Neurometabolic profile of the amygdala in smokers assessed with 1H-magnetic resonance spectroscopy.

Tobacco smoking is one of the main causes of premature death worldwide and quitting success remains low, highlighting the need to understand the neurobiological mechanisms underlying relapse. Preclinical models have shown that the amygdala and glutamate play an important role in nicotine addiction. The aims of this study were to compare glutamate and other metabolites in the amygdala between smokers and controls, and between different smoking states. Furthermore, associations between amygdalar metabolite levels and smoking characteristics were explored. A novel non-water-suppressed proton magnetic resonance spectroscopy protocol was applied to quantify neurometabolites in 28 male smokers (≥15 cigarettes/day) and 21 non-smoking controls, matched in age, education, verbal IQ, and weekly alcohol consumption. Controls were measured once (baseline) and smokers were measured in a baseline state (1-3 h abstinence), during withdrawal (24 h abstinence) and in a satiation state (directly after smoking). Baseline spectroscopy data were compared between groups by independent t-tests or Mann-Whitney-U tests. Smoking state differences were investigated by repeated-measures analyses of variance (ANOVAs). Associations between spectroscopy data and smoking characteristics were explored using Spearman correlations. Good spectral quality, high anatomical specificity (98% mean gray matter) and reliable quantification of most metabolites of interest were achieved in the amygdala. Metabolite levels did not differ between groups, but smokers showed significantly higher glutamine levels at baseline than satiation. Glx levels were negatively associated with pack-years and smoking duration. In summary, this study provides first insights into the neurometabolic profile of the amygdala in smokers with high anatomical specificity. By applying proton magnetic resonance spectroscopy, neurometabolites in smokers during different smoking states and non-smoking controls were quantified reliably. A significant shift in glutamine levels between smoking states was detected, with lower concentrations in satiation than baseline. The negative association between Glx levels and smoking quantity and duration may imply altered glutamate homeostasis with more severe nicotine addiction.

Accumbal-thalamic connectivity and associated glutamate alterations in human cocaine craving: A state-dependent rs-fMRI and 1H-MRS study.

Craving is a core symptom of cocaine use disorder and a major factor for relapse risk. To date, there is no pharmacological therapy to treat this disease or at least to alleviate cocaine craving as a core symptom. In animal models, impaired prefrontal-striatal signalling leading to altered glutamate release in the nucleus accumbens appear to be the prerequisite for cocaine-seeking. Thus, those network and metabolic changes may constitute the underlying mechanisms for cocaine craving and provide a potential treatment target. In humans, there is recent evidence for corresponding glutamatergic alterations in the nucleus accumbens, however, the underlying network disturbances that lead to this glutamate imbalance remain unknown. In this state-dependent randomized, placebo-controlled, double-blinded, cross-over multimodal study, resting state functional magnetic resonance imaging in combination with small-voxel proton magnetic resonance spectroscopy (voxel size: 9.4 × 18.8 × 8.4 mm3) was applied to assess network-level and associated neurometabolic changes during a non-craving and a craving state, induced by a custom-made cocaine-cue film, in 18 individuals with cocaine use disorder and 23 healthy individuals. Additionally, we assessed the potential impact of a short-term challenge of N-acetylcysteine, known to normalize disturbed glutamate homeostasis and to thereby reduce cocaine-seeking in animal models of addiction, compared to a placebo. We found increased functional connectivity between the nucleus accumbens and the dorsolateral prefrontal cortex during the cue-induced craving state. However, those changes were not linked to alterations in accumbal glutamate levels. Whereas we additionally found increased functional connectivity between the nucleus accumbens and a midline part of the thalamus during the cue-induced craving state. Furthermore, obsessive thinking about cocaine and the actual intensity of cocaine use were predictive of cue-induced functional connectivity changes between the nucleus accumbens and the thalamus. Finally, the increase in accumbal-thalamic connectivity was also coupled with craving-related glutamate rise in the nucleus accumbens. Yet, N-acetylcysteine had no impact on craving-related changes in functional connectivity. Together, these results suggest that connectivity changes within the fronto-accumbal-thalamic loop, in conjunction with impaired glutamatergic transmission, underlie cocaine craving and related clinical symptoms, pinpointing the thalamus as a crucial hub for cocaine craving in humans.

Cannabis Consumers' View of Regulated Access to Recreational Cannabis: A Multisite Survey in Switzerland.

INTRODUCTION: There is considerable effort in legalizing recreational use of cannabis globally. The successful implementation of a program of regulated access to recreational cannabis (PRAC) depends on the consumers' engagement. The aim of this study was to examine the acceptability of twelve different regulatory aspects by cannabis users including those obtaining cannabis from the illicit market and vulnerable populations such as young adults and problematic users. METHODS: The current study is a multisite online survey conducted in Switzerland. A total of 3,132 adult Swiss residents who consumed cannabis within the previous 30 days represented the studied population. Mean age was 30.5 years, 80.5% were men, and 64.2% of the participants stated that they always or often obtain cannabis from the illicit market. We described consumers' acceptability of twelve regulatory aspects concerning THC content control, disclosure of sensitive personal data, security aspects, and follow-up procedures by applying descriptive statistics and multiple regression models. RESULTS: THC content regulation showed most discrepancy with 89.4% of the participants stating to engage in a PRAC if five different THC contents were available as compared to 54% if only 12% THC was available. The least accepted regulatory aspect was disposal of contact details with an acceptability rate of 18.1%. Consumers mainly obtaining cannabis from the illicit market, young adults, and problematic users showed similar acceptability patterns. Participants obtaining cannabis from the illicit market were more likely to engage in a PRAC if five different THC contents were available as compared to participants obtaining cannabis from other sources (OR 1.94, 95% CI: 1.53-2.46). CONCLUSION: A carefully designed PRAC that takes into account the consumers' perspective is likely to transfer them to the regulated market and to engage vulnerable populations. We cannot recommend the distribution of cannabis with only 12% THC content as this is unlikely to engage the target population.

Thalamic volume and functional connectivity are associated with nicotine dependence severity and craving.

Tobacco smoking is associated with deleterious health outcomes. Most smokers want to quit smoking, yet relapse rates are high. Understanding neural differences associated with tobacco use may help generate novel treatment options. Several animal studies have recently highlighted the central role of the thalamus in substance use disorders, but this research focus has been understudied in human smokers. Here, we investigated associations between structural and functional magnetic resonance imaging measures of the thalamus and its subnuclei to distinct smoking characteristics. We acquired anatomical scans of 32 smokers as well as functional resting-state scans before and after a cue-reactivity task. Thalamic functional connectivity was associated with craving and dependence severity, whereas the volume of the thalamus was associated with dependence severity only. Craving, which fluctuates rapidly, was best characterized by differences in brain function, whereas the rather persistent syndrome of dependence severity was associated with both brain structural differences and function. Our study supports the notion that functional versus structural measures tend to be associated with behavioural measures that evolve at faster versus slower temporal scales, respectively. It confirms the importance of the thalamus to understand mechanisms of addiction and highlights it as a potential target for brain-based interventions to support smoking cessation, such as brain stimulation and neurofeedback.

Disentangling craving- and valence-related brain responses to smoking cues in individuals with nicotine use disorder.

Tobacco smoking is one of the leading causes of preventable death and disease worldwide. Most smokers want to quit, but relapse rates are high. To improve current smoking cessation treatments, a better understanding of the underlying mechanisms of nicotine dependence and related craving behaviour is needed. Studies on cue-driven cigarette craving have been a particularly useful tool for investigating the neural mechanisms of drug craving. Here, functional neuroimaging studies in humans have identified a core network of craving-related brain responses to smoking cues that comprises of amygdala, anterior cingulate cortex, orbitofrontal cortex, posterior cingulate cortex and ventral striatum. However, most functional Magnetic Resonance Imaging (fMRI) cue-reactivity studies do not adjust their stimuli for emotional valence, a factor assumed to confound craving-related brain responses to smoking cues. Here, we investigated the influence of emotional valence on key addiction brain areas by disentangling craving- and valence-related brain responses with parametric modulators in 32 smokers. For one of the suggested key regions for addiction, the amygdala, we observed significantly stronger brain responses to the valence aspect of the presented images than to the craving aspect. Our results emphasize the need for carefully selecting stimulus material for cue-reactivity paradigms, in particular with respect to emotional valence. Further, they can help designing future research on teasing apart the diverse psychological dimensions that comprise nicotine dependence and, therefore, can lead to a more precise mapping of craving-associated brain areas, an important step towards more tailored smoking cessation treatments.

Neurometabolic alterations in the nucleus accumbens of smokers assessed with 1 H magnetic resonance spectroscopy: The role of glutamate and neuroinflammation.

Tobacco use is one of the leading causes of premature death and morbidity worldwide. For smokers trying to quit, relapse rates are high, even after prolonged periods of abstinence. Recent findings in animal models highlight the role of alterations in glutamatergic projections from the prefrontal cortex onto the nucleus accumbens (NAc) in relapse vulnerability. Moreover, inflammatory responses in the NAc have been reported during withdrawal. A novel proton magnetic resonance spectroscopy (1 H-MRS) protocol was applied in humans to measure molar concentrations for glutamate, its sum with glutamine (Glx), and myoinositol plus glycine (mI + Gly) in the NAc (19 smokers, 20 matched controls). Smokers were measured at baseline and during withdrawal and satiation. No difference between groups or smoking states was found for glutamate or Glx, but, in smokers, stronger craving and more severe nicotine dependence were associated with lower baseline glutamate and Glx levels, respectively. Interestingly, mI + Gly concentrations were higher during withdrawal than baseline and correlated negatively with nicotine dependence severity and pack years of smoking. The lack of glutamatergic changes between groups and smoking states may imply that glutamate homeostasis is not significantly altered in smokers or that changes are too small for detection by 1 H-MRS. Moreover, the observed increase in mI + Gly may imply that neuroinflammatory processes occur in the NAc during nicotine withdrawal. These findings shed light on neurobiological relapse mechanisms in smokers and may provide the opportunity to develop more effective treatment options targeting the glutamate and neuroinflammation system.

Use of psychotropic substances among elite athletes - a narrative review.

BACKGROUND AND AIMS: Elite athletes may use psychotropic substances for recreational reasons, (perceived) performance enhancement or self-medication. Causes can overlap. For athletes, substance use may be associated with various medical and social risks. Psychoactive substances include alcohol and nicotine, illicit and various prescription drugs, which all have a potential for abuse and dependence. This paper reviews the existing literature on the use of psychoactive substances and associated substance use disorders among elite athletes in terms of prevalence, patterns of use, as well as underlying causes and risk factors. METHODS: Due to the heterogeneous and partially fragmentary study data, a narrative approach with selection of applicable publications of a Medline search was chosen. RESULTS: The most commonly used psychoactive substances among elite athletes were alcohol, nicotine, cannabis, stimulants and (prescription) opioids. Overall consumption rates are lower in professional sports than in the general population, but use of several substances (smokeless tobacco products, prescription opioids, stimulants) have high prevalence in specific sports and athlete groups. Substance use is subject to multiple risk factors and varies by substance class, sport discipline, country and gender, among other factors. CONCLUSION: Knowledge on the underlying causes and patterns of substance use, as well as the prevalence of substance use disorders in professional sports, is still limited. High prevalence of various substances (i.e., nicotine, prescription opioids) may indicate potentially harmful patterns of use, requiring further research. Specific preventive and therapeutic concepts for the treatment of substance use disorders in elite athletes should be developed.

SmoCuDa: A Validated Smoking Cue Database to Reliably Induce Craving in Tobacco Use Disorder.

BACKGROUND: Cue-reactivity paradigms provide valuable insights into the underlying mechanisms of nicotine craving in nicotine-dependent subjects. In order to study cue-driven nicotine craving, robust and validated stimulus datasets are essential. OBJECTIVES: The aim of this study was to generate and validate a large set of individually rated smoking-related cues that allow for assessment of different stimulus intensities along the dimensions craving, valence, and arousal. METHODS: The image database consisted of 330 visual cues. Two hundred fifty smoking-associated pictures (Creative Commons license) were chosen from online databases and showed a widespread variety of smoking-associated content. Eighty pictures from previously published databases were included for cross-validation. Forty volunteers with tobacco use disorder rated "urge-to-smoke," "valence," and "arousal" for all images on a 100-point visual analogue scale. Pictures were also labelled according to 18 categories such as lit/unlit cigarettes in mouth, cigarette end, and cigarette in ashtray. RESULTS: Ratings (mean ± SD) were as follows: urge to smoke, 44.9 ± 13.2; valence, 51.2 ± 7.6; and arousal, 54.6 ± 7.1. All ratings, particularly "urge to smoke," were widely distributed along the whole scale spectrum. CONCLUSIONS: We present a novel image library of well-described smoking-related cues, which were rated on a continuous scale along the dimensions craving, valence, and arousal that accounts for inter-individual differences. The rating software, image database, and their ratings are publicly available at https://smocuda.github.io.

Cannabis use in Switzerland 2015-2045: A population survey based model.

BACKGROUND: Alternative cannabis regulation models are discussed and implemented worldwide. A baseline scenario under the assumption of no policy or market changes may prove useful to forecast cannabis use and treatment demand and evaluate changes in legislation. METHODS: Based on data of the Continuous Rolling Survey of Addictive Behaviours and Related Risks on cannabis use, age, gender and nationality from 2011 to 2015, we used general estimating equation analysis to model lifetime and 30-days prevalence from 2015 to 2045 in Switzerland accounting for demographic trends. RESULTS: Lifetime prevalence of cannabis use is projected to grow from 28.3% (CI 95% 27.8-28.8) in 2015 to 42.0% (CI 95% 41.0-43.0) in 2045. 30-days prevalence would increase slightly from 2.70% (CI 95% 2.53-2.88) to 3.39% (CI 95% 3.11-3.66). Due to population growth, absolute numbers with past 30-day cannabis use are estimated to increase from 202,784 (CI 95% 189,534-216,035) to 314,302 (CI 95% 288,504-340,100). Among those aged under 30 years no substantial change in lifetime and 30-days prevalence of cannabis use is projected. Larger changes are estimated to occur in the age group 30+. The mean age of past 30-day cannabis users would increase for men with Swiss nationality from 30.3 to 38.7 years. DISCUSSION: Population-based survey data and demographic projections can be used to develop baseline scenarios of future cannabis use. Assuming no changes in cannabis legislation, growing absolute numbers of users will likely increase treatment demand. Cannabis use is estimated to increase among the group aged >30 years, which is currently underrepresented in clinical treatment and research. Our findings highlight the need for prospective baseline scenarios to evaluate the impact of legislative changes on cannabis use. Moreover, in Switzerland effective prevention and treatment interventions for cannabis use disorders are required even if cannabis legislation remains unchanged.

Human pharmacology for addiction medicine: From evidence to clinical recommendations.

Substance use disorders (SUD) are complex and often chronic diseases with negative health outcomes and social consequences. Pharmacological treatment options for SUD can be separated in medications for (i) intoxication, (ii) withdrawal, and (iii) reduction of use together with relapse prevention. This chapter will focus on approved or clinically established pharmacological strategies suited to manage symptoms of withdrawal, and to reduce substance use or to promote abstinence. Hereby SUD involving alcohol, nicotine, stimulants, and opioids are primarily discussed as these substances are considered most harmful for both the individual and the society. Moreover, the pharmacotherapy of SUD related to the use of cannabis, benzodiazepines, and gamma-hydroxybutyrate is also briefly reviewed. Since most approved pharmacological treatment options show only moderate effect sizes especially in the long term, the development of new treatment strategies including new drugs, new combinations of available compounds, and biomarkers for response prediction is still warranted.

Clinical potential of methylphenidate in the treatment of cocaine addiction: a review of the current evidence.

BACKGROUND: Cocaine use continues to be a public health problem, yet there is no proven effective pharmacotherapy for cocaine dependence. A promising approach to treating cocaine dependence may be agonist-replacement therapy, which is already used effectively in the treatment of opioid and tobacco dependence. The replacement approach for cocaine dependence posits that administration of a long-acting stimulant medication should normalize the neurochemical and behavioral perturbations resulting from chronic cocaine use. One potential medication to be substituted for cocaine is methylphenidate (MPH), as this stimulant possesses pharmacobehavioral properties similar to those of cocaine. AIM: To provide a qualitative review addressing the rationale for the use of MPH as a cocaine substitute and its clinical potential in the treatment of cocaine dependence. METHODS: We searched MEDLINE for clinical studies using MPH in patients with cocaine abuse/dependence and screened the bibliographies of the articles found for pertinent literature. RESULTS: MPH, like cocaine, increases synaptic dopamine by inhibiting dopamine reuptake. The discriminative properties, reinforcing potential, and subjective effects of MPH and cocaine are almost identical and, importantly, MPH has been found to substitute for cocaine in animals and human volunteers under laboratory conditions. When taken orally in therapeutic doses, its abuse liability, however, appears low, which is especially true for extended-release MPH preparations. Though there are promising data in the literature, mainly from case reports and open-label studies, the results of randomized controlled trials have been disappointing so far and do not corroborate the use of MPH as a substitute for cocaine dependence in patients without attention deficit hyperactivity disorder. CONCLUSION: Clinical studies evaluating MPH substitution for cocaine dependence have provided inconsistent findings. However, the negative findings may be explained by specific study characteristics, among them dosing, duration of treatment, or sample size. This needs to be considered when discussing the potential of MPH as replacement therapy for cocaine dependence. Finally, based on the results, we suggest possible directions for future research.

A comprehensive model of treatment participation in chronic disease allowed prediction of opioid substitution treatment participation in Zurich, 1992-2012.

OBJECTIVES: Chronic diseases are often associated with cycling in and out of treatment. We used data of a large opioid substitution treatment case register to (1) identify associated factors and (2) integrate retention and readmission into a model of overall participation over subsequent treatment episodes of various groups. STUDY DESIGN AND SETTING: Data of all 9,407 patients undergoing 26,545 methadone or buprenorphine substitution treatment episodes between 1992 and 2012 in the canton of Zurich, Switzerland, were analyzed. We used extended survival analysis to estimate the duration of, and time between, treatment episodes, with the number of episodes, gender, nationality, administration route, age at onset of first regular heroin use, and provider type as independent variables. A similar analysis was applied to estimate overall participation (the probability of being in treatment at a given day after first entry independent of current number of treatment episode) and to test for group differences. RESULTS: The time between treatment episodes shortened with the increasing number of episodes. Retention slightly increased after the first episode and then shortened for later treatment episodes. Effect sizes were generally rather weak (odds ratio ≤ 1.47). Effects were usually equal for all episodes, and if changing, weakened for later episodes. CONCLUSION: The complex process of leaving and entering treatment as well as the daily probability of being in treatment independent of treatment episode can be predicted by comprehensible statistical models applied to patient-period data sets.

[Substance abuse in older adults]. / Sucht im Alter.

In respect of demographic change, the number of older patients with substance abuse and addiction is on the raise. In this review we present important clinical and therapeutic aspects of substance abuse and addiction in the elderly and focus on alcohol, benzodiazepines and opioids. Daily and risky alcohol consumption is common among older people. They also have an increased risk getting alcohol-related complications. For early detection, laboratory parameters and questionnaires such as the AUDIT-C are suitable. Therapeutically brief interventions have been proved successful. Also, abuse of benzodiazepines, especially low-dose addiction, is widespread among older persons, although often overlooked, and patients often do not recognize their addiction. The physician has to know the correct indication, adequate dosage and pharmacological interactions. A slow-dose reduction is recommended in case of addiction. Thanks to opioid substitution therapy, patients with an opioidaddiction can reach a higher age. Age influences the effects of the substitute, which may require an adjustment of the dosage. Treatment of elderly patients should be based on their needs and resources and is usually very effective.

Sur le plan démographique le nombre de personnes âgées abusant ou dépendant de substances est en augmentation. Dans cette revue seront présentés des aspects cliniques et thérapeutiques de l'abus et de la dépendance de substances dans cette classe de la population, en particulier en ce qui concerne l'alcool, les benzodiazépines et les opioïdes. La consommation d'alcool quotidienne est fréquente chez les personnes âgées et augmente chez elles le risque de complications. Pour la détection précoce d'un abus d'alcool des paramètres de laboratoire et des questionnaires comme le AUDIT-C sont appropriés. Des interventions thérapeutiques brèves se sont avérées efficaces. L'abus de benzodiazépines, en particulier la dépendance à ces substances à petites doses, est aussi très répandu et souvent négligé chez les personnes âgées, de telle sorte que ces dernières n'en ont pas conscience. Le médecin doit connaître l'indication correcte, le dosage adéquat et les interactions des benzodiazépines. Une réduction lente des doses est recommandée en cas de dépendance. Les patients présentant une dépendance aux opioïdes ont leur vie prolongée grâce à un traitement substitutif. L'âge influence les effets des substances substitutives, ce qui peut nécessiter des adaptations de dosage. Le traitement des personnes âgées devrait être basé sur leurs besoins et leurs ressources. Il est généralement très efficace.

Insula-specific H magnetic resonance spectroscopy reactions in heavy smokers under acute nicotine withdrawal and after oral nicotine substitution.

The aim of this study was to clarify whether addiction-specific neurometabolic reaction patterns occur in the insular cortex during acute nicotine withdrawal in tobacco smokers in comparison to nonsmokers. Fourteen male smokers and 10 male nonsmokers were included. Neurometabolites of the right and the left insular cortices were quantified by magnetic resonance spectroscopy (MRS) on a 3-Tesla scanner. Three separate MRS measurements were performed in each subject: among the smokers, the first measurement was done during normal smoking behavior, the second measurement during acute withdrawal (after 24 h of smoking abstinence), and the third shortly after administration of an oral nicotine substitute. Simultaneously, craving, withdrawal symptoms, and CO levels in exhaled air were determined during the three phases. The participants in the control group underwent the same MR protocol. In the smokers, during withdrawal, the insular cortex showed a significant increase in glutamine (Gln; p = 0.023) as well as a slight increase not reaching significance for glutamine/glutamate (Glx; p = 0.085) and a nonsignificant drop in myoinositol (mI; p = 0.381). These values tended to normalize after oral nicotine substitution treatment, even though differences were not significant: Gln (p = 0.225), Glx (p = 0.107) and mI (p = 0.810). Overall, the nonsmokers (control group) did not show any metabolic changes over all three phases (p > 0.05). In smokers, acute nicotine withdrawal produces a neurometabolic reaction pattern that is partly reversed by the administration of an oral nicotine substitute. The results are consistent with the expression of an addiction-specific neurometabolic shift in the brain and confirm the fact that the insular cortex seems to play a possible role in nicotine dependence.