Medical and Non-Medical Opioid Use at the Intersection of Gender and Sexual Identity: Associations with State Medical Cannabis Law Status in a U.S. National Sample of Adults.

At the structural level, medical cannabis laws (MCLs) have been negatively associated with opioid prescribing practices, and sexual minority adults report disproportionately high non-medical prescription opioid use. We examined medical/non-medical prescription opioid use by intersecting sexual identity and gender and explored associations with MCLs using the 2015-2017 National Survey on Drug Use and Health, which captured sexual identity and MCL state residence for adults 18 + years (N = 126,463). Survey-weighted gender-stratified multinomial logistic models estimated adjusted relative risk ratios (aRRR) of medical vs. no prescription opioid use, and any non-medical vs. no prescription opioid use, by sexual identity and MCL, and tested moderation by MCL. Past-year medical prescription opioid use was higher among women than men across sexual identities (e.g., bisexual: 38.5% women vs. 30.2% men). Non-medical prescription opioid use was lower among women than men, except for bisexual adults (12.4% women vs. 7.6% men). MCL was associated with lower medical prescription opioid vs. no use among heterosexual women (aRRR = 0.86, 95% confidence interval [CI] = 0.81-0.91), bisexual women (aRRR = 0.74, 95% CI = 0.62-0.89), and heterosexual men (aRRR = 0.91, 95% CI = 0.85-0.97). Living in an MCL state was associated with lower non-medical vs. no use among heterosexual and bisexual women, but not among men or lesbian/gay women. MCL status did not moderate associations between sexual identity and prescription opioid outcomes. Future studies should assess whether implementing MCLs could particularly affect bisexual women who reported the highest prescription opioid use and may need targeted services.

Neighborhood and Network Characteristics and the HIV Care Continuum among Gay, Bisexual, and Other Men Who Have Sex with Men.

In order for treatment as prevention to work as a national strategy to contain the HIV/AIDS epidemic in the United States (US), the HIV care continuum must become more robust, retaining more individuals at each step. The majority of people living with HIV/AIDS (PLWHA) in the US are gay, bisexual, and other men who have sex with men (MSM). Within this population, there are distinct race- and ethnicity-based disparities in rates of HIV infection, engagement, and retention in HIV care, and viral suppression. Compared with White MSM, HIV-infected Black MSM are less likely to be on anti-retroviral therapy (ART), adhere to ART, and achieve viral suppression. Among MSM living in urban areas, falling off the continuum may be influenced by factors beyond the individual level, with new research identifying key roles for network- and neighborhood-level characteristics. To inform multi-level and multi-component interventions, particularly to support Black MSM living in urban areas, a clearer understanding of the pathways of influence among factors at various levels of the social ecology is required. Here, we review and apply the empirical literature and relevant theoretical perspectives to develop a series of potential pathways of influence that may be further evaluated. Results of research based on these pathways may provide insights into the design of interventions, urban planning efforts, and assessments of program implementation, resulting in increased retention in care, ART adherence, and viral suppression among urban-dwelling, HIV-infected MSM.

Commonalities and Differences Across Substance Use Disorders: Phenomenological and Epidemiological Aspects.

BACKGROUND: Although psychoactive substances vary in many ways, they have important commonalties, particularly in their ability to lead to an addiction syndrome. The field lacks an updated review of the commonalities and differences in the phenomenology of alcohol, cannabis, tobacco, stimulants, opioids, hallucinogens, sedatives/tranquilizers, and inhalants and their related substance use disorders (SUDs). METHODS: DSM-IV and DSM-5 SUD diagnostic criteria were reviewed, as was evidence from recent epidemiological and clinical research: psychometric studies (test-retest reliability, latent trait analysis); physiological indicators (tolerance, withdrawal); prevalence and age of onset. Information was incorporated from previous reviews, PubMed and Scopus literature searches, and data from large U.S. national surveys. RESULTS: Empirical evidence in the form of test-retest reliability and unidimensionality supports use of the same DSM-IV dependence or DSM-5 SUD diagnostic criteria across substances. For most substances, the criteria sets were generally most informative in general population samples at moderate-to-severe levels of SUD. Across substances, 2 criteria (tolerance and use in hazardous situations) were identified as functioning differently in population subgroups. Since substances have different pharmacological effects, withdrawal is assessed using substance-specific symptoms, while tolerance is not; issues remain with the assessment of tolerance. Alcohol, tobacco, and cannabis were consistently identified as the substances with earliest onset of use, highest prevalence of lifetime use, and highest prevalence of lifetime disorder. CONCLUSIONS: Despite differences between psychoactive substances, the generic DSM criteria set appears equally applicable across substances. Additional studies of tolerance and hazardous use will be useful for future nosologies. Alcohol, cannabis, and tobacco are the substances with the greatest public health impact due to the high prevalence and early onset of their use, and the potential all 3 substances have to lead to addiction.

SOCS3 is an endogenous inhibitor of pathologic angiogenesis.

Inflammatory cytokines and growth factors drive angiogenesis independently; however, their integrated role in pathologic and physiologic angiogenesis is not fully understood. Suppressor of cytokine signaling-3 (SOCS3) is an inducible negative feedback regulator of inflammation and growth factor signaling. In the present study, we show that SOCS3 curbs pathologic angiogenesis. Using a Cre/Lox system, we deleted SOCS3 in vessels and studied developmental and pathologic angiogenesis in murine models of oxygen-induced retinopathy and cancer. Conditional loss of SOCS3 leads to increased pathologic neovascularization, resulting in pronounced retinopathy and increased tumor size. In contrast, physiologic vascularization is not regulated by SOCS3. In vitro, SOCS3 knockdown increases proliferation and sprouting of endothelial cells costimulated with IGF-1 and TNFα via reduced feedback inhibition of the STAT3 and mTOR pathways. These results identify SOCS3 as a pivotal endogenous feedback inhibitor of pathologic angiogenesis and a potential therapeutic target acting at the converging crossroads of growth factor- and cytokine-induced vessel growth.

Age-related patterns of cocaine and methamphetamine use across the life course in the United States: Disparities by gender and sexual identity among adults.

PURPOSE: Research showing substance use decreases over the life course has focused primarily on heterosexual adults. We examined how age-related patterns of cocaine and methamphetamine use vary by sexual identity and gender among a national sample. METHODS: We included 191,954 adults aged 18-64 from the 2015-2019 National Survey on Drug Use and Health. We described the weighted prevalence of past-year cocaine and methamphetamine use and used logistic regressions to estimate relative odds of past-year cocaine and methamphetamine use by age, stratified by gender and sexual identity (heterosexual, gay/lesbian, bisexual). RESULTS: Cocaine and methamphetamine use was highest among lesbian, gay, and bisexual (LGB) adults compared to their heterosexual counterparts. Gay/lesbian men and women and bisexual men were also more likely to use cocaine at later ages. Heterosexual adults ages 26-34 (adjusted odds ratio [aOR] = 0.73; confidence interval [CI] = 0.65-0.83) were less likely than those 21-25 to report past-year cocaine use, but there were no differences between those ages 26-34 and 21-25 among any LGB sub-group. Heterosexual (aOR = 1.62; CI = 1.28-2.04) and gay (aOR = 2.93; CI = 1.26-6.80), men ages 26-34 were more likely to report past-year methamphetamine use than their counterparts ages 21-25. There were no age-related differences in past-year methamphetamine use between bisexual men and gay/lesbian women. CONCLUSIONS: Patterns of cocaine and methamphetamine use across the life course for LGB individuals differ from those of heterosexuals. This has implications for targeted prevention efforts to address stimulant use among minoritized populations.

EET signaling in cancer.

Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in tumorigenesis. Endogenously produced lipid autacoids, locally acting small-molecule mediators, play a central role in inflammation and tissue homeostasis. These lipid mediators, collectively referred to as eicosanoids, have recently been implicated in cancer. Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This eicosanoid pathway consists of two main branches: ω-hydroxylases which converts arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. EET signaling was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology. To date, most research on eicosanoids in cancer has focused on the COX and LOX pathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as EETs and HETEs, in cancer has received little attention. While CYP epoxygenases are expressed in human cancers and promote human cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis, inflammation, and cancer is discussed.

Daily cannabis use, cannabis use disorder, and any medical cannabis use among US adults: Associations within racial, ethnic, and sexual minoritized identities in a changing policy context.

Differences in cannabis use patterns among racial, ethnic and sexual minoritized identity subgroups have been attributed to marginalized identity stressors. However, associations at the intersection of these minoritized identities remain underexplored in a changing medical cannabis law (MCL) context. We estimated medical cannabis and daily cannabis use, and cannabis use disorder (CUD) by intersecting racial, ethnic and sexual minoritized identity subgroups. We included 189,800 adults in the 2015-2019 National Survey on Drug Use and Health identifying as non-Hispanic white, non-Hispanic Black, or Hispanic and self-reported heterosexual, gay/lesbian, or bisexual sexual identity. We estimated the adjusted odds of past-year: (a) any medical cannabis, (b) daily cannabis use (i.e., 300 + days/year), and (c) DSM-5-proxy CUD by sexual identity, stratified by race and ethnicity. Cannabis measures were higher among sexual minoritized groups than heterosexual adults across racial and ethnic subgroups. Bisexual adults had higher odds of any medical cannabis use than their heterosexual counterparts: non-Hispanic white (6.4% vs. 1.8%; aOR = 2.6, 95% CI = [2.5-3.5]), non-Hispanic Black (4.1% vs. 1.7%; aOR = 2.7, 95% CI = [1.6-4.5]), and Hispanic adults (5.3% vs. 1.8 %; aOR = 2.6, 95% CI = [1.9-3.3]). We found heterogeneous associations with state MCL status across subgroups stratified by race and ethnicity. Bisexual adults in MCL states had higher odds of any medical cannabis use among non-Hispanic white (aOR = 2.0, 95% CI = [1.4-2.9]) and Hispanic (aOR = 3.6, 95% CI = [1.2-10.2]) adults compared to their non-MCL counterparts, but this was marginal among non-Hispanic Black bisexual adults (aOR = 1.6, 95% CI = [1.0-2.6]). Studies should assess intended and unintended cannabis policy effects among racial, ethnic, and sexual identity subgroups.

Cytochrome P450-derived eicosanoids: the neglected pathway in cancer.

Endogenously produced lipid autacoids are locally acting small molecule mediators that play a central role in the regulation of inflammation and tissue homeostasis. A well-studied group of autacoids are the products of arachidonic acid metabolism, among which the prostaglandins and leukotrienes are the best known. They are generated by two pathways controlled by the enzyme systems cyclooxygenase and lipoxygenase, respectively. However, arachidonic acid is also substrate for a third enzymatic pathway, the cytochrome P450 (CYP) system. This third eicosanoid pathway consists of two main branches: ω-hydroxylases convert arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases convert it to epoxyeicosatrienoic acids (EETs). This third CYP pathway was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology; but, unlike prostaglandins and leukotrienes the link between cytochome P450 metabolites and cancer has received little attention. In this review, the emerging role in cancer of cytochrome P450 metabolites, notably 20-HETE and EETs, are discussed.

Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas.

Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors. We now report the in vitro and orthotopic in vivo results of combination therapy using radiation, temozolomide and lonafarnib (SCH66336), an oral farnesyl transferase inhibitor, in a murine model of glioblastoma. We examined the viability, proliferation, farnesylation of H-Ras, and activation of downstream signaling of combination-treated U87 cells in vitro. Lonafarnib alone or in combination with radiation and temozolomide had limited tumor cell cytotoxicity in vitro although it did demonstrate significant inhibition in tumor cell proliferation. In vivo, lonafarnib alone had a modest ability to inhibit orthotopic U87 tumors, radiation and temozolomide demonstrated better inhibition, while significant anti-tumor activity was found with concurrent lonafarnib, radiation, and temozolomide, with the majority of animals demonstrating a decrease in tumor volume. The use of tumor neurospheres derived from freshly resected adult human glioblastoma tissue was relatively resistant to both temozolomide and radiation therapy. Lonafarnib had a significant inhibitory activity against these neurospheres and could potentate the activity of temozolomide and radiation. These data support the continued research of high grade glioma treatment combinations of farnesyl transferase inhibitors, temozolomide, and radiation therapy.

Regulation of inflammation in cancer by eicosanoids.

Inflammation in the tumor microenvironment is now recognized as one of the hallmarks of cancer. Endogenously produced lipid autacoids, locally acting small molecule lipid mediators, play a central role in inflammation and tissue homeostasis, and have recently been implicated in cancer. A well-studied group of autacoid mediators that are the products of arachidonic acid metabolism include: the prostaglandins, leukotrienes, lipoxins and cytochrome P450 (CYP) derived bioactive products. These lipid mediators are collectively referred to as eicosanoids and are generated by distinct enzymatic systems initiated by cyclooxygenases (COX 1 and 2), lipoxygenases (5-LOX, 12-LOX, 15-LOXa, 15-LOXb), and cytochrome P450s, respectively. These pathways are the target of approved drugs for the treatment of inflammation, pain, asthma, allergies, and cardiovascular disorders. Beyond their potent anti-inflammatory and anti-cancer effects, non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 specific inhibitors have been evaluated in both preclinical tumor models and clinical trials. Eicosanoid biosynthesis and actions can also be directly influenced by nutrients in the diet, as evidenced by the emerging role of omega-3 fatty acids in cancer prevention and treatment. Most research dedicated to using eicosanoids to inhibit tumor-associated inflammation has focused on the COX and LOX pathways. Novel experimental approaches that demonstrate the anti-tumor effects of inhibiting cancer-associated inflammation currently include: eicosanoid receptor antagonism, overexpression of eicosanoid metabolizing enzymes, and the use of endogenous anti-inflammatory lipid mediators. Here we review the actions of eicosanoids on inflammation in the context of tumorigenesis. Eicosanoids may represent a missing link between inflammation and cancer and thus could serve as therapeutic target(s) for inhibiting tumor growth.

Medical cannabis laws and medical and non-medical prescription stimulant use among a nationally representative sample of US Adults: Examining the role of sexual identity and gender.

BACKGROUND: Medical marijuana laws (MMLs) can impact marijuana and opioid use, but the relationship between MMLs and other drugs, such as prescription stimulants, remains unexamined. Because lesbian, gay and bisexual (LGB) individuals report higher levels of prescription stimulant use than heterosexuals, we explored the relationship between MMLs and past-year medical and non-medical stimulant use by sexual identity and gender. METHODS: We pooled 2015-2017 National Survey on Drug Use and Health data for adults (n = 126 463), and used survey-weighted multinomial logistic regression to estimate odds of past-year (a) medical prescription stimulant use, (b) non-medical prescription stimulant use and (c) non-medical versus medical stimulant use. We stratified by gender, adjusted for sociodemographic characteristics, and tested the interaction between MML state residence and sexual identity. RESULTS: Bisexual men had higher medical (6.4% versus 4.1%; aROR=1.93[1.29-2.88]) and non-medical stimulant use 6.6% versus 2.4%; aROR=2.23[1.44-3.44]) than heterosexual men. Bisexual women had higher non-medical stimulant use (6.8% versus 1.6%; aROR=1.54[1.23-2.93] than heterosexual women. Female (aROR=0.70[0.62-0.78]) and male (aROR=0.74[0.66-0.82]) heterosexuals in MML states had lower odds of medical stimulant use than in non-MML states. Bisexual men in MML states had lower odds of medical (aROR=0.36[0.21-0.61]) and non-medical stimulant use (aROR=0.48[0.29-0.81]) than bisexual men in non-MML states. Similar patterns emerged for bisexual women's non-medical use (aROR=0.57[0.40-0.81]). CONCLUSION: Prescription stimulant use was higher in non-MML states for most LGB subgroups. MMLs may differentially impact stimulant use, primarily for bisexual men and women. States enacting MMLs should consider potential impacts on drugs other than marijuana, especially among LGB populations.

Medical, Nonmedical, and Illegal Stimulant Use by Sexual Identity and Gender.

INTRODUCTION: Major knowledge gaps regarding medical and nonmedical prescription stimulant use and illegal stimulant use (i.e., cocaine/crack/methamphetamine) by sexual identity and gender have implications for individuals' health and well-being. This study improves stimulant use measurement by differentiating the type of stimulant use and focusing on lesbian, gay, and bisexual subpopulations. METHODS: Data were pooled for adults in the 2015-2017 National Survey on Drug Use and Health (n=126,463; analyzed in 2019). Gender-stratified logistic regression models examined associations between sexual identity and past-year illegal stimulant use. Gender-stratified multinomial logistic regression models estimated odds of (1) medical use only versus no past-year prescription stimulant use, (2) any nonmedical stimulant use versus no past-year use, and (3) any nonmedical stimulant use versus medical use only. RESULTS: Illegal stimulant use varied by sexual identity (men: gay, 9.2%; bisexual, 7.5%; heterosexual, 3.2%; women: gay/lesbian, 3.2%; bisexual, 7.8%; heterosexual, 1.5%), as did nonmedical prescription stimulant use. Relative to same-gender heterosexuals, gay (AOR=2.61, 95% CI=2.00, 3.40) and bisexual (AOR=1.70, 95% CI=1.24, 2.33) men had higher odds of past-year illegal stimulant use, as did gay/lesbian (AOR=1.63, 95% CI=1.16, 2.28) and bisexual (AOR=2.70, 95% CI=2.23, 3.26) women. Sexual minorities reported higher odds of nonmedical prescription stimulant use than heterosexuals. Any nonmedical prescription opioid use was reported by 26.4% of people who reported nonmedical stimulant use and 27.0% of people who reported illegal stimulant use. CONCLUSIONS: Lesbian, gay, and bisexual individuals had a higher prevalence of stimulant use than their heterosexual counterparts. This has important implications for health disparities, especially given the high levels of polysubstance use. Taking a multilevel approach is crucial to reduce stimulant-related harms for lesbian, gay, and bisexual individuals.

State-level marijuana policies and marijuana use and marijuana use disorder among a nationally representative sample of adults in the United States, 2015-2017: Sexual identity and gender matter.

BACKGROUND: Research demonstrates an association between state-level medical marijuana laws (MMLs) and increased marijuana use (MU) and MU disorder (MUD) among adults, but has yet to explore this association among lesbian, gay and bisexual (LGB) individuals, including gender differences. METHODS: We pooled the 2015-2017 National Survey on Drug Use and Health data for adults (n = 126,463) and used gender-stratified adjusted multivariable logistic regression to model the odds of past-year MU, past-year medical MU, daily/near-daily MU, and MUD; we also tested the interaction between MML state residence and sexual identity. RESULTS: Bisexual women had higher past-year MU (40% versus 10.3%; aOR = 2.9[2.4-3.4]), daily/near-daily MU (9.8% versus 1.5%; aOR = 4.6[3.3-6.2]), and medical MU ((5.5% versus 1.2%) aOR = 5.5[3.8-8.1]) than heterosexual women. Gay/lesbian women also had higher past-year MU (26.1% versus 10.3%; aOR = 2.8[2.2-3.7]), daily/near-daily MU (5.6% versus 1.5%; aOR = 2.9[1.8-4.6]), and medical MU (4.7% versus 1.2%; aOR = 3.0(1.4-6.6]) than heterosexual women. Bisexual women in MML states had higher past-year MU ((44.4% vs. 34.1%); aOR = 1.8[1.5-2.1]) and medical use (7.1% vs. 3.3% (aOR = 2.5[1.5-3.9]) than bisexual women in non-MML states. The odds of any past-year medical MU for bisexual versus heterosexual women was different in MML versus non-MML states (Exponentiated ß = 0.53, p = 0.01). Gay men in MML states had higher past year MU (31.2% versus 25.7%; aOR = 1.6[1.1-2.5] and medical MU (6.4% vs 1.7%; aOR = 5.0[4.2-6.1]) than gay men in non-MML states. CONCLUSIONS: Results suggest that MMLs may differentially impact MU for sexual minority individuals-particularly bisexual women. Findings demonstrate the need for states enacting MMLs to consider potential differential impacts on LGB populations.

Resolvins suppress tumor growth and enhance cancer therapy.

Cancer therapy reduces tumor burden by killing tumor cells, yet it simultaneously creates tumor cell debris that may stimulate inflammation and tumor growth. Thus, conventional cancer therapy is inherently a double-edged sword. In this study, we show that tumor cells killed by chemotherapy or targeted therapy ("tumor cell debris") stimulate primary tumor growth when coinjected with a subthreshold (nontumorigenic) inoculum of tumor cells by triggering macrophage proinflammatory cytokine release after phosphatidylserine exposure. Debris-stimulated tumors were inhibited by antiinflammatory and proresolving lipid autacoids, namely resolvin D1 (RvD1), RvD2, or RvE1. These mediators specifically inhibit debris-stimulated cancer progression by enhancing clearance of debris via macrophage phagocytosis in multiple tumor types. Resolvins counterregulate the release of cytokines/chemokines, including TNFα, IL-6, IL-8, CCL4, and CCL5, by human macrophages stimulated with cell debris. These results demonstrate that enhancing endogenous clearance of tumor cell debris is a new therapeutic target that may complement cytotoxic cancer therapies.

Epoxyeicosanoids stimulate multiorgan metastasis and tumor dormancy escape in mice.

Epoxyeicosatrienoic acids (EETs) are small molecules produced by cytochrome P450 epoxygenases. They are lipid mediators that act as autocrine or paracrine factors to regulate inflammation and vascular tone. As a result, drugs that raise EET levels are in clinical trials for the treatment of hypertension and many other diseases. However, despite their pleiotropic effects on cells, little is known about the role of these epoxyeicosanoids in cancer. Here, using genetic and pharmacological manipulation of endogenous EET levels, we demonstrate that EETs are critical for primary tumor growth and metastasis in a variety of mouse models of cancer. Remarkably, we found that EETs stimulated extensive multiorgan metastasis and escape from tumor dormancy in several tumor models. This systemic metastasis was not caused by excessive primary tumor growth but depended on endothelium-derived EETs at the site of metastasis. Administration of synthetic EETs recapitulated these results, while EET antagonists suppressed tumor growth and metastasis, demonstrating in vivo that pharmacological modulation of EETs can affect cancer growth. Furthermore, inhibitors of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs, elevated endogenous EET levels and promoted primary tumor growth and metastasis. Thus, our data indicate a central role for EETs in tumorigenesis, offering a mechanistic link between lipid signaling and cancer and emphasizing the critical importance of considering possible effects of EET-modulating drugs on cancer.