Randomized controlled trial of zolpidem as a pharmacotherapy for cannabis use disorder.

BACKGROUND: Sleep disturbance is commonly reported among individuals meeting criteria for cannabis use disorder (CUD), and people who use cannabis frequently report sleep disturbance as a contributor to failed quit attempts. The purpose of this study was to measure sleep in individuals enrolled in treatment for CUD, and to determine whether use of hypnotic medication during treatment increased abstinence rates. METHOD: The study enrolled 127 adults seeking treatment for CUD in a 12-week clinical trial and randomized to receive extended-release zolpidem (zolpidem-XR) or placebo. All participants received computerized behavioral therapy and abstinence-based contingency management. The study conducted in-home ambulatory polysomnography (PSG) assessments at baseline and during treatment to objectively measure sleep. Self-report measures of recent sleep, Insomnia Severity Index (ISI), and drug use (Timeline Follow-Back) were collected at each study visit, and the study confirmed self-reported abstinence via quantitative urine drug testing. RESULT: Participants randomized to placebo, but not zolpidem-XR exhibited significant sleep disturbance during week 1 of treatment. Sleep disturbance emerged in the zolpidem-XR group after study medication was stopped at the end of treatment. Though participants assigned to the zolpidem-XR condition had qualitatively greater rates of abstinence compared with placebo (27 % versus 15 % negative at end of treatment), the difference was not statistically significant. Treatment retention was poor (about 50 % drop out in both groups) and medication adherence was a challenge without the use of contingent incentives. CONCLUSION: Results from this randomized controlled trial suggest that zolpidem-XR can attenuate abstinence-induced sleep disturbance early in treatment for CUD, but that sleep problems are likely to emerge after the medication is stopped. Further research should identify alternative pharmacotherapies and behavioral treatments for CUD and elucidate the role of sleep disturbance in the development and maintenance of CUD.

Sex differences in endocannabinoid tone in a pilot study of cannabis use disorder and acute cannabis abstinence.

Cannabis use disorder (CUD) presents differently in men and women, particularly in symptoms of cannabis withdrawal. Novel pharmacotherapeutic interventions for CUD, such as those that target the endocannabinoid (eCB) system, must be developed in a manner consistent with these sex differences. The present pilot study sought to prospectively assess sex differences in cannabis withdrawal in a small sample of adults with moderate-to-severe CUD and to determine if withdrawal was associated with peripheral eCB and eCB congener tone. Men and women (n = 5/sex) completed 2 weeks of study participation separated by 1 month; in the latter week, participants abstained from cannabis use. Each week, participants attended in-person laboratory visits during which blood was drawn repeatedly to assess plasma eCB and eCB congener tone. Participants also completed multiple daily ambulatory assessments to assess cannabis use and withdrawal symptoms. As anticipated, women reported a greater increase in withdrawal symptoms during the abstinent week [Δ = 9.4 (SE = 1.1); p < 0.001] than men [Δ = 1.2 (SE = 1.2); p = 0.35]. Sex differences in levels of the eCB N-arachidonoylethanolamide (AEA), as well as the eCB congeners stearoylethanolamide (SEA) and linoleylethanolamide (LEA), were evident during abstinence at the morning time point only (p's < 0.05). LEA was associated with withdrawal symptom expression in both sexes [ß = 0.16 (SE = 0.09)] and palmitoylethanolamide (PEA) [ß = 0.22 (SE = 0.13)] and 2-arachidonoylglycerol (2-AG) [ß = 0.32 (SE = 0.15)] were associated with withdrawal symptoms in women only. Pharmacotherapeutic development for CUD should consider evident sex differences in eCB and eCB congener tone during abstinence and their associations with cannabis withdrawal, as eCB-based interventions may produce differential effects by sex.

Differential prevalence of Adverse Childhood Experiences (ACEs) by gender and substance used in individuals with cannabis, cocaine, opioid, and tobacco use disorders.

Background: Adverse childhood experiences (ACEs) show a graded association with the development of substance use disorders (SUDs) and engagement in risky substance use behaviors. Women are overrepresented among individuals with more severe childhood adversity (≥4 types of ACEs) and may be at particular risk for aberrant substance use.Objectives: To assess the prevalence of ACEs among men and women with cannabis, opioid, cocaine, and tobacco use disorders.Methods: Non-treatment-seeking individuals participating in clinical addiction research at a single site completed the ACE questionnaire and provided a detailed substance use history. Data were analyzed using proportional odds models and logistic regression.Results: Most participants (424/565; 75%) reported at least one ACE, and more than one-quarter (156/565; 27%) reported severe childhood adversity. Relative to men (n = 283), women (n = 282) reported more ACEs (OR = 1.49; p = .01) and more experiences of emotional/physical abuse (OR = 1.52; p = .02), sexual abuse (OR = 4.08; p = .04), and neglect (OR = 2.30; p < .01). Participants in the cocaine (OR = 1.87; n = .01) and opioid (OR = 2.21; p = .01) use disorder, but not cannabis use disorder (OR = 1.46; p = .08), studies reported more severe adversity relative to the tobacco group. Relative to tobacco users, emotional/physical abuse (OR = 1.92; p = .02) and neglect (OR = 2.46; p = .01) scores were higher in cocaine users and household dysfunction scores were higher in opioid users (OR = 2.67; p = .01).Conclusion: The prevalence of ACEs differs with respect to both participant gender and primary substance used. Novel SUD treatment strategies that incorporate ACEs may be uniquely beneficial in specific subpopulations of people with SUDs.

A resource for automated search and collation of geochemical datasets from journal supplements.

This article presents a resource for automated search, extraction and collation of geochemical and geochronological data from the Figshare repository using web scraping code. To answer fundamental questions about the Earth's evolution, such as spatial and temporal evolution and interrelationships between the planet's solid and surficial reservoirs, researchers must utilize global geochemical datasets. Due to the volume of data being published, these datasets become quickly outdated. We present a resource that allows researchers to rapidly curate and update their own databases from existing published data. We use open-source Python code to web scrape the Figshare repository for journal supplementary files using the application programming interface, allowing for the collection and download of hundreds of supplementary files and metadata in minutes. Use of this web scraping tool is demonstrated here by collation of a zircon geochronology and chemistry database of >150,000 analyses. The database is consistent in reproducing trends in other published zircon compilations. Providing a resource for automated collection of Figshare data files will encourage data sharing and reuse.

Online survey of medicinal cannabis users: Qualitative analysis of patient-level data.

Aim: To characterize perceived benefits and challenges experienced by medicinal cannabis users. Methods: An anonymous online survey collected demographics, health information, and open-ended responses from medicinal cannabis users regarding perceptions, motivations, and experience of treatment. Qualitative open-ended responses were thematically analyzed. Results: Respondents (N = 808) were predominantly White (79%), female (63%), with a mean (SD) age of 38 (20). Two hundred eighty-four (35%) respondents provided data on a dependent family member (e.g., child; 22% of total sample). Most used cannabidiol (CBD)-dominant products (58%), primarily for neurological disorders (38%) or pain (25%). Primary motivations for medicinal cannabis use were based on beliefs that traditional treatments were ineffective and/or had intolerable side effects (51%), positive scientific or media portrayals of the safety/efficacy of cannabis as a therapeutic (29%), or preference for "natural" treatments over pharmaceuticals (21%). A majority of respondents (77%) attributed positive effects to the medicinal use of cannabis/cannabinoids. These included physical symptom improvements such as reduced pain (28%), improved sleep (18%), and seizure reduction (18%), and mental health improvements including reduced anxiety (22%) and improved mood (11%). Additionally, respondents reported reduced use of other medications (e.g., opioids) (12%), and improved quality of life (14%). Problems associated with use were cited by 41% of respondents, and included unwanted side effects (16%), lack of information or medical support (16%), prohibitive costs (12%), and legal concerns (10%). Conclusion: Most participants reported benefits from cannabis use for a variety of conditions where traditional treatments were ineffective or unacceptable. Concerns regarding cannabis side effects, legality, lack of information, and cost were raised. Data indicate greater research and education on the safety and efficacy of medicinal cannabis/cannabinoid use is warranted.

Urinary Excretion Profile of Cannabinoid Analytes Following Acute Administration of Oral and Vaporized Cannabis in Infrequent Cannabis Users.

Traditionally, smoking has been the predominant method for administering cannabis, but alternative routes of administration have become more prevalent. Additionally, research examining urinary cannabinoid excretion profiles has primarily focused on 11-nor-9-carboxy-∆9-tetrahydrocannabinol (∆9-THC-COOH), a metabolite of ∆9-tetrahydrocannabinol (∆9-THC), as the primary analyte. The aim of the current study was to characterize the urinary excretion profile of ∆9-THC-COOH, ∆9-THC, ∆8-tetrahydrocannabinol (∆8-THC), 11-hydroxy-∆9-tetrahydrocannabinol (11-OH-∆9-THC), ∆9-tetrahydrocannabivarin (THCV), 11-nor-∆9-tetrahydrocannabivarin-9-carboxlic acid (THCV-COOH), cannabidiol (CBD), cannabinol (CBN) and 8,11-dihydroxytetrahydrocannabinol (8,11-diOH-∆9-THC) following controlled administration of both oral and vaporized cannabis. Participants (n = 21, 11 men/10 women) who were infrequent cannabis users ingested cannabis-containing brownies (0, 10 and 25 mg ∆9-THC) and inhaled vaporized cannabis (0, 5 and 20 mg ∆9-THC) across six double-blind outpatient sessions. Urinary concentrations of ∆9-THC analytes were measured at baseline and for 8 h after cannabis administration. Sensitivity, specificity and agreement between the three immunoassays (IAs) for ∆9-THC-COOH (cutoffs of 20, 50 and 100 ng/mL) and liquid chromatography-tandem mass spectrometry (LC-MS-MS) analyses (confirmatory cutoff concentrations of 15 ng/mL) were assessed. Urinary concentrations for ∆9-THC-COOH, ∆9-THC, 11-OH-∆9-THC, THCV, CBN and 8,11-diOH-∆9-THC all peaked at 5-6 h and 4 h following oral and vaporized cannabis administration, respectively. At each active dose, median maximum concentrations (Cmax) for detected analytes were quantitatively higher after oral cannabis administration compared to vaporized. Using current recommended federal workplace drug-testing criteria (screening via IA with a cutoff of ≥50 ng/mL and confirmation via LC-MS-MS at a cutoff of ≥15 ng/mL), urine specimens tested positive for ∆9-THC-COOH in 97.6% of oral sessions and 59.5% of vaporized sessions with active ∆9-THC doses. These data indicate that while ∆9-THC-COOH may serve as the most consistent confirmatory analyte under the current drug-testing guidelines, future work examining 11-OH-∆9-THC under similar parameters could yield an alternative analyte that may be helpful in distinguishing between licit and illicit cannabis products.

Antidepressant and Anxiolytic Effects of Medicinal Cannabis Use in an Observational Trial.

Background: Anxiety and depressive disorders are highly prevalent. Patients are increasingly using medicinal cannabis products to treat these disorders, but little is known about the effects of medicinal cannabis use on symptoms of anxiety and depression. The aim of the present observational study was to assess general health in medicinal cannabis users and non-using controls with anxiety and/or depression. Methods: Participants (368 Cannabis Users; 170 Controls) completed an online survey assessing anxiety and depressive symptoms, cannabis product use, sleep, quality of life, and comorbid chronic pain. Participants that completed this baseline survey were then invited to complete additional follow-up surveys at 3-month intervals. Baseline differences between Cannabis Users and Controls were assessed using independent-samples t-tests and generalized linear mixed effects models were used to assess the impact of initiating cannabis product use, sustained use, or discontinuation of use on anxiety and depressive symptoms at follow-up. Results: Medicinal cannabis use was associated with lower self-reported depression, but not anxiety, at baseline. Medicinal cannabis users also reported superior sleep, quality of life, and less pain on average. Initiation of medicinal cannabis during the follow-up period was associated with significantly decreased anxiety and depressive symptoms, an effect that was not observed in Controls that never initiated cannabis use. Conclusions: Medicinal cannabis use may reduce anxiety and depressive symptoms in clinically anxious and depressed populations. Future placebo-controlled studies are necessary to replicate these findings and to determine the route of administration, dose, and product formulation characteristics to optimize clinical outcomes.

Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking.

Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α2-adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target ß-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neuroactive steroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.

Cross-sectional and longitudinal evaluation of cannabidiol (CBD) product use and health among people with epilepsy.

Recent approval of Epidiolex® (pharmaceutical cannabidiol/CBD) for the treatment of Lennox Gastaut syndrome (LGS) and Dravet syndrome highlights a therapeutic efficacy of CBD in the treatment of epilepsy. However, a large number of patients with epilepsy elect to use alternative artisanal CBD products due to cost or access constraints. Despite widespread availability and variety of these artisanal CBD products, studies evaluating their safety or efficacy are rare, making conclusions about clinical utility uncertain. The purpose of the present study was to evaluate cross-sectional and longitudinal associations of artisanal CBD product use with quality of life, mental health, healthcare utilization, and epilepsy-specific outcomes within a large, observational cohort of people with epilepsy. Participants who reported using artisanal CBD products at baseline (Artisanal CBD Users; n = 280) and participants who used no cannabis-based products (Controls; n = 138) completed web-based assessments evaluating psychiatric symptoms, healthcare utilization, and epilepsy-specific factors. Follow-up surveys were collected in a subset of participants (n = 190) following baseline assessment for longitudinal comparison. Cross-sectionally, higher quality of life, lower psychiatric symptom severity, and improved sleep were observed among Artisanal CBD Users at baseline compared with Controls. Initiation of artisanal CBD product use was also related to improved health outcomes longitudinally. No group differences were observed for seizure control, but both groups included a high number of individuals with no past month seizures. Artisanal CBD Users reported significantly better epilepsy medication tolerability, use of fewer prescription medications overall, and reduced healthcare utilization compared with Controls. These findings are consistent with research indicating that practitioners recommending CBD in clinical care for epilepsy report integrating the use of CBD both as a means to improve patient quality of life as well as for seizure control.

A Cross-Sectional and Prospective Comparison of Medicinal Cannabis Users and Controls on Self-Reported Health.

Introduction: Despite widespread legalization, the impact of medicinal cannabis use on patient-level health and quality of life (QOL) has not been carefully evaluated. The objective of this study was to characterize self-reported demographics, health characteristics, QOL, and health care utilization of Cannabis Users compared with Controls. Methods: A longitudinal, cross-sectional web-based survey study was completed between April 2016 and February 2018. Study participants (n=1276) were a convenience sample of either patients with a diagnosed health condition or caregivers of a patient with a diagnosed health condition registered with the Realm of Caring Foundation (a nonprofit organization dedicated to therapeutic cannabis research and education). Participants were invited through e-mail to complete follow-up assessments every 3 months with 33% of participants completing one or more prospective follow-ups. Assessments included self-reported demographics, health care utilization, medication use, pain, anxiety, depression, sleep, and QOL. Cannabis Users (n=808) were compared with Controls (n=468) using negative binomial regression and linear mixed effects models testing the effect of initiation, cessation, and maintenance of medicinal cannabis use. Results: Cannabis Users self-reported significantly better QOL [t(1054)=-4.19, p<0.001], greater health satisfaction [t(1045)=-4.14, p<0.001], improved sleep [children: t(224)=2.90, p<0.01; adults: [t(758)=3.03, p<0.01], lower average pain severity [t(1150)=2.34, p<0.05], lower anxiety [t(1151)=4.38, p<0.001], and lower depression [t(1210)=5.77, p<0.001] compared with Controls. Cannabis Users reported using fewer prescription medications (rate ratio [RR]=0.86; 95% confidence interval [CI]: 0.77-0.96) and were less likely to have a past-month emergency department visit (RR=0.61; 95% CI: 0.44-0.84) or hospital admission (RR=0.54; 95% CI: 0.34-0.87). Controls who initiated cannabis use after baseline showed significant health improvements at follow-up, and the magnitude of improvement mirrored the between-group differences observed at baseline. Conclusions: Cannabis use was associated with improved health and QOL. Longitudinal testing suggests that group differences may be due to the medicinal use of cannabis. Although bias related to preexisting beliefs regarding the health benefits of cannabis in this sample should be considered, these findings indicate that clinical trials evaluating the efficacy of defined cannabinoid products for specific health conditions are warranted.

Assessment of cognitive and psychomotor impairment, subjective effects, and blood THC concentrations following acute administration of oral and vaporized cannabis.

BACKGROUND: Cannabis legalization is expanding, but there are no established methods for detecting cannabis impairment. AIM: Characterize the acute impairing effects of oral and vaporized cannabis using various performance tests. METHODS: Participants (N = 20, 10 men/10 women) who were infrequent cannabis users ingested cannabis brownies (0, 10, and 25 mg Δ-9-tetrahydrocannabinol, THC) and inhaled vaporized cannabis (0, 5, and 20 mg THC) in six double-blind outpatient sessions. Cognitive/psychomotor impairment was assessed with a battery of computerized tasks sensitive to cannabis effects, a novel test (the DRiving Under the Influence of Drugs, DRUID®), and field sobriety tests. Blood THC concentrations and subjective drug effects were evaluated. RESULTS: Low oral/vaporized doses did not impair cognitive/psychomotor performance relative to placebo but produced positive subjective effects. High oral/vaporized doses impaired cognitive/psychomotor performance and increased positive and negative subjective effects. The DRUID® was the most sensitive test to cannabis impairment, as it detected significant differences between placebo and active doses within both routes of administration. Women displayed more impairment on the DRUID® than men at the high vaporized dose only. Field sobriety tests showed little sensitivity to cannabis-induced impairment. Blood THC concentrations were far lower after cannabis ingestion versus inhalation. After inhalation, blood THC concentrations typically returned to baseline well before pharmacodynamic effects subsided. CONCLUSIONS: Standard approaches for identifying impairment due to cannabis exposure (i.e. blood THC and field sobriety tests) have severe limitations. There is a need to identify novel biomarkers of cannabis exposure and/or behavioral tests like the DRUID® that can reliably and accurately detect cannabis impairment at the roadside and in the workplace.

Evidence for the Endocannabinoid System as a Therapeutic Target in the Treatment of Cannabis Use Disorder.

PURPOSE OF REVIEW: Cannabis use disorder (CUD) is highly prevalent. Psychotherapy alone is not adequately effective, with few individuals achieving abstinence. Pharmacotherapeutic supplementation may improve efficacy, and the endocannabinoid system presents a target specifically dysregulated by heavy cannabis use. This review compiles current literature evaluating endocannabinoid modulation as a treatment strategy for CUD, with implications for future research. RECENT FINDINGS: Cannabinoid receptor agonists have been found to reduce cannabis withdrawal symptoms without a notable effect on relapse, and antagonists can produce severe psychiatric symptoms. Fatty acid amide hydrolase inhibitors and cannabidiol demonstrate the most promising efficacy in treating CUD thus far, but research with these compounds is still preliminary. SUMMARY: Components of the endocannabinoid system may serve as unique treatment targets with differential efficacy for the treatment of cannabis use disorder as a whole. Further research is needed exploring novel methods for targeting endocannabinoid dysfunction in CUD.