Use of Lysergic Acid Diethylamide by Major Depression Status.

Importance: Renewed interest in the clinical potential of hallucinogens may lead people with depression to a generally more positive view of the use of lysergic acid diethylamide (LSD). Therefore, past-year LSD use among people with depression may be increasing in prevalence. Objective: To assess time trends in the prevalence of past-year nonmedical LSD use by past-year major depression status and the variation in this association by sociodemographic characteristics. Design, Setting, and Participants: This survey study used pooled publicly available data from 478 492 adults aged 18 years or older who were administered the National Survey on Drug Use and Health from 2008 through 2019. Statistical analysis was conducted from December 2022 to June 2023. Main Outcome and Measures: Past-year major depression diagnoses per criteria from the DSM-IV were analyzed. Logistic regression models examined whether time trends in past-year nonmedical LSD use differed between adults with vs without past-year depression, adjusting for sociodemographic characteristics. Secondary analyses examined whether the trends in LSD use by depression status differed between sociodemographic subgroups. Results: The analytic sample included 478 492 adults, of whom 51.8% were female, 56.1% were younger than 50 years, 11.7% were Black, 15.1% were Hispanic, 65.8% were White, and 7.5% were another race. Weighted interview response rates ranged from 64.9% to 75.6% during the study time frame. From 2008 to 2019, past-year use of LSD increased significantly more among adults with major depression (2008 prevalence, 0.5%; 2019 prevalence, 1.8%; prevalence difference [PD], 1.3% [95% CI, 1.0%-1.6%]) compared with adults without major depression (2008 prevalence, 0.2%; 2019 prevalence, 0.8%; PD, 0.6% [95% CI, 0.5%-0.7%]) (difference in difference, 0.8% [95% CI, 0.5%-1.1%]). This difference was particularly pronounced among young adults aged 34 years or younger (PD among those aged 18-25 years with depression, 3.3% [95% CI, 2.5%-4.2%]; PD among those aged 26-34 years with depression, 2.7% [95% CI, 1.6%-3.8%]) and individuals with incomes less than $75 000 per year (PD among those with income <$20 000, 1.9% [95% CI, 1.3%-2.6%]; PD among those with income $20 000-$49 999, 1.5% [95% CI, 1.0%-2.1%]; PD among those with income $50 000-$74 999, 1.3% [95% CI, 0.7%-2.0%]). Conclusions and Relevance: This study suggests that, from 2008 to 2019, there was a disproportionate increase in the prevalence of past-year LSD use among US adults with past-year depression. Among those with depression, this increase was particularly strong among younger adults and those with lower household incomes. Among individuals with depression who also report LSD use, clinicians should discuss potential strategies for mitigating harm and maximizing benefits in medically unsupervised settings.

Evaluating age-related disparities in cannabis-related problems among LGBT+ versus non-LGBT+ adults.

LGBT+ adults demonstrate greater cannabis-related problems (e.g., Cannabis Use Disorder [CUD]) compared to non-LGBT+ counterparts. No study has explored age-related disparities in cannabis problems across the adult lifespan, nor have studies identified specific CUD criteria that contribute to elevated CUD among LGBT+ adults. The purpose of this study was to examine associations between LGBT+ identity and age with endorsement of CUD criteria in a sample of regular cannabis consumers. An online sample of N = 4334 (25.1% LGBT+) adults aged 18-64 residing in the U.S. completed an online survey about cannabis use behaviors and CUD diagnostic criteria. Bivariate contrasts revealed significantly greater CUD criteria endorsement among LGBT+ respondents, largely driven by differences at younger ages. However, this effect disappeared in the majority of adjusted logistic regression models. LGBT+ identity was associated with greater probability of use in larger amounts (adjOR = 2.10, 95% CI: 1.22-3.60) and use despite physical/mental health problems (adjOR = 2.51, 95% CI:1.23-5.03). No age*LGBT+ identity interactions were detected. Plotted trends depict more pronounced disparities in outcomes among LGBT+ adults under 35 years. Several potential risk and protective factors including employment, education, and reasons for use were identified. There were age-related differences in these characteristics among LGBT+ and non-LGBT+ respondents. Initial findings highlight the need for LGBT+ research examining trends in health outcomes and sociodemographic and cannabis characteristics across the lifespan. The study also provides a substantive contribution regarding specific cannabis-related problems that young LGBT+ cannabis consumers may be more likely to endorse than their non-LGBT+ counterparts.

Evaluating cannabis exposure in survey items: Insights, strategies, and remaining challenges identified from cognitive interviewing.

Background: The diversity in characteristics of cannabis products and behavior patterns make evaluation of cannabis exposure in population-based, self-report surveys challenging. Accurate identification of cannabis exposure and related outcomes necessitates a thorough understanding of participants' interpretations of survey questions assessing cannabis consumption behaviors. Objectives: The current study utilized cognitive interviewing to gain insight on participants' interpretation of items in a self-reported survey instrument used to estimate the quantity of THC consumed in population samples. Methods: Cognitive interviewing was used to evaluate survey items assessing cannabis use frequency, routes of administration, quantity, potency, and perceived "typical patterns" of use. Ten participants ≥18 years (n = 4 cisgender-men; n = 3 cisgender-women; n = 3 non-binary/transgender) who had used cannabis plant material or concentrates in the past week were recruited to take a self-administered questionnaire and subsequently answer a series of scripted probes regarding survey items. Results: While most items presented no issues with comprehension, participants identified several areas of ambiguity in question or response item wording or in visual cues included in the survey. Generally, participants with irregular use patterns (i.e., non-daily use) reported more difficulty recalling the time or quantity of cannabis use. Findings resulted in several changes to the updated survey, including updated reference images and new quantity/frequency of use items specific to the route of administration. Conclusion: Incorporating cognitive interviewing into cannabis measurement development among a sample of knowledgeable cannabis consumers led to improvements in assessing cannabis exposure in population surveys, which may otherwise have been missed.

Dimensionality and differential functioning of DSM-5 cannabis use disorder criteria in an online sample of adults with frequent cannabis use.

The DSM-5 criteria for cannabis use disorder (CUD) combine DSM-IV dependence and abuse criteria (without legal problems) and new withdrawal and craving criteria. Information on dimensionality, internal reliability, and differential functioning of the DSM-5 CUD criteria is lacking. Additionally, dimensionality of the DSM-5 withdrawal items is unknown. This study examined the psychometric properties of the DSM-5 CUD criteria among adults who used cannabis in the past 7 days (N = 5,119). Adults with frequent cannabis use were recruited from the US general population through social media and filled in a web-based survey about demographics and cannabis use behaviors. Factor analysis was used to assess dimensionality, and item response theory analysis models were used to explore relationships between the criteria and the underlying latent trait (CUD), and whether each criterion and the criteria set functioned differently by demographic and clinical characteristics: sex, age, state-level cannabis laws, reasons for cannabis use, and frequency of use. The DSM-5 CUD criteria showed unidimensionality and provided information about the CUD latent trait across the severity spectrum. The cannabis withdrawal items indicated one underlying latent factor. While some CUD criteria functioned differently in specific subgroups, the criteria set as a whole functioned similarly across subgroups. In this online sample of adults with frequent cannabis use, evidence supports the reliability, validity, and utility of the DSM-5 CUD diagnostic criteria set, which can be used for determining a major risk of cannabis use, i.e., CUD, to inform cannabis policies and public health messaging, and for developing intervention strategies.

Use of plant-based hallucinogens and dissociative agents: U.S. Time Trends, 2002-2019.

Aims: Information on time trends in use of different plant-based hallucinogens is lacking. The current study used nationally representative U.S. data to assess overall and age-specific time trends in the prevalence of lifetime and 12-month use of plant-based hallucinogens and dissociative agents. Methods: Participants were respondents aged ≥ 12 years (N = 1,006,051) from the National Survey on Drug Use and Health, 2002-2019. Predictors were continuous years. Outcomes included illicit use of peyote, mescaline, psilocybin, ketamine, salvia, and tryptamine. Sociodemographic variables (gender; age; race/ethnicity; educational level; family income) were modeled as covariates. Trends were estimated overall and by age (12-17, 18-25, 26+). Prevalence differences [PDs] were obtained for each category, along with 95 % confidence intervals [CI]. Results: Increases in lifetime use were observed for psilocybin (2002-2019 PD=+1.61), tryptamine (2006-2014 PD=+0.55; 2015-2019 PD=+0.44), and ketamine (2006-2014 PD=+0.27; 2015-2019 PD=+0.21). Mescaline use decreased (PD = -0.89). While overall lifetime salvia use increased between 2006 and 2014 (PD=+1.81), prevalence did not change between 2015 and 2019. Twelve-month use of tryptamine and ketamine increased between 2006 and 2014 (PD=+0.14; +0.03, respectively). Twelve-month ketamine use also increased from 2015 to 2019 (PD=+0.03). By age, participants aged 12-17 and 18-25 showed decreases in use of most types of hallucinogens, but those age 26+ generally showed increases. Conclusions: While use of plant-based hallucinogens and dissociative agents remains rare, lifetime use of ketamine, tryptamine, and psilocybin is increasing in adults. Considering these increases alongside concerns about unsupervised use of illicit products whose dose and composition is uncertain, clinicians and policymakers should remain mindful of the rising rates of illicit use in the general population.

The mevalonate precursor enzyme HMGCS1 is a novel marker and key mediator of cancer stem cell enrichment in luminal and basal models of breast cancer.

The definitive characterization of common cancer stem cell (CSCs) subpopulations in breast cancer subtypes with distinct genotypic and phenotypic features remains an ongoing challenge. In this study, we have used a non-biased genome wide screening approach to identify transcriptional networks that may be specific to the CSC subpopulations in both luminal and basal breast cancer subtypes. In depth studies of three CSC-enriched breast cancer cell lines representing various subtypes of breast cancer revealed a striking hyperactivation of the mevalonate metabolic pathway in comparison to control cells. The upregulation of metabolic networks is a key feature of tumour cells securing growth and proliferative capabilities and dysregulated mevalonate metabolism has been associated with tumour malignancy and cellular transformation in breast cancer. Furthermore, accumulating evidence suggests that Simvastatin therapy, a mevalonate pathway inhibitor, could affect breast cancer progression and reduce breast cancer recurrence. When detailing the mevalonate pathway in breast cancer using a single-cell qPCR, we identified the mevalonate precursor enzyme, HMGCS1, as a specific marker of CSC-enriched subpopulations within both luminal and basal tumour subtypes. Down-regulation of HMGCS1 also decreased the CSC fraction and function in various model systems, suggesting that HMGCS1 is essential for CSC-activities in breast cancer in general. These data was supported by strong associations between HMGCS1 expression and aggressive features, such as high tumour grade, p53 mutations as well as ER-negativity in lymph node positive breast cancer. Importantly, loss of HMGCS1 also had a much more pronounced effect on CSC-activities compared to treatment with standard doses of Simvastatin. Taken together, this study highlights HMGCS1 as a potential gatekeeper for dysregulated mevalonate metabolism important for CSC-features in both luminal and basal breast cancer subtypes. Pharmacological inhibition of HMGCS1 could therefore be a superior novel treatment approach for breast cancer patients via additional CSC blocking functions.

Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis.

Transcriptional control is the major determinant of cell fate. The steroid receptor coactivator (SRC)-1 enhances the activity of the estrogen receptor in breast cancer cells, where it confers cell survival benefits. Here, we report that a global analysis of SRC-1 target genes suggested that SRC-1 also mediates transcriptional repression in breast cancer cells. Combined SRC-1 and HOXC11 ChIPseq analysis identified the differentiation marker, CD24, and the apoptotic protein, PAWR, as direct SRC-1/HOXC11 suppression targets. Reduced expression of both CD24 and PAWR was associated with disease progression in patients with breast cancer, and their expression was suppressed in metastatic tissues. Investigations in endocrine-resistant breast cancer cell lines and SRC-1(-/-)/PyMT mice confirmed a role for SRC-1 and HOXC11 in downregulation of CD24 and PAWR. Through bioinformatic analysis and liquid chromatography/mass spectrometry, we identified AP1 proteins and Jumonji domain containing 2C (JMD2C/KDM4C), respectively, as members of the SRC-1 interactome responsible for transcriptional repression. Our findings deepen the understanding of how SRC-1 controls transcription in breast cancers.

The function of steroid receptor coactivator-1 in normal tissues and cancer.

In 1995, the steroid receptor coactivator-1 (SRC-1) was identified as the first authentic steroid receptor coactivator. Since then, the SRC proteins have remained at the epicenter of coregulator biology, molecular endocrinology and endocrine-related cancer. Cumulative works on SRC-1 have shown that it is primarily a nuclear receptor coregulator and functions to construct highly specific enzymatic protein complexes which can execute efficient and successful transcriptional activation of designated target genes. The versatile nature of SRC-1 enables it to respond to steroid dependent and steroid independent stimulation, allowing it to bind across many families of transcription factors to orchestrate and regulate complex physiological reactions. This review highlights the multiple functions of SRC-1 in the development and maintenance of normal tissue functions as well as its major role in mediating hormone receptor responsiveness. Insights from genetically manipulated mouse models and clinical data suggest SRC-1 is significantly overexpressed in many cancers, in particular, cancers of the reproductive tissues. SRC-1 has been associated with cellular proliferation and tumor growth but its major tumorigenic contributions are promotion and execution of breast cancer metastasis and mediation of resistance to endocrine therapies. The ability of SRC-1 to coordinate multiple signaling pathways makes it an important player in tumor cells' escape of targeted therapy.