Peripheral endocannabinoids in major depressive disorder and alcohol use disorder: a systematic review.

BACKGROUND: Major Depressive Disorder (MDD) and Alcohol Use Disorder (AUD) are two high-prevalent conditions where the Endocannabinoid system (ECS) is believed to play an important role. The ECS regulates how different neurotransmitters interact in both disorders, which is crucial for controlling emotions and responses to stress and reward stimuli. Measuring peripheral endocannabinoids (eCBs) in human serum and plasma can help overcome the limitations of detecting endocannabinoid levels in the brain. This systematic review aims to identify levels of peripheral eCBs in patients with MDD and/or AUD and find eCBs to use as diagnostic, prognostic biomarkers, and potential therapeutic targets. METHODS: We conducted a systematic literature search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines from the earliest manuscript until October 22, 2023, in three electronic databases. We included studies of human adults who had a current diagnosis of AUD and/or MDD and evaluated plasma or serum endocannabinoids. We carefully considered known variables that may affect endocannabinoid levels. RESULTS: We included 17 articles in this systematic review, which measured peripheral eCBs in 170 AUD and 359 MDD patients. Stressors increase peripheral 2-arachidonyl-glycerol (2-AG) concentrations, and 2-AG may be a particular feature of depression severity and chronicity. Anxiety symptoms are negatively correlated with anandamide (AEA) concentrations, and AEA significantly increases during early abstinence in AUD. Studies suggest a negative correlation between Oleoylethanolamide (OEA) and length of abstinence in AUD patients. They also show a significant negative correlation between peripheral levels of AEA and OEA and fatty acid amide hydrolase (FAAH) activity. Eicosapentaenoylethanolamide (EPEA) is correlated to clinical remission rates in depression. Included studies show known variables such as gender, chronicity, symptom severity, comorbid psychiatric symptoms, length of abstinence in the case of AUD, and stress-inducibility that can affect peripheral eCBs. CONCLUSIONS: This systematic review highlights the important role that the ECS plays in MDD and AUD. Peripheral eCBs appear to be useful biomarkers for these disorders, and further research may identify potential therapeutic targets. Using accessible biological samples such as blood in well-designed clinical studies is crucial to develop novel therapies for these disorders.

Clinical impact of COVID-19 on people with substance use disorders.

BACKGROUND: People with substance use disorders are considered at increased risk of COVID-19 and its more serious complications, however data on the impact of COVID-19 are lacking. The study aimed to describe the clinical characteristics and outcomes of COVID-19 on people with substance use disorders. METHODS: an observational study was carried out including patients aged ≥ years with COVID-19 pneumonia admitted to an urban hospital during March 12 to June 21,2020. RESULTS: Among 2078 patients admitted, 27 (1.3%) were people with substance use disorders: 23(85.2%) were men with a median age of 56.1 + 10.3 years and. The main SUD were alcohol in 18(66.7%) patients, heroine in 6(22.2%) and cocaine in 3(11.1%) and 24(88.8%) patients were on ongoing substance use disorder treatment. One or more comorbidities associated to COVID-19 risk were observed in 18(66.6%) of patients. During a median length of stay of 10 days (IQR:7-19), severe pneumonia developed in 7(25.9%) patients, acute respiratory distress syndrome in 5 (18.5%) and none died. CONCLUSION: Larger sample sizes and sero-epidemiological studies are needed to confirm the low incidence of severe COVID-19 on patients with SUD.

Trends in AIDS Mortality, Retention in Opioid Agonist Therapy, and HIV RNA Suppression in HIV-Infected People Who Injected Drugs from 2000 to 2015.

AIDS is a major cause of preventable mortality in HIV-infected people who inject drugs (HIV-PWID). An observational study was conducted to examine trends in AIDS mortality and related factors among HIV-infected individuals who died between 2000 and 2015 at an urban hospital. Overall HIV-mortality was 6.5% (413/6307) with no changes over time (p 0.76). AIDS mortality dropped in HIV-PWID (p 0.02) although it represented 26.4% at the end of study period. Age (per one-year increase) [odds ratio (OR) 0.95], third study period (2010-2015) (OR 0.54), HIV-PWID on opioid agonist therapy (OAT) (OR 0.39), and HIV RNA suppression (OR 0.15) were associated with AIDS mortality. OAT was reported in 58.3% (161/276) and RNA suppression in 30.9% (85/276) of HIV-PWID. OAT non-retention was due to drop-outs [85.2% (98/115)] and rejection [14.8% (17/115)] in HIV-PWID. Therefore, additional strategies are required to improve OAT retention and HIV RNA suppression to continue reducing AIDS mortality.

Quality of life in a community sample of young cocaine and/or heroin users: the role of mental disorders.

PURPOSE: Drug addiction and psychiatric disorders are frequently concomitant; however, few studies have investigated the impact of psychiatric disorders other than substance use disorder (SUD) on health-related quality of life (HRQoL) in drug users not in treatment. We studied the association of psychiatric disorders other than SUD with HRQoL in a street-recruited sample of cocaine and/or heroin users. METHODS: It is a cross-sectional study involving 287 young users of cocaine and/or heroin in Barcelona, Spain. HRQoL was assessed with the Nottingham health profile (NHP). Patterns of drug use and mental disorders were assessed using the Spanish version of the psychiatric research interview for substance and mental disorders IV, and degree of dependence through the severity of dependence scale (SDS). The association of mental disorders with HRQoL was assessed through a Tobit regression analysis. RESULTS: The overall NHP score was 23.9 (SD = 20.5, range 0-91.7). Sixty-one percent of the sample had two or more SUDs; 22 % had at least one non-SUD Axis I disorder (anxiety, mood, psychotic, or eating disorder); and 27.2 % had a borderline personality disorder (BPD) and/or antisocial personality disorder. Variables negatively associated with the global NHP score were psychosis [transformed beta coefficient: 15.23; 95 % confidence interval [CI] 4.48-25.97], BPD (9.55; 95 % CI 2.95-16.15), severity of dependence (8.12; 95 % CI 3.37-12.87), having two or more SUDs (for two or three SUDs: 6.83; 95 % CI 2.08-11.59) (>3 SUDs: 7.70; 95 % CI 1.72-13.68) and the intravenous use of some substance (10.20; 95 % CI 6.00-14.40). CONCLUSION: HRQoL among street-recruited illegal substance users was impaired, particularly among those with psychiatric comorbidity, psychosis, and BPD being especially relevant.

CANreduce-SP-adding psychological support to web-based adherence-focused guided self-help for cannabis users: study protocol for a three-arm randomized control trial.

BACKGROUND: Cannabis is the most-frequently used illicit drug in Europe. Over the last few years in Spain, treatment demand has increased, yet most cannabis users do not seek treatment despite the related problems. A web-based self-help tool, like CANreduce 2.0, could help these users to control their consumption. METHODS: This study protocol describes a three-arm randomized controlled trial (RCT) comparing the effectiveness of three approaches, in terms of reducing cannabis use among problematic cannabis users, the first two treatment arms including the Spanish version of CANreduce 2.0 (an adherence-focused, guidance-enhanced, web-based self-help tool) (1) with and (2) without psychological support; and the third group (3) treatment as usual (TAU). Study hypotheses will be tested concerning the primary outcome: change in the number of days of cannabis use over the previous week, comparing assessments at 6 weeks and 3 and 6 months follow-up between groups and against baseline. Secondary outcomes related to cannabis use will be tested similarly. Mental disorders will be explored as predictors of adherence and outcomes. Analyses will be performed on an intention-to-treat basis, then verified by complete case analyses. DISCUSSION: This study will test how effective the Spanish version of CANreduce 2.0 (CANreduce-SP) is at reducing both the frequency and quantity of cannabis use in problematic users and whether adding psychological support increases its effectiveness. TRIAL REGISTRATION: This trial is registered with the Clinical Trials Protocol Registration and Results System (PRS) number: NCT04517474 . Registered 18 August 2020, (Archived by archive.is https://archive.is/N1Y64 ). The project commenced in November 2020 and recruitment is anticipated to end by November 2022.

Clinical guideline for the treatment of dual pathology in the adult population.

Editorial del vol 28-1.

Protocol for The International Cohort on Lifestyle Determinants of Health Study: A Longitudinal Investigation of Complementary and Integrative Health Utilization in Postsecondary Education Students.

Objectives: The specific aims are: 1) To characterize the health, wellness, and lifestyle of graduate and undergraduate students, and how these characteristics change over time; 2) To evaluate associations between lifestyle factors and gut microbiota populations and diversity; and 3) To evaluate associations between stress and stress management practices with sleep habits, quality of life, and overall health. Design: The International Cohort on Lifestyle Determinants of Health (INCLD Health) longitudinal cohort study is designed to assess health behaviors and lifestyle practices amongst adults studying complementary and integrative health (CIH) and higher-education students more generally after at least one to six years of exposure to CIH education. INCLD Health will adhere to the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines. Settings/Location: Colleges and universities with a CIH focus or interest with the flagship site being the National University of Natural Medicine. Participants: Adults currently enrolled in a college or university with a CIH focus or interest. Outcome Measures: Study visits will be conducted at baseline, 6 months, then every 12 months until the end of each participants' degree program. Measures include anthropometrics; serum and salivary biomarkers of cardiovascular risk, reproductive hormones, and cortisol; nutritional intake measured by a digital food frequency questionnaire; sequencing of fecal microbiota; plus validated questionnaires investigating mood, perceived stress, stress management practices, physical activity, sleep, and wellness. Conclusions: The INCLD Health Study, approved by the NUNM IRB in late 2018, will enroll a unique cohort of adults to characterize the use of CIH practices in relation to short- and long-term health. Our study design provides a breadth of information that could be implemented at multiple sites internationally allowing for comparisons across diverse student cohorts with relatively low cost and personnel.

Gamma knife output factor measurements using VIP polymer gel dosimetry.

PURPOSE: Water equivalent polymer gel dosimeters and magnetic resonance imaging were employed to measure the output factors of the two smallest treatment fields available in a Gamma Knife model C radiosurgery unit, those formed employing the 4 and 8 mm final collimator helmets. METHODS: Three samples of the VIP normoxic gel formulation were prepared and irradiated so that a single shot of the field whose output factor is to be measured and a single shot of the reference 18 mm field were delivered in each one. Emphasis is given to the development and benchmarking of a refined data processing methodology of reduced uncertainty that fully exploits the 3D dose distributions registered in the dosimeters. RESULTS: Polymer gel results for the output factor of the 8 mm collimator helmet are found to be in close agreement with the corresponding value recommended by the vendor (0.955 +/- 0.007 versus 0.956, respectively). For the 4 mm collimator helmet, however, polymer gel results suggest an output factor 3% lower than the value recommended by the vendor (0.841 +/- 0.009 versus 0.870, respectively). CONCLUSIONS: A comparison with corresponding measurements published in the literature indicates that output factor results of this work are in agreement with those obtained using dosimetric systems which, besides fine spatial resolution and lack of angular and dose rate dependence of the dosimeter's response, share with polymer gels the favorable characteristic of minimal radiation field perturbation.

Key interindividual determinants in MDMA pharmacodynamics.

INTRODUCTION: MDMA, 3,4-methylenedioxymethamphetamine, is a synthetic phenethylamine derivative with structural and pharmacological similarities to both amphetamines and mescaline. MDMA produces characteristic amphetamine-like actions (euphoria, well-being), increases empathy, and induces pro-social effects that seem to motivate its recreational consumption and provide a basis for its potential therapeutic use. Areas covered: The aim of this review is to present the main interindividual determinants in MDMA pharmacodynamics. The principal sources of pharmacodynamic variability are reviewed, with special emphasis on sex-gender, race-ethnicity, genetic differences, interactions, and MDMA acute toxicity, as well as possible therapeutic use. Expert opinion: Acute MDMA effects are more pronounced in women than they are in men. Very limited data on the relationship between race-ethnicity and MDMA effects are available. MDMA metabolism includes some polymorphic enzymes that can slightly modify plasma concentrations and effects. Although a considerable number of studies exist about the acute effects of MDMA, the small number of subjects in each trial limits evaluation of the different interindividual factors and does not permit a clear conclusion about their influence. These issues should be considered when studying possible MDMA therapeutic use.

Psychiatric comorbidity in young heroin users.

In order to determine the prevalence of psychiatric comorbidity in a population of young heroin users recruited from outside of the healthcare context, a sample was assembled by targeted sampling and nomination techniques; it was comprised of regular current users of heroin aged between 18 and 30 years and resident in Barcelona, Spain. Psychiatric evaluation was done with the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) semi-structured interview. Of 149 individuals evaluated, 33% were women, whose mean age was 25.1 years; 93% received a diagnosis of heroin dependence and 71% of cocaine dependence. Thirty-two percent of the subjects had never been treated for substance use. Around two-thirds (67.1%, 95% CI: 59.6-74.7%) of the sample had lifetime psychiatric comorbidity, with antisocial personality and mood disorders being the most frequent conditions (33% and 26%, respectively). Mood, anxiety and eating disorders were more common among women than men. There were no differences in ever having been in treatment for drug use according to the presence of psychiatric comorbidity, although comorbidity was lower among those currently in treatment. Young heroin users recruited on the street presented a high prevalence of psychiatric comorbidity which was unrelated to past treatment history.

On the development of a comprehensive MC simulation model for the Gamma Knife Perfexion radiosurgery unit.

This work presents a comprehensive Monte Carlo (MC) simulation model for the Gamma Knife Perfexion (PFX) radiosurgery unit. Model-based dosimetry calculations were benchmarked in terms of relative dose profiles (RDPs) and output factors (OFs), against corresponding EBT2 measurements. To reduce the rather prolonged computational time associated with the comprehensive PFX model MC simulations, two approximations were explored and evaluated on the grounds of dosimetric accuracy. The first consists in directional biasing of the (60)Co photon emission while the second refers to the implementation of simplified source geometric models. The effect of the dose scoring volume dimensions in OF calculations accuracy was also explored. RDP calculations for the comprehensive PFX model were found to be in agreement with corresponding EBT2 measurements. Output factors of 0.819 ± 0.004 and 0.8941 ± 0.0013 were calculated for the 4 mm and 8 mm collimator, respectively, which agree, within uncertainties, with corresponding EBT2 measurements and published experimental data. Volume averaging was found to affect OF results by more than 0.3% for scoring volume radii greater than 0.5 mm and 1.4 mm for the 4 mm and 8 mm collimators, respectively. Directional biasing of photon emission resulted in a time efficiency gain factor of up to 210 with respect to the isotropic photon emission. Although no considerable effect on relative dose profiles was detected, directional biasing led to OF overestimations which were more pronounced for the 4 mm collimator and increased with decreasing emission cone half-angle, reaching up to 6% for a 5° angle. Implementation of simplified source models revealed that omitting the sources' stainless steel capsule significantly affects both OF results and relative dose profiles, while the aluminum-based bushing did not exhibit considerable dosimetric effect. In conclusion, the results of this work suggest that any PFX simulation model should be benchmarked in terms of both RDP and OF results.

Three-dimensional dose verification of the clinical application of gamma knife stereotactic radiosurgery using polymer gel and MRI.

This work seeks to verify multi-shot clinical applications of stereotactic radiosurgery with a Leksell Gamma Knife model C unit employing a polymer gel-MRI based experimental procedure, which has already been shown to be capable of verifying the precision and accuracy of dose delivery in single-shot gamma knife applications. The treatment plan studied in the present work resembles a clinical treatment case of pituitary adenoma using four 8 mm and one 14 mm collimator helmet shots to deliver a prescription dose of 15 Gy to the 50% isodose line (30 Gy maximum dose). For the experimental dose verification of the treatment plan, the same criteria as those used in the clinical treatment planning evaluation were employed. These included comparison of measured and GammaPlan calculated data, in terms of percentage isodose contours on axial, coronal and sagittal planes, as well as 3D plan evaluation criteria such as dose-volume histograms for the target volume, target coverage and conformity indices. Measured percentage isodose contours compared favourably with calculated ones despite individual point fluctuations at low dose contours (e.g., 20%) mainly due to the effect of T2 measurement uncertainty on dose resolution. Dose-volume histogram data were also found in a good agreement while the experimental results for the percentage target coverage and conformity index were 94% and 1.17 relative to corresponding GammaPlan calculations of 96% and 1.12, respectively. Overall, polymer gel results verified the planned dose distribution within experimental uncertainties and uncertainty related to the digitization process of selected GammaPlan output data.

Buprenorphine versus heroin dependence: comparison of toxicologic and psychopathologic characteristics.

Sociodemographic, toxicologic, and psychopathologic characteristics of 22 buprenorphine addicts and 45 heroin addicts admitted for inpatient detoxification were compared. Although the buprenorphine addicts were older, clinically significant differences were not apparent. The availability of buprenorphine may be the main reason for its abuse.

Abuse liability of flunitrazepam among methadone-maintained patients.

Abuse liability and acute subjective and psychomotor effects of flunitrazepam were assessed in ten methadone-maintained males with history of benzodiazepine and alcohol use, who voluntarily participated in a double-blind, controlled, cross-over, randomized clinical trial. There were six experimental sessions in which a single oral dose of flunitrazepam 1, 2, and 4 mg; triazolam 0.5 and 0.75 mg; and placebo was given. Evaluations included physiological measures; psychomotor performance tasks (simple reaction time, Digit Symbol Substitution Test, balance task, Maddox-wing device); and self-administered subjective effects questionnaires [Addiction Research Center Inventory (ARCI), Profile of Mood States (POMS), a series of visual analog scales (VAS)]. All drugs but flunitrazepam 1 mg caused an impairment of psychomotor tasks. Effects were more evident with the highest doses of both drugs. Only flunitrazepam 4 mg produced a significant decrease in balance time. Triazolam 0.75 mg induced increases in sedation measured by ARCI-PCAG, depression in POMS, and VAS-drowsiness scores. Flunitrazepam 4mg caused euphoria-related effects as measured by increases in ARCI-MBG and "high" scores in the VAS. Our findings of flunitrazepam-induced euphoria in methadone-maintained subjects together with epidemiological evidence of flunitrazepam abuse by opioid dependents, suggest that it may be included in the group of benzodiazepines with a relatively high abuse potential.

Repeated doses administration of MDMA in humans: pharmacological effects and pharmacokinetics.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is increasingly used by young people for its euphoric and empathic effects. MDMA presents non-linear pharmacokinetics, probably by inhibition of cytochrome P450 isoform 2D6. Users are known to often take more than one dose per session. This practice could have serious implications for the toxicity of MDMA. OBJECTIVE: To evaluate the pharmacological effects and pharmacokinetics of MDMA following the administration of two repeated doses of MDMA (24 h apart). METHODS: A randomised, double-blind, cross-over, placebo controlled trial was conducted in nine healthy male subjects. Variables included physiological, psychomotor performance, subjective effects, endocrine response and pharmacokinetics. MDMA 100 mg or placebo was administered in two successive doses separated by an interval of 24 h. RESULTS: MDMA produced the prototypical effects of the drug. Following a second dose, plasma concentrations of MDMA increased (AUC 77% and Cmax 29%) in comparison with the first. The increase is greater than those expected by simple accumulation and indicates metabolic inhibition. The pharmacological effects after the second dose were slightly higher than those observed after the first in the majority of variables including blood pressure, heart rate, most subjective effects and cortisol concentrations. The effects were similar in the case of pupil diameter, esophoria and prolactin. CONCLUSIONS: Pharmacological effects after the second administration were higher than those following the first but lower than expected. A disproportionate increase in plasma concentrations in MDMA and MDA was observed most likely due to metabolic inhibition. This inhibition lasts at least 24 h. Further experiments need to be conducted to evaluate its duration.

Consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment: results from cross-sectional studies in 1988 and 1990.

We assessed the prevalence of consumption of buprenorphine and other drugs among heroin addicts under ambulatory treatment in two cross-sectional studies conducted in 1988 (188 subjects) and in 1990 (197 subjects). Patients were enrolled in one of three different programmes: methadone maintenance programme (MMP), antagonist maintenance programme (AMP) and drug-free programme (DFP). Information given by participants was compared with results of urine screening for drugs. Urine samples were tested using enzyme immunoassay for the detection of heroin, cocaine, dextropropoxyphene, cannabis and benzodiazepines, and radioimmunoassay for buprenorphine. Sixty-six percent of patients in 1988 and 71% of patients in 1990 reported having consumed buprenorphine at some time during their history of drug dependence (period prevalence) and 5.9% and 6.1%, respectively, tested positive to the drug (point prevalence). In over 70% of these patients consumption was by the intravenous route. Consumption of cannabis, cocaine and benzodiazepines was also very high in the study population. Overall, patients in the DFP group consumed the largest number of the drugs tested, while those in the AMP group consumed the smallest number. Abuse of buprenorphine could be more widespread than previously reported.

Use of the Nottingham Health Profile for measuring health status of patients in methadone maintenance treatment.

This study was conducted to assess changes in health-related quality of life over a 3-year follow-up period in a cohort of 135 opioid dependent patients using the Nottingham Health Profile (NHP) questionnaires. Data obtained at 12 months from 80 patients retained in the programme are presented. In summary, opioid addicts in a methadone maintenance programme for a 12-month period experienced an early and substantial improvement in health-related quality of life. The use of the NHP questionnaire to monitor changes in the subjective health of opioid-dependent patients over time provides new insights in the assessment of treatment effectiveness of methadone maintenance programmes.

Bladder denervation procedures.

Bladder denervation can provide useful rehabilitation of bladder function when other measures have failed. Idiopathic hyperactivity may respond best to hyperbaric distension or bladder transection. Procedures performed close to the bladder seem, at present, to be more effective than those near the central nervous system. Procedures have little morbidity, apart from transection. On the average a 50 per cent improvement may be expected, but in all cases it is most important to consider the length of follow-up in reported series.