroin or saline (2 mg/kg) was randomly assigned and administered to six pregnant Sprague Dawley rat dams via osmotic minipump. A total of 63 rat neonates underwent naloxone-precipitated (5 mg/kg, subcutaneous injection) withdrawal testing at postnatal day 10 (PN10). Following withdrawal testing, neonates were randomly assigned to undergo perfusion and subsequent immunohistochemistry experiments to fluoresce Iba-1 for microglia detection, or to undergo the MWM task at three separate developmental time points (PN21-23; PN37; PN60) for cognitive testing. RESULTS: Results suggest that in-utero heroin exposure led to an increase in ultrasonic vocalizations during naloxone-precipitated withdrawal; a sensitive index of withdrawal in rat neonates. Additional results suggest increased microglial reactivity in the HC and VTA, but not the NAc, as well as reduced performance during the MWM in the group exposed to heroin in-utero. DISCUSSION: Together, these data suggest that in-utero opioid exposure is associated with microglial reactivity in brain regions associated with learning and memory, and may be associated with later cognitive deficits. Further research is needed to characterize these findings, which may inform future therapeutic strategies for this vulnerable population.

First Response to Opioids Survey Tool (FROST): Pilot study of a brief screening tool to assess opioid use disorder risk.

OBJECTIVE: Early work suggests the type of subjective experiences upon first opioid use may predict opioid use disorder (OUD) risk. This study developed and pilot-tested a brief survey to evaluate the "first response" to opioids. DESIGN: A cross-sectional survey research study. The survey was administered to a subsample for the second time to assess test-retest reliability. SETTING: Outpatient. PARTICIPANTS: Convenience sample of adults treated for OUD at an opioid treatment program. MAIN OUTCOME MEASURES: A seven-question First Response to Opioids Survey Tool (FROST), developed based on the existing questionnaires and stakeholder-advisor feedback, was evaluated. RESULTS: Participants (N = 157) were 36.8 (standard deviation [SD] = 9.4) years old, with 79.6 percent identifying as Caucasian and 56.7 percent male. They reported opioid initiation at 20.6 (SD = 8.8) years old, with a prescription-based (78.3 percent), orally administered (66.2 percent), and illicitly procured (51.0 percent) opioids. Upon opioid initiation, positive-valence, euphoria-like subjective experiences of feeling "comfortable" (65.0 percent), "happy" (61.1 percent), "euphoria" (58.6 percent), and "energized" (44.6 percent) were common, and different (p < 0.05) from other types of subjective experiences. Among 64 individuals who answered a question about "drug-liking," 50 (78.1 percent) reported drug-liking. Among 31 respondents who completed the survey a second time, the test-retest consistency was 78.2 percent for subjective experience characteristics and 72 percent for drug-liking responses. Qualitative results corroborated quantitative findings. CONCLUSION: These results suggest that euphoria-type experiences and drug-liking upon opioid initiation are common among adults with OUD and FROST's promising psychometric properties. Future research should assess clinical utility of this brief survey, which could be applied at bedside and help identify those at risk for OUD, guide safer opioid prescribing, and reduce opioid-related harm.

Synthetic Marijuana: Assessment of Usage, Motivation and Associated Risks in Adolescent Substance Users.

Objectives: Use of Synthetic and designer products, including synthetic marijuana (SM), among adolescents poses a major risk to public health. Little is known about the motivating factors of synthetic substance use in adolescents. This study examined the motivations, predictors, perceived risks and benefits, and differences with SM versus natural marijuana among adolescents. Methods: Between April 2016 and May 2018, a convenience sample of adolescents receiving substance use treatment from a local counseling center completed an anonymous survey to assess the use of natural and synthetic marijuana use, the Strengths and Difficulties Questionnaire to assess levels of current psychiatric symptoms and the Community Assessment of Psychic Experiences-Positive Scale to assess symptoms of psychosis. Results: A total of 80 adolescents (age range of 14-18 years; 71% male; 53% Caucasian) completed the study. Of these, 39 (49%) reported natural marijuana use (natural marijuana users) and 41 (51%) reported both synthetic and natural marijuana use (dual users). The most commonly reported reasons for using SM were its low cost and reduced risk of detection. Participants who were familiar with SM and reported a desire to avoid detection on drug tests were likelier to use SM (all P < .05). Dual users reported more benefits and risks associated with SM use when compared to natural marijuana users (P ⩽ .05). The use of SM also heightened the perceived medical risks of natural marijuana, including seizures and respiratory issues (P < .05), compared with natural marijuana users. While dual users self-reported more conduct (P = .009) and externalizing problems (P = .024) when compared to natural marijuana users, there were no group differences in psychotic symptoms, nor correlations with the frequency of synthetic or natural marijuana use and psychotic symptoms except that persecutory ideation correlated with the frequency of natural marijuana use during the past 12 months (rp = 0.28, P = .04). Conclusions: These results suggest that reports of cost savings, and lack of detection on urine drug screens are common reasons for SM use in adolescents despite being aware of the risks of using SM. Perceived benefits of using synthetics and other novel substances appear diverse, and merit further exploration as a better understanding of what motivates adolescents to use specific novel substances may guide prevention and treatment efforts.

Cannabidiol-Derived Cannabinoids: The Unregulated Designer Drug Market Following the 2018 Farm Bill.

Background: In this review, we summarize current scientific knowledge on psychoactive cannabinoids synthesized from cannabidiol (CBD) and sold in the semi-legal market established in response to the passage of the US Agriculture Improvement Act of 2018, commonly known as the 2018 Farm Bill. The discussion focuses on recent developments that suggest this unregulated market may be fertile ground for a potential health crisis. Summary: Current research into CBD-derived cannabinoids is mainly limited to Δ8-tetrahydrocannabinol (Δ8-THC) products, with some recent publications beginning to explore O-acetyl-THC, a term describing the acetate ester of Δ8-THC or Δ9-THC, and its potential pulmonary toxicity. We advance the discussion on the CBD-derived cannabinoid market, shedding light on the introduction and associated dangers of novel cannabinoids, likely produced via fully synthetic routes using sidechain variants of CBD, with purportedly greater agonist activity at the human cannabinoid receptor 1 (as a source of euphorigenic activity) than Δ9-THC. We discuss the expanded incorporation of the acetate ester motif into other THC analogues. We also discuss the lack of regulatory oversight for the production of CBD-derived cannabinoids and the unlabeled presence of under-researched cannabinoids formed as reaction side products in the CBD-derived cannabinoid products being sold. Accordingly, we suggest approaches to monitoring the CBD-derived cannabinoid market and investigating the pharmacology of the cannabinoids being consumed. Finally, important epidemiological findings are discussed and future directions for research are suggested to call investigators to this critically understudied field. Key Messages: The CBD-derived cannabinoid market is growing internationally, and the market has diversified to include potent synthetic cannabinoids. The products sold on this unregulated market are under-researched despite growing availability and consumer interest. Ernest investigation of the pharmacology of these novel cannabinoids and the contents of CBD-derived cannabinoid products is critical for monitoring this potential source of another vaping-related epidemic.

Potential problems and solutions of opioid-based treatment in neonatal opioid withdrawal syndrome (NOWS): a scoping review protocol.

INTRODUCTION: Rates of neonatal opioid withdrawal syndrome (NOWS) have paralleled the rise of opioid use during pregnancy. While short-term phenotypic symptoms of NOWS are well defined, molecular implications and long-term effects are not well understood. Preferred and first-line of treatment for NOWS includes non-pharmacological interventions; however, more than half of the NOWS neonates will need pharmacologics, with opioids as the primary pharmacological treatment. While effective at reducing symptoms, treating NOWS with opioids is paradoxical given that molecular and long-term developmental consequences with such exposure are unknown. There is a pressing need for a synthesis of current and potential/ novel treatment options for NOWS. METHODS AND ANALYSIS: Following a published framework, a scoping review will be conducted to evaluate NOWS treatment, including established treatment methods and novel methods that may warrant future research and consideration. Using broad search terms, as well as Medical Subject Headings terms, a comprehensive search of PubMed, Cochrane Library, Google Scholar, CINAHL, Web of Science and Scopus, as well as references of selected literature, will take place, followed by a screening procedure to identify included and excluded articles. Included studies must address NOWS treatment, or opioid withdrawal treatment of any age group, that may or may not have been tested in preclinical or clinical models. Results will summarise the current pharmacological and non-pharmacological treatment methods for NOWS, as well as potential novel treatments with a specific interest in non-opioid pharmacological interventions. ETHICS AND DISSEMINATION: This scoping review aims to broadly search preclinical and clinical literature as it relates to treatment of NOWS, including potential novel treatments with a specific interest in non-opioid pharmacological interventions. Given that this study does not directly involve human subjects or animal subjects research, Institutional Review Board (IRB) or Institutional Animal Care and Use Committee (IACUC) approval is not required. Results of this scoping review will be disseminated at conferences and submitted for publication in a peer-reviewed journal.

Can the type of subjective response to first opioid exposure predict the risk of opioid use disorder? A scoping review.

BACKGROUND: Effective identification of individuals at increased risk for developing opioid use disorder (OUD) could reduce the overdose fatalities and mitigate the harm of the opioid epidemic. Early evidence has linked certain subjective experiences during the first substance exposure to subsequent substance misuse. This is consistent with anecdotal evidence that "first response" to opioids may distinguish those who later develop OUD from those who do not, further suggesting individual differences in neural activity and responses to specific substances. OBJECTIVE: The objective of this scoping review was to evaluate the evidence on the relationship between the subjective first response to opioids and the risk of developing OUD. METHODS: Ovid MEDLINE search (through 1/29/2021), followed by the search for articles published by the first/senior authors (PubMed) and references citing (Web of Science Citing Reference) identified eligible publications, was focused on studies involving humans, published in English, and describing the initial subjective response to opioid exposure and its association with OUD development or its risk. Systematic data extraction was completed for each eligible study. RESULTS: 3364 title/abstracts and 48 full-text articles were reviewed. Four articles, describing six studies (526 adult participants) were eligible and included. These studies were methodologically heterogeneous, including 2 randomized controlled trials, and 1 case-control, and 3 cross-sectional studies, with small sample sizes, precluding data pooling and meta-analysis. Results suggested that individuals with OUD or at elevated risk for OUD (determined by the validated OUD risk assessment surveys) were more likely to report their "first opioid response" as euphoric compared to their counterparts. CONCLUSIONS: Limited evidence suggests that subjectively-reported euphoric response to first opioid exposure could predict the OUD risk. Prospective studies are needed to evaluate the utility of assessing first response (e.g., via brief point-of-care screening surveys) for informing clinical decisions when prescribing opioids.

Patient- and Provider-Reported Experiences of a Mobile Novel Digital Therapeutic in People With Opioid Use Disorder (reSET-O): Feasibility and Acceptability Study.

BACKGROUND: Medications for the treatment of opioid use disorder, such as buprenorphine, are effective and essential for addressing the opioid epidemic. However, high dropout rates from medication remain a challenge. Behavioral treatment with contingency management and cognitive behavioral counseling has shown promise for improving the outcomes of buprenorphine treatment but is complicated to deliver. The delivery of behavioral treatment through technology-based platforms has the potential to make it more feasible for widespread dissemination. OBJECTIVE: reSET-O is a prescription digital therapeutic and a commercial adaptation of the Therapeutic Education System, an internet-based program with a Community Reinforcement Approach to cognitive behavioral therapy. It delivers cognitive behavioral therapy modules and contingency management rewards upon completion of modules and negative urine drug screens. This pilot study aims to assess the feasibility and acceptability of reSET-O in a community-based opioid treatment program with a Hub and Spoke model of care as part of a larger strategy to maintain individuals in treatment. Objective and qualitative results, as well as acceptability and likeability of reSET-O, were obtained from 15 individuals. METHODS: English-speaking individuals aged ≥18 years with a diagnosis of current opioid use disorder were recruited after being on buprenorphine for at least 1 week of treatment. Two 12-week prescriptions for reSET-O were written for the 24-week study. Patient reports of drug use and likeability scales of reSET-O were conducted at weeks 4, 8, 12, and 24 of the study. Qualitative interviews were also conducted. A total of 4 providers were recruited and provided feedback on the acceptability and feasibility of reSET-O. RESULTS: Of the 15 participants who participated in this pilot study, 7 (47%) completed 24 weeks, and 8 (53%) were unable to complete because of dropout after enrollment, attrition in treatment, or incarceration. An average of US $96 in contingency management rewards were earned by participants for the completion of modules for the duration of the pilot study. Participants' subjective feedback revealed that reSET-O was easy to use, enjoyable, and helped provide a safe space to admit recurring substance use. CONCLUSIONS: reSET-O was well accepted based on patient and provider feedback in this pilot study; however, adherence and retention in treatment remain areas for improvement. Randomized control trials are needed to assess whether retention of community-based buprenorphine treatment is enhanced through the use of technology-based behavioral interventions such as reSET-O.

Glucagon-like peptide-1 receptor agonist, liraglutide, reduces heroin self-administration and drug-induced reinstatement of heroin-seeking behaviour in rats.

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse. In this study, we test the effectiveness of the GLP-1 analogue, liraglutide (LIR), in reducing heroin addiction-like behaviour, and the potential side effects associated with the treatment. We show that daily treatment with LIR (0.1 mg/kg sc) increases the latency to take heroin, reduces heroin self-administration, prevents escalation of heroin self-administration and reduces drug-induced reinstatement of heroin-seeking behaviour in rats. A 1-h pretreatment time, however, was too short to reduce cue-induced seeking in our study. Moreover, we showed that, while LIR (0.1, 0.3, 0.6 and 1.0 mg/kg sc) supported conditioned taste avoidance of a LIR-paired saccharin cue, it did not elicit intake of the antiemetic kaolin in heroin-naïve or heroin-experienced rats. Further, 0.1 mg/kg LIR did not produce great disruptions in food intake or body weight. Overall, the data show that LIR is effective in reducing heroin taking and heroin seeking at doses that do not cause malaise and have a modest effect on food intake and body weight gain.