A Preliminary Pharmacokinetic Comparison of Δ-9 Tetrahydrocannabinol and Cannabidiol Extract Versus Oromucosal Spray in Healthy Men and Women.

Few studies have directly compared the bioavailability of different cannabinoid formulations. Our goal was to assess the pharmacokinetic parameters and relative bioavailability of two Δ9-tetrahydrocannabinol:cannabidiol (THC:CBD) formulations: orally administered THC:CBD extract and oromucosally administered nabiximols. This pilot crossover study counterbalanced (1) 1 mL of orally administered THC:CBD extract (10 mg/mL each of THC and CBD in grapeseed oil) and (2) oromucosally administered nabiximols (four sprays of 2.

The influence of drug class on reward in substance use disorders.

In the United States, the societal costs associated with drug use surpass $500 billion annually. The rewarding and reinforcing properties that drive the use of these addictive substances are typically examined concerning the neurobiological effects responsible for their abuse potential. In this review, terms such as "abuse potential," "drug," and "addictive properties" are used due to their relevance to the methodological, theoretical, and conceptual framework for understanding the phenomenon of drug-taking behavior and the associated body of preclinical and clinical literature.

Signaling-specific inhibition of the CB receptor for cannabis use disorder: phase 1 and phase 2a randomized trials.

Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB-SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ-tetrahydrocannabinol (THC) binding without modifying behavior per se.

Racial differences in COVID-19 severity associated with history of substance use disorders and overdose: Findings from multi-site electronic health records in New York City.

Substance use disorders (SUD) are associated with increased risk of worse COVID-19 outcomes. Likewise, racial/ethnic minority patients experience greater risk of severe COVID-19 disease compared to white patients. Providers should understand the role of race and ethnicity as an effect modifier on COVID-19 severity among individuals with SUD.

The impact of preexisting psychiatric disorders and antidepressant use on COVID-19 related outcomes: a multicenter study.

Pre-existing mental disorders are linked to COVID-19-related outcomes. However, the findings are inconsistent and a thorough analysis of a broader spectrum of outcomes such as COVID-19 infection severity, morbidity, and mortality is required. We investigated whether the presence of psychiatric diagnoses and/or the use of antidepressants influenced the severity of the outcome of COVID-19.

Support for COVID-19-Related Substance Use Services Policy Changes: a New York State-Wide Survey.

This study aims to describe which substance use service (SUS) organizations and who within these organizations support the maintenance of policies targeted at improving substance use treatment services. An online survey assessing respondent, organizational and program demographics, and knowledge and support regarding policy changes was distributed to all certified SUS and harm reduction programs in NYS. Bivariate and latent class analyses were used to identify patterns and associations to policy choices.

A placebo-controlled investigation of the analgesic effects, abuse liability, safety and tolerability of a range of oral cannabidiol doses in healthy humans.

Aims: Preclinical studies demonstrate that cannabidiol (CBD) elicits an antinociceptive response in animal models of neuropathic pain; in humans, limited data are available to support such analgesic effects. Few studies have examined CBD's analgesic effects when administered without other compounds, and little is known regarding dose-dependent effects in noncannabis users.

Methods: This double-blind, placebo-controlled, within-subject outpatient clinical laboratory study sought to determine the analgesic effects, abuse liability, safety and tolerability of acute CBD (0, 200, 400 and 800 mg orally) in healthy noncannabis-using volunteers (n = 17; 8 men, 9 women).

COVID-19 related substance use services policy changes: Policymaker perspectives on policy development & implementation.

Introduction: Due to the COVID-19 pandemic, regulations for substance use services changed to accommodate stay-at-home orders and physical distancing guidelines.

Methods: Using in-depth interviews (N = 14) and framework analysis, we describe how policymakers developed, adopted, and implemented regulations governing services for substance use disorders during COVID-19, and how policymakers' perceived the impacts of these regulations in New York State.

Results: During the COVID-19 pandemic, policymakers shifted to more inclusive approaches of knowledge generation and co-production of recommendations.

5HT-2C agonist lorcaserin decreases cannabis self-administration in daily cannabis smokers.

There are no FDA-approved treatments for cannabis use disorder (CUD). Preclinical research has shown that the 5HT-2C agonist lorcaserin attenuates cue-induced reinstatement of THC seeking and self-administration. The goal of this placebo-controlled, counterbalanced, within-subject human laboratory study was to examine lorcaserin's effects on cannabis intoxication and self-administration.

Acute effects of cannabinoids on symptoms of obsessive-compulsive disorder: A human laboratory study.

Background: Preclinical data implicate the endocannabinoid system in the pathology underlying obsessive-compulsive disorder (OCD), while survey data have linked OCD symptoms to increased cannabis use. Cannabis products are increasingly marketed as treatments for anxiety and other OCD-related symptoms. Yet, few studies have tested the acute effects of cannabis on psychiatric symptoms in humans.

Thiopental Does Not Produce Hyperalgesia: A Laboratory Study Using Two Human Experimental Pain Models.

Objective: Past investigations assessing the effects of thiopental on pain are conflicting. Although several studies demonstrate hyperalgesia as a result of barbiturate administration, others show analgesia. Our objective was to assess the effects of an infusion of the GABAA agonist thiopental, compared with placebo, in healthy participants on two subjective experimental pain paradigms: noxious electrical stimulation and intradermal capsaicin.

Minocycline does not affect experimental pain or addiction-related outcomes in opioid maintained patients.

Rationale: Minocycline, a tetracycline antibiotic, inhibits activation of microglia. In preclinical studies, minocycline prevented development of opioid tolerance and opioid-induced hyperalgesia (OIH). The goal of this study was to determine if minocycline changes pain threshold and tolerance in individuals with opioid use disorder who are maintained on agonist treatment.

Gender Differences in the Prevalence of Fibromyalgia and in Concomitant Medical and Psychiatric Disorders: A National Veterans Health Administration Study.

Background: Fibromyalgia is a poorly understood, chronically disabling pain syndrome. While research has focused on its clinical presentation and treatment, less is known about fibromyalgia's clinical epidemiology in real-world healthcare systems. Gender differences have been difficult to study because relatively few males are diagnosed with fibromyalgia.

Rates and Correlates of Pain Specialty Clinic Use Nationally in the Veterans Health Administration.

Objective: Chronic pain management is a growing focus of attention, in part because of concern over excessive use of opioids for treatment of chronic noncancer pain. In the Veterans Health Administration (VHA), pain specialty clinics have been established to address the needs of patients with challenging pain issues. The current study identified characteristics of such patients in a national sample of VHA service users in fiscal year 2012.

Effect of Intravenous Ethanol on Capsaicin-Induced Hyperalgesia in Human Subjects.

Background: The objective of this study was to assess ethanol's (EtOH's) effects on capsaicin-induced hyperalgesia in healthy participants. Specifically, we investigated the change in area of capsaicin-induced hyperalgesia following 3 interventions: intravenous EtOH at 2 targeted breath alcohol concentrations (BrAC), or placebo.

Methods: Eighteen participants participated in 3 test days in a randomized order.

Targeting Opioid-Induced Hyperalgesia in Clinical Treatment: Neurobiological Considerations.

Opioid analgesics have become a cornerstone in the treatment of moderate to severe pain, resulting in a steady rise of opioid prescriptions. Subsequently, there has been a striking increase in the number of opioid-dependent individuals, opioid-related overdoses, and fatalities. Clinical use of opioids is further complicated by an increasingly deleterious profile of side effects beyond addiction, including tolerance and opioid-induced hyperalgesia (OIH), where OIH is defined as an increased sensitivity to already painful stimuli.

Spinal and supraspinal N-methyl-D-aspartate and melanocortin-1 receptors contribute to a qualitative sex difference in morphine-induced hyperalgesia.

Morphine elicits a paradoxical state of increased pain sensitivity, known as morphine-induced hyperalgesia (MIH), which complicates its clinical efficacy. We have previously shown that systemic injections of N-methyl-d-aspartate receptor (NMDAR) and melanocortin-1 receptor (MC1R) antagonists sex-dependently reverse MIH during morphine infusion (40mg/kg/24h) in male and female mice, respectively. This qualitative sex difference is ovarian hormone dependent, as NMDAR antagonists reverse MIH in ovariectomized females but are rendered ineffective following progesterone injection in OVX mice.

C-Fos activation in the periaqueductal gray following acute morphine-3β-D-glucuronide or morphine administration.

Morphine-3β-D-glucuronide (M3G), a primary morphine metabolite, evokes hyperalgesia in mice and rats and putatively mediates hyperalgesia associated with morphine (MOR) administration. However, M3G does not act via opioid receptors and its locus of activity in the CNS is unknown. Here we assessed the density of neurons immunoreactive for c-Fos, an immediate early gene regulated by neuronal activity, in the periaqueductal gray (PAG), a midbrain region critical to pain modulation, in male CD-1 mice after MOR and M3G exposure.

Morphine induces hyperalgesia without involvement of μ-opioid receptor or morphine-3-glucuronide.

Opioid-induced hyperalgesia (OIH) is a paradoxical increase in pain perception that may manifest during opioid treatment. For morphine, the metabolite morphine-3-glucuronide (M3G) is commonly believed to underlie this phenomenon. Here, in three separate studies, we empirically assess the role of M3G in morphine-induced hyperalgesia.

Progesterone rapidly recruits female-typical opioid-induced hyperalgesic mechanisms.

Continuous morphine treatment can paradoxically increase nociception (i.e. hyperalgesia) in male and female mice, but sex differences have been reported.

Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor.

Background: N-Methyl-D-aspartate receptor antagonists reverse hyperalgesia during morphine infusion in male mice only. Because the melanocortin-1 receptor can act as a female-specific counterpart to N-methyl-D-aspartate receptors in kappa-opioid analgesic mechanisms, the authors assessed the contribution of melanocortin-1 receptors to the sex-specific mechanisms underlying morphine hyperalgesia.

Methods: The tail-withdrawal test was used to compare the nociceptive responses of male and female C57BL/6J (B6) mice with those of C57BL/6J-Mc(1r(e/e)) mice, spontaneous mutants of the B6 background lacking functional melanocortin-1 receptors, during continuous morphine infusion (1.

Acute and chronic fentanyl administration causes hyperalgesia independently of opioid receptor activity in mice.

Although mu-receptor opioids are clinically important analgesics, they can also paradoxically cause hyperalgesia independently of opioid receptor activity, presumably via the action of neuroexcitatory glucoronide metabolites. However, it is unknown whether the commonly used mu-receptor opioid analgesic fentanyl, which is not subject to glucuronidation, can also induce hyperalgesia independently of opioid receptor activity. Thus, here we examined whether fentanyl increases nociception on the tail-withdrawal test in CD-1 mice concurrently treated with the opioid receptor antagonist naltrexone or in opioid receptor triple knock-out mice lacking mu, delta, and kappa opioid receptors.

Morphine-6beta-glucuronide rapidly increases pain sensitivity independently of opioid receptor activity in mice and humans.

Background: Previous data indicate that morphine-6beta-glucuronide (M6G), a morphine metabolite with analgesic properties, can paradoxically increase pain sensitivity in mice and humans. The authors tested mice and humans for M6G hyperalgesia and assessed the contribution of N-methyl-D-aspartate receptor activity in mice.

Methods: Nociception after acute injection (10 mg/kg) and chronic infusion (1.

A survey of acute and chronic heroin dependence in ten inbred mouse strains: evidence of genetic correlation with morphine dependence.

Heroin and morphine exposure can cause physical dependence, with symptoms manifesting during their withdrawal. Inter-individual differences in symptom frequency during morphine withdrawal are a common finding that, in rodents, is demonstrably attributable to genotype. However, it is not known whether inter-individual differences characterize heroin withdrawal, and whether such variation can be similarly influenced by genotype.