The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

ContextAlcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.ObjectivesTo evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.Design, Setting, and ParticipantsRandomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.InterventionsEight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.Main Outcome MeasuresPercent days abstinent from alcohol and time to first heavy drinking day.ResultsAll groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone × behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.ConclusionsPatients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.Trial Registrationclinicaltrials.gov Identifier: NCT00006206

/pdf/combined-pharmacotherapies-and-behavioral-interventions-for-2vogia99j0.pdf

Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence: The COMBINE Study: A Randomized Controlled Trial

Inhibition and impulsivity: Behavioral and neural basis of response control

http://homepages.se.edu/cvonbergen/files/2013/01/Fifty-Years-of-the-Barratt-Impulsivenss-Scale_An-Update-and-Review.pdf

Fifty years of the Barratt Impulsiveness Scale: An update and review

The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the br...

Endocannabinoid-Mediated Control of Synaptic Transmission

Sex differences in the comorbidity of patients seeking a first treatment for Alcohol Use Disorder

Hypomagnesemia (hypoMg) has not yet been extensively studied in alcohol use disorder (AUD) . We hypothesize that chronic, excessive alcohol consumption favors oxidative stress and pro-inflammatory alterations that may be exacerbated by hypoMg. The objective of this study was to analyze the prevalence and associations of hypoMg in AUD.Cross-sectional study in patients admitted for a first treatment of AUD in six tertiary centers between 2013 and 2020. Socio-demographic, alcohol use characteristics, and blood parameters were ascertained at admission.753 patients (71% men) were eligible; age at admission was 48 years [IQR, 41-56 years]. Prevalence of hypoMg was 11.2%, higher than that observed for hypocalcemia (9.3%), hyponatremia (5.6%), and hypokalemia (2.8%). HypoMg was associated with older age, longer duration of AUD, anemia, higher erythrocyte sedimentation rate, gamma-glutamyl transpeptidase, glucose levels, advanced liver fibrosis (FIB-4 ≥3.25) and estimated glomerular filtration rate (eGFR) < 60 mL/min. In multivariate analysis, advanced liver fibrosis (OR, 8.91; 95% CI, 3.3-23.9) and eGFR < 60 mL (OR, 5.2; 95% CI, 1.0-26.2) were the only factors associated with hypoMg.Mg deficiency in AUD is associated with liver damage and glomerular dysfunction suggesting that both comorbidities should be assessed in the course of serum hypoMg. 

Associations of hypomagnesemia in patients seeking a first treatment of alcohol use disorder.

Brief Counseling Intervention (BCI) and Medical advice (MA) are psychotherapeutic approaches used for the treatment of binge drinkers in Primary Care. Although binge drinking is a common pattern of alcohol misuse in Europe and in the US, no studies have evaluated those subjects who do not respond to Brief Counseling Interventions or Medical Advice. Objective. To determine the clinical and demographic characteristics of binge drinkers in whom BCI or MA are not effective in reducing harmful alcohol use. Methods. This is a secondary analysis of data from a randomized alcohol brief intervention trial with a 12-month follow-up period. A total of 674 subjects (89%) participated right through to the end of the study. The primary outcome measure was change in harmful alcohol use from baseline to 12 months. Results. The strongest baseline predictors of harmful alcohol use during follow-up were educational status, young adults, and high number of cigarettes smoked, present family history of alcoholism, treatment condition and number of drinks per episode of binge drinking. Conclusions. Binge drinkers are a heterogeneous group that responds to brief intervention or MA but in a subgroup of them these interventions fail to prevent harmful alcohol use. Other interventions should be implemented for these subjects.

Clinical and Demographic Characteristics of Binge Drinkers Associated with Lack of Efficacy of Brief Intervention and Medical Advice Características clínicas y demográficas de bebedores "por atracones" que se relacionan con una falta de eficacia de la intervención breve y el consejo médico

Introduction: Dual Diagnosis (DD), defined as the co-occurrence of a Substance Use Disorder (SUD) and a Severe Mental Illness (SMI), is associated with several negative outcomes. Typical antipsychotics (TAP) are not of great value for patients with DD as they are associated with poorer responses and can worsen SUD. Atypical antipsychotics (AAP) offer several advantages compared to TAP. In DD, they have been found to be effective in treating both, psychiatric symptoms and substance use. The aim of this article is to review the use of AAP for treating DD patients. Methods: A search of MEDLINE, EMBASE and Pubmed was performed in order to identify publications that examined the use of AAP in the treatment of DD. Results: The largest number of studies focuse on clozapine, with consistently positive data. Data regarding aripiprazole are also consistent but less substantial. Olanzapine, risperidone and quetiapine have given inconclusive and inconsistent results. Finally, there is little use of amisulpride, ziprasidone, paliperidone and asenapine or it is has not been documented. Discussion: Today, there is a consensus on using AAT instead of TAP for treating patients with DD. Patients with DD show a poorer response to treatment with TAP, and TAP may even worsen the addictive behaviour. AAP are as effective as TAP in treating psychiatric symptoms, but they are more effective in reducing substance use in DD patients. Because with the exception of CLO none of the AAP have shown to be superior to the others, when choosing between the different AAP agents clinicians should take into account other variables such as medical comorbidity, possible pharmacological interactions of concomitant treatments and profile of side effects. Even though a growing body of evidence suggests the beneficial effects of AAP in DD patients, further randomized, blinded, controlled trials, with larger sample sizes and longer followups are needed.

Gabriel Rubio

Papers

Sex differences in the comorbidity of patients seeking a first treatment for Alcohol Use Disorder

Associations of hypomagnesemia in patients seeking a first treatment of alcohol use disorder.

Clinical and Demographic Characteristics of Binge Drinkers Associated with Lack of Efficacy of Brief Intervention and Medical Advice Características clínicas y demográficas de bebedores "por atracones" que se relacionan con una falta de eficacia de la intervención breve y el consejo médico

Atypical Antipsychotic Drugs in Dual Diagnosis Patients: A Review

Neurophysiological and Neuropsychological Models of Depression