Gender differences in the prevalence of stimulant misuse in the United States: 2015-2019.

BACKGROUND AND OBJECTIVES: The gender gap in prevalence of substance-use disorders has narrowed. However, gender differences in stimulant misuse have not been well-characterized in recent years. The aim of this study was to quantify gender differences in past-year stimulant misuse and stimulant-use disorder, separated by stimulant type (cocaine/crack, prescription stimulants, and methamphetamine). In an exploratory aim, we investigated whether gender differences were moderated by age or sexual orientation. METHODS: We combined data from the National Survey on Drug Use and Health from 2015 to 2019 (unweighted N = 282,768) to test gender differences in the prevalence of past-year stimulant misuse. RESULTS: Results indicated that stimulant misuse was significantly more prevalent in men than women for all stimulant types for both past-year use and past-year use disorder. The magnitude of this sex difference was smallest for prescription stimulants, where men had 1.37 times higher odds of past-year misuse and no gender difference was observed in the prevalence of prescription stimulant-use disorder. The magnitude of gender differences also varied based on both age and sexual orientation. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Illicit stimulant misuse continues to be more common in men than in women; however, gender differences are more modest for prescription stimulant misuse, suggesting a narrowing of this historical gender difference.

A pilot study of benzodiazepine cue-induced craving.

OBJECTIVES: The misuse of benzodiazepines is a growing concern due to increases in both access to these medications and their associated public health harms, most concerningly risk for overdose when combined with other substances. Although cue reactivity-the subjective and physiological response to cues or reminders of substance use-has been identified for most major classes of substances, it has yet to be studied with benzodiazepines. In this preliminary study, our objective was to assess whether images of benzodiazepines were associated with greater craving and anxiety than neutral images in adults who reported misuse of benzodiazepines. METHODS: We recruited a sample of 38 adults from a substance use disorder treatment setting and administered a standard cue reactivity task using pictorial images along with a battery of self-report measures. RESULTS: Results indicated significantly higher craving and anxiety in response to benzodiazepine relative to neutral cues, with cues eliciting a moderate to high level of craving, on average. Craving was associated with several risk factors for benzodiazepine misuse, including insomnia and distress intolerance. CONCLUSIONS: This preliminary study suggests that benzodiazepine cues can become conditioned to elicit craving responses and that the degree of cue reactivity is correlated with known risk factors for benzodiazepine misuse.

Benzodiazepine misuse among adults receiving psychiatric treatment.

Benzodiazepines are among the most commonly prescribed psychiatric medications and have the potential for misuse. People with psychiatric disorders may have a heightened liability to the reinforcing effects of benzodiazepines. Yet, the prevalence of benzodiazepine misuse in psychiatric care settings is not well characterized. The aim of the current study was to characterize the prevalence and correlates of benzodiazepine misuse in a sample of adults receiving psychiatric treatment (N = 589). The majority of participants reported a lifetime history of benzodiazepine prescription (68%) and 26% reported a lifetime history of misuse (defined as use without a prescription or at a dose or frequency higher than prescribed). Multivariable analyses indicated that history of a benzodiazepine prescription and drug use problems were significantly associated with lifetime benzodiazepine misuse. People with a history of benzodiazepine prescription had four times higher odds of misusing benzodiazepines and the primary source of misused benzodiazepines was from family or friends. Results suggest that benzodiazepine misuse is not exclusive to substance use disorder populations. The misuse of benzodiazepines should be assessed in psychiatric settings. Further research is needed to understand the impact of benzodiazepine misuse in this population and to develop tools to identify those at risk for misuse.

Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice.

Inhalational exposure to crystalline silica is linked to several debilitating systemic autoimmune diseases characterized by a prominent humoral immune component, but the mechanisms by which silica induces autoantibodies is poorly understood. To better understand how silica lung exposure breaks B cell tolerance and unleashes autoreactive B cells, we exposed both wildtype mice of healthy C57BL/6 and lupus-prone BXSB, MRL, and NZB strains and mice carrying an autoantibody transgene on each of these backgrounds to instilled silica or vehicle and monitored lung injury, autoimmunity, and B cell fate. Silica exposure induced lung damage and pulmonary lymphoid aggregates in all strains, including in genetically diverse backgrounds and in autoantibody transgenic models. In wildtype mice strain differences were observed in specificity of autoantibodies and site of enhanced autoantibody production, consistent with genetic modulation of the autoimmune response to silica. The unique autoantibody transgene reporter system permitted the in vivo fate of autoreactive B cells and tolerance mechanisms to be tracked directly, and demonstrated the presence of transgenic B cells and antibody in pulmonary lymphoid aggregates and bronchoalveolar lavage fluid, respectively, as well as in spleen and serum. Nonetheless, B cell enumeration and transgenic antibody quantitation indicated that B cell deletion and anergy were intact in the different genetic backgrounds. Thus, silica exposure sufficient to induce substantial lung immunopathology did not overtly disrupt central B cell tolerance, even when superimposed on autoimmune genetic susceptibility. This suggests that silica exposure subverts tolerance at alternative checkpoints, such as regulatory cells or follicle entry, or requires additional interactions or co-exposures to induce loss of tolerance. This possibility is supported by results of differentiation assays that demonstrated transgenic autoantibodies in supernatants of Toll-like receptor (TLR)7/TLR9-stimulated splenocytes harvested from silica-exposed, but not vehicle-exposed, C57BL/6 mice. This suggests that lung injury induced by silica exposure has systemic effects that subtly alter autoreactive B cell regulation, possibly modulating B cell anergy, and that can be unmasked by superimposed exposure to TLR ligands or other immunostimulants.

A murine Ig light chain transgene reveals IGKV3 gene contributions to anti-collagen types IV and II specificities.

A subset of autoimmune diseases result from autoantibodies targeting epitopes on matrix collagen. The most extensively studied are anti-glomerular basement membrane glomerulonephritis (or its systemic counterpart Goodpasture's disease) that destroys kidneys and lungs, and rheumatoid arthritis that leads to disabling arthritis. Autoantibodies in these disorders bind evolutionarily conserved conformational epitopes on the noncollagenous domain 1 (NC1) of the alpha3 chain of type IV [alpha3(IV)NC1] collagen in glomerular and alveolar basement membranes, and on native or citrullinated type II collagen (CII) in joint cartilage, respectively. The genetic origins of pathogenic anti-collagen B cells in these diseases is unknown, but observations from murine models raise the possibility that they overlap despite distinct in vivo immunopathologies. Monoclonal autoantibodies isolated from mice immunized with alpha3(IV)NC1 collagen or CII show a biased use of Ig light chains (LC) encoded by genes of the IGKV3 subgroup (previously Vk21 family), paired with diverse Ig heavy chains. To further explore this relationship and determine if a single murine IGKV3 LC independently predisposes to both anti-collagen responses, we generated a novel transgenic (Tg) C57BL/6 mouse that expresses a productively rearranged IGKV3-encoded LC, termed mLCV3-Tg, in conjunction with endogenously rearranged Ig heavy chains. Tg mice are also genetically deficient in endogenous kappa chains to permit tracking of the mLCV3 transgene. We show that mLCV3-Tg mice are susceptible to humoral autoimmunity against both collagen chains. Anti-alpha3(IV)NC1 collagen, but not anti-CII, mLCV3-encoded Ig are detected in serum of unmanipulated Tg mice, while Toll-like receptor ligands induce secretion of mLCV3-Tg autoantibodies of both collagen specificities from splenocytes ex vivo. This indicates developmental survival of mLCV3-Tg B cells reactive with each antigen, and is consistent with production of the two anti-collagen autoIg from distinct B cell populations. Reduced B cell numbers, low serum Ig kappa levels, low cell surface Ig kappa density, and abundant endogenous lambda chain expression suggest that subsets of IGKV3-encoded B cells are regulated in vivo by mechanisms that include deletion, anergy, and LC editing. These results support the notion that murine IGKV3 LCs contribute structural fitness to antigen binding sites that support diverse anti-collagen autoimmune responses, that these responses are regulated in vivo, and that these cells can nonetheless readily escape immune regulation.