Sleep time differs among people who co-use cocaine and cannabis compared to people who only use cocaine.

OBJECTIVE: People who use cocaine experience numerous sleep problems and often use cannabis to mitigate these problems. However, co-using cocaine and cannabis may result in worse sleep outcomes when compared to using cocaine only. The current study examined group differences in subjective sleep outcomes among people who use cocaine and people who co-use cocaine and cannabis. METHODS: Participants were 82 individuals with cocaine use disorder who were enrolled in a randomized clinical trial for cocaine treatment. Sleep outcomes, assessed at baseline prior to treatment, were measured with the Saint Mary's Hospital Sleep Questionnaire and included total sleep time, perceived sleep quality, difficulty falling asleep, and daytime alertness. Analysis of covariance and Kruskal-Wallis tests were used to compare sleep outcomes between participants with urine samples that tested positive for both cocaine and cannabis at baseline, those who tested positive for cocaine only, and those who tested negative for all drugs. RESULTS: Total reported sleep time was highest among those with a drug negative urine, followed by those with a cocaine positive urine and those who tested positive for cocaine and cannabis. There were no differences in perceived sleep quality, difficulty falling asleep, or daytime alertness between groups. CONCLUSIONS: People who co-use cocaine and cannabis may report reduced sleep time relative to those who only use cocaine. Co-use of cannabis may exacerbate sleep difficulties in people who use cocaine by decreasing total sleep time, although it is important to note that the groups each reported similar sleep quality. Implications for treatment and directions for future research are discussed.

Investigation on the consumption of synthetic cannabinoids among teenagers by the analysis of herbal blends and urine samples.

The use of synthetic cannabinoids (SCs), which escape conventional detection systems, may be a good alternative to elude routine drug analysis for cannabis. The detection of these drugs in urine is unusual due to their complete and fast metabolism, therefore requiring alternative strategies. In this work, an investigation has been made on SCs consumption by minors (less than 18 years old) in juvenile offenders' centres. 667 urine samples (from 127 minors) were collected after their permits with stay at home. We also studied the SCs from 7 herbal blends available at the smartshop frequented by the minors. Both, urine and herbal blends, were analysed by liquid chromatography coupled to high resolution mass spectrometry. The analysis of urine confirmed the absence of more than 200 SCs investigated. Thus, the focus was made on metabolites reported for those SCs identified in the herbal blends collected from the smart-shop. The major metabolites of XLR-11 and UR-144 (N-pentanoic acid and N-(5-hydroxypentyl)) were found in several urine samples. Apart from the main metabolites included in the initial searching, a thorough investigation of more metabolites for these SCs was additionally performed, including MS/MS experiments for the tentative identification of compounds detected in the urine samples. The 16 samples positive to the XLR-11 metabolites were assigned to 6 minors, only 2 of which had recognized consumption. On the basis of the results obtained, preventive and therapeutic interventions must be implemented to reduce the consumption of psychoactive substances and to improve the risk-perception of these substances by minors.

Using Sesame Seed Oil to Preserve and Preconcentrate Cannabinoids for Paper Spray Mass Spectrometry.

Cannabinoids present a unique set of analytical challenges. An increasing number of states have voted to decriminalize recreational marijuana use, creating a need for new kinds of rapid testing. At the same time, synthetic compounds with activity similar to THC, termed synthetic cannabinoids, have become more prevalent and pose significant health risks. A rapid method capable of detecting both natural and synthetic cannabinoids would be useful in cases of driving under the influence of drugs, where it might not be obvious whether the suspect consumed marijuana, a synthetic cannabinoid, or both. Paper spray mass spectrometry is an ambient ionization technique which allows for the direct ionization of analyte from a biofluid spot on a piece of paper. Natural cannabinoids like THC, however, are labile and rapidly disappear from dried sample spots, making it difficult to detect them at clinically relevant levels. Presented here is a method to concentrate and preserve THC and synthetic cannabinoids in urine and oral fluid on paper for analysis by paper spray mass spectrometry. Sesame seed oil was investigated both as a means of preserving THC and as part of a technique, termed paper strip extraction, wherein urine or oral fluid is flowed through an oil spot on a strip of paper to preconcentrate cannabinoids. This technique preserved THC in dried biofluid samples for at least 27 days at room temperature; paper spray MS/MS analysis of these preserved dried spots was capable of detecting THC and synthetic cannabinoids at low ng/mL concentrations, making it suitable as a rapid screening technique. The technique was adapted to be used with a commercially available autosampler.

Interest of adjusting urine cannabinoids to creatinine level to monitor cannabis cessation therapy in heavy smokers with psychiatric disorders.

Up to 25% of hospitalized patients in a psychiatric department exhibit troubles linked to cannabis use. Weaning patients with psychiatric disorders off drugs of abuse requires specific care to improve their clinical outcome. The present study aims to develop a predictive model of urinary excretion of creatinine-normalized cannabinoids (UCNC ) and to determine UCNC thresholds corresponding to the widely used cut-offs of 20 ng/mL and 50 ng/mL for cannabinoids. One hundred thirty-two patients with 452 urine samples were included between 2013 and 2017. Urinary cannabinoids and UCNC elimination curves were computed for each patient. Using a mono-exponential mixed effect model with 88 samples from 26 subjects exhibiting at least 3 decreasing UCNC in a row, the average calculated elimination rate constant was 0.0108 ± 0.0026 h-1 , corresponding to a mean elimination half-life of 64 ± 12 hours. The use of UCNC is of particular interest because of a high inter- and intra-individual variability of urinary creatinine concentration (from 0.06 to 3.81 mg/mL). Moreover, UCNC allows for the detection of diluted or concentrated urine specimens that may lead to false positive (FP) or false negative (FN) results. Receiver operator characteristic (ROC) curves were used to assess UCNC thresholds of 32.4 and 124.7 ng/mg that provide a strong discrimination between positive and negative samples for cannabinoids cut-offs of 20 and 50 ng/mL respectively. The developed model and the defined UCNC thresholds allowed for the accurate prediction of the time needed to reach a negative UCNC result that could be used by clinicians to optimize clinical care.

Evaluating novel silica hydride-based stationary phases for the analysis of phytocannabinoids and other psychoactive drugs.

Three silica hydride based novel chromatographic phases chemically-bonded with allyloxy-DL-alpha-tocopherol, allylpentafluorophenyl, and 1-eicosene moieties were evaluated as separation media for selected phytocannabinoids and other substances of abuse. In order to assess column selectivity, a series of reference standards was analyzed and detected by using liquid chromatography with mass spectrometry. Further, quantitative detections of cannabidiol and tetrahydrocannabinol were attempted for the extracts of cannabis plants and cannabidiol gummy formulation. For potential bioanalytical applications, the columns were evaluated for substance screening in a human urine matrix. In summary, the newly developed columns are functional and effective for the analysis of phytocannabinoids and various psychoactive drugs with or without the presence of biological matrices.

Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.

Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child's seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of samples rated by families as "effective" versus those rated "ineffective". Results showed that children given cannabis extracts tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. There was high variability in the cannabinoid content and profile of cannabis extracts rated as "effective", with no clear differences between extracts perceived as "effective" and "ineffective". Contrary to family's expectations, most samples contained low concentrations of cannabidiol, while Δ9-tetrahydrocannabinol was present in nearly every sample. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy.

Biological correlates of self-reported new and continued abstinence in cannabis cessation treatment clinical trials.

BACKGROUND: The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence. METHODS: Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials. RESULTS: Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component. CONCLUSION: Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement.

Predictive Value of Positive Drug Screening Results in an Urban Outpatient Population.

Urine drug testing (UDT) has become an essential component in the management of patients prescribed opioid analgesics for the treatment of chronic non-malignant pain. Several laboratory methods are available to monitor adherence with the pharmacological regimen and abstinence from illicit or unauthorized medications. Immunochemical screening methods are rapid and economical, but they have limitations, including lack of specificity, and confirmatory methods are often necessary to verify presumptive positive results. We analyzed the results of confirmatory assays in an outpatient setting to determine the predictive value of presumptive positive urine drug screen results using an automated immunoassay for eight common drugs or drug classes. Positive predictive values (PPVs), in descending order, were as follows: cannabinoids (100%), cocaine (100%), opiates (86.8%), benzodiazepines (74.6%), oxycodone (67.6%), methadone (44.1%) and amphetamines (9.3%). The number of positive barbiturate results was too small to be included in the statistical analysis.

In Vitro and In Vivo Human Metabolism of Synthetic Cannabinoids FDU-PB-22 and FUB-PB-22.

In 2014, FDU-PB-22 and FUB-PB-22, two novel synthetic cannabinoids, were detected in herbal blends in Japan, Russia, and Germany and were quickly added to their scheduled drugs list. Unfortunately, no human metabolism data are currently available, making it challenging to confirm their intake. The present study aims to identify appropriate analytical markers by investigating FDU-PB-22 and FUB-PB-22 metabolism in human hepatocytes and confirm the results in authentic urine specimens. For metabolic stability, 1 µM FDU-PB-22 and FUB-PB-22 was incubated with human liver microsomes for up to 1 h; for metabolite profiling, 10 µM was incubated with human hepatocytes for 3 h. Two authentic urine specimens from FDU-PB-22 and FUB-PB-22 positive cases were analyzed after ß-glucuronidase hydrolysis. Metabolite identification in hepatocyte samples and urine specimens was accomplished by high-resolution mass spectrometry using information-dependent acquisition. Both FDU-PB-22 and FUB-PB-22 were rapidly metabolized in HLM with half-lives of 12.4 and 11.5 min, respectively. In human hepatocyte samples, we identified seven metabolites for both compounds, generated by ester hydrolysis and further hydroxylation and/or glucuronidation. After ester hydrolysis, FDU-PB-22 and FUB-PB-22 yielded the same metabolite M7, fluorobenzylindole-3-carboxylic acid (FBI-COOH). M7 and M6 (hydroxylated FBI-COOH) were the major metabolites. In authentic urine specimens after ß-glucuronidase hydrolysis, M6 and M7 also were the predominant metabolites. Based on our study, we recommend M6 (hydroxylated FBI-COOH) and M7 (FBI-COOH) as suitable urinary markers for documenting FDU-PB-22 and/or FUB-PB-22 intake.

Gender-specific predictors of retention and opioid abstinence during methadone maintenance treatment.

AIMS: Retention in methadone maintenance treatment (MMT) for 1 year is associated with positive outcomes including opioid abstinence, however, most studies have not investigated gender differences. We hypothesized that predictors of retention and opioid abstinence would differ between men and women, and aimed to determine which factors best predict retention and abstinence for each gender. METHODS: Data were available for 290 patients (173 M, 117 F) admitted to outpatient MMT. Regression analyses, stratified by gender, were conducted to identify unique predictors of MMT retention (<1 vs. >1 year) and opioid abstinence rate (proportion of opioid-free urine samples up to 1 year retention). RESULTS: Gender did not significantly predict treatment retention (mean = 231 days, 39% retained > 1 year) or opioid abstinence (49% overall). For males, significant predictors of > 1-year retention were urine samples negative for opioids (odds ratio [OR] = 6.67) and cannabinoids (OR = 5.00) during the first month, and not cocaine dependent (OR = 2.70). Significant predictors of higher long-term opioid abstinence were first-month urine samples negative for opioids and cocaine metabolites. For females, significant predictors of >1-year retention were first-month urine samples negative for cocaine metabolites (OR = 4.00) and cannabinoids (OR = 9.26), and no history of sexual victimization (OR = 3.03). The only significant predictor of higher opioid abstinence rate was first-month opioid-free urine samples. CONCLUSIONS: These findings indicate gender-specific predictors of MMT retention and opioid abstinence. Future studies on MMT outcomes should examine each gender separately, and consider unique pathways by which females and males adhere to, and benefit from MMT.

Cognitive performance in a placebo-controlled pharmacotherapy trial for youth with marijuana dependence.

BACKGROUND: Adolescent marijuana use is associated with neurocognitive impairment, but further work is needed to assess the relationship between treatment-associated abstinence and cognitive performance. METHODS: This secondary analysis, conducted in the context of a marijuana cessation pharmacotherapy trial in adolescents, examined cognitive performance at baseline and at two time points during treatment using the CNS Vital Signs assessment battery. RESULTS: Abstinence from marijuana, relative to continued use, as assessed via urine cannabinoid testing, was associated with significant improvement in composite memory (p<0.001), verbal memory (the most impacted component of composite memory) (p<0.001), and psychomotor performance (p=0.045) scores. CONCLUSIONS: These findings suggest that some domains of cognitive performance improve significantly even in the early stages of treatment-associated abstinence.

A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents.

OBJECTIVE: Preclinical findings suggest that the over-the-counter supplement N-acetylcysteine (NAC), via glutamate modulation in the nucleus accumbens, holds promise as a pharmacotherapy for substance dependence. The authors investigated NAC as a novel cannabis cessation treatment in adolescents, a vulnerable group for whom existing treatments have shown limited efficacy. METHOD: In an 8-week double-blind randomized placebo-controlled trial, treatment-seeking cannabis-dependent adolescents (ages 15-21 years; N=116) received NAC (1200 mg) or placebo twice daily as well as a contingency management intervention and brief (<10 minutes) weekly cessation counseling. The primary efficacy measure was the odds of negative weekly urine cannabinoid test results during treatment among participants receiving NAC compared with those receiving placebo, in an intent-to-treat analysis. The primary tolerability measure was frequency of adverse events, compared by treatment group. RESULTS: Participants receiving NAC had more than twice the odds, compared with those receiving placebo, of having negative urine cannabinoid test results during treatment (odds ratio=2.4, 95% CI=1.1-5.2). Exploratory secondary abstinence outcomes favored NAC but were not statistically significant. NAC was well tolerated, with minimal adverse events. CONCLUSIONS: This is the first randomized controlled trial of pharmacotherapy for cannabis dependence in any age group to yield a positive primary cessation outcome in an intent-to-treat analysis. Findings support NAC as a pharmacotherapy to complement psychosocial treatment for cannabis dependence in adolescents.

Spice: a new "legal" herbal mixture abused by young active duty military personnel.

Spice is an herbal mixture smoked for euphoria and mixed with synthetic cannabinoids that are undetected on urine drug screens. Spice use has increased in the military because it is considered legal and is not detected on urine drug screen. The authors describe 3 cases of Spice use in military members. Case 1: 19-year-old male presented with paranoia, agitation, and visual hallucinations after smoking the "Space" brand of Spice. Urine thin-layer chromatography (TLC) and gas chromatography-mass spectrometry (GC-MS) were negative. Case 2: 19-year-old female presented with sedation, amnesia, and agitation. She smoked the "Space" brand. She was alert within 3 hours of arrival. Urine GC-MS detected levorphanol. Case 3: 23-year-old male presented with delusions and paranoia. He complained of "monsters on his back." His symptoms improved in the emergency department (ED). His urine TLC and GC-MS were negative. All cases were admitted and evaluated by a toxicologist; all 3 had their history corroborated by family or friends, or with drug paraphernalia. Spice is a new herbal mixture that is increasingly used in the military. Expected effects are similar to cannabis, but may include more paranoia and hallucinations, and may differ for each brand.

Identification of the major urinary metabolites in man of seven synthetic cannabinoids of the aminoalkylindole type present as adulterants in 'herbal mixtures' using LC-MS/MS techniques.

Herbal mixtures, such as 'Spice', containing cannabimimetic compounds are easily available on the Internet and have become increasingly popular among people having to undergo urine drug testing, as these compounds are not detected by current immunochemical tests. For analysis of urine samples, knowledge of the main metabolites is necessary as the unchanged compounds are usually not found in urine after consumption. In this paper, the identification of the major metabolites of the currently most common seven synthetic cannabinoids is presented. Urine samples from patients of psychiatric facilities known to have consumed synthetic cannabinoids were screened by LC-MS/MS and HR-MS/MS techniques, and the major metabolites for each of the following synthetic cannabinoids were identified by their enhanced product ion spectra and accurate mass measurement: JWH-018, JWH-073, JWH-081, JWH-122, JWH-210, JWH-250 and RCS-4. The major metabolic pathway is monohydroxylation either at the N-alkyl side chain, the naphthyl moiety or the indole moiety. In addition, metabolites with carboxylated alkyl chains were identified for some of the compounds. These results facilitate the design of urine screening methods for detecting consumption of synthetic cannabinoids.

Cannabinoid hyperemesis syndrome: an underreported entity causing nausea and vomiting of pregnancy.

INTRODUCTION: In the western world, cannabis is the most widely used drug of abuse. Cannabinoid hyperemesis syndrome, which seems to be a rare paradoxical reaction in individuals with a particular predisposition, is characterized by cyclic severe nausea and vomiting in long-term cannabis users. While the symptoms are unresponsive to antiemetic drugs, compulsive hot baths result in a considerable symptom relief. METHODS: We report the first case of cannabinoid hyperemesis syndrome in pregnancy. A 26-year-old patient was admitted to our clinic in the 10th week of gestation. CONCLUSION: Before undertaking time-consuming and expensive medical examinations to rule out other medical reasons for therapy-resistant hyperemesis in pregnancy, obstetricians should determine whether compulsive bathing or showering provides symptomatic relief and ask specific questions regarding possible/suspected cannabis consumption.

A placebo-controlled trial of buspirone for the treatment of marijuana dependence.

The present study investigated the potential efficacy of buspirone for treating marijuana dependence. Participants received either buspirone (maximum 60mg/day) (n=23) or matching placebo (n=27) for 12 weeks, each in conjunction with motivational interviewing. In the modified intention-to-treat analysis, the percentage of negative UDS results in the buspirone-treatment group was 18 percentage points higher than the placebo-treatment group (95% CI: -2% to 37%, p=0.071). On self-report, participants receiving buspirone reported not using marijuana 45.2% of days and participants receiving placebo reported not using 51.4% of days (p=0.55). An analysis of participants that completed the 12-week trial showed a significant difference in the percentage negative UDS (95% CI: 7-63%, p=0.014) and a trend for participants randomized to the buspirone-treatment group who completed treatment to achieve the first negative UDS result sooner than those participants treated with placebo (p=0.054). Further study with buspirone in this population may be warranted; however, strategies to enhance study retention and improve outcome measurement should be considered in future trials.

Sensitivity and specificity of urinary cannabinoid detection with two immunoassays after controlled oral administration of cannabinoids to humans.

For forensic and clinical toxicologic purposes, cannabis consumption is screened using easy-to-handle immunoassays. The sensitivity and specificity of these immunoassays have not yet been established in samples from volunteers receiving oral synthetic tetrahydrocannabinol or cannabis extracts using liquid chromatography-mass spectrometry/mass spectrometry as the reference method. Urine samples were collected in an open, randomized, single-center, three-period crossover study including 18 healthy male volunteers given either 20 mg synthetic tetrahydrocannabinol (Marinol) as a control substance or five different types of Cannabis sativa extracts.

Development of a LC/MS/MS method for the analysis of cannabinoids in human EDTA-plasma and urine after small doses of Cannabis sativa extracts.

A novel high-performance liquid chromatographic separation method with tandem-mass spectrometry detection was developed for the simultaneous determination of Delta(9)-tetrahydrocannabinol (THC) and its major metabolites 11-hydroxy-Delta(9)-tetrahydrocannabinol (11-OH-THC) and 11-nor-Delta(9)-tetrahydrocannabinol-9-carboxylic acid (THC-COOH) as well as the components cannabidiol (CBD) and cannabinol (CBN) in human EDTA-plasma and urine. Run time was 25 min. Lower limit of quantification was 0.2 ng/ml. The coefficients of variation of all inter- and intra-assay determinations were between 1.3 and 15.5%. The method was successfully applied to the determination of cannabinoids in human plasma and human urine after administration of Delta(9)-tetrahydrocannabinol or Cannabis sativa extracts.

The construct and predictive validity of different approaches to combining urine and self-reported drug use measures among older adolescents after substance abuse treatment.

Reconciling urine results and self-reports is a classic challenge in substance abuse treatment research in general. For adolescents, the problems are compounded by the facts that they are more likely to use marijuana (which takes longer to metabolize) and to be coerced into treatment (which may increase lying). This article examines the construct and predictive validity of several different approaches for combining urine and self reported drug use including using common individual measures (urine tests and self-reported recency, frequency, and peak use), taking either as positive, using a summary scale, and using a latent model. Data are from 819 older adolescents 24 to 42 months after intake in seven sites. Days of use, the GAIN's substance frequency scale, and a latent model were the three best methods in terms of construct and predictive validity. Implications for treatment and longitudinal evaluation will be discussed.