BPRS domains, items and subgroups analyses, and CGI-I ratings in pooled data from non-interventional studies of aripiprazole once-monthly in schizophrenia (REACT study).

BACKGROUND: Patients with schizophrenia may benefit from treatment with long-acting injectable (LAI) formulations of antipsychotics. Aripiprazole once-monthly (AOM) is an LAI that was tested in two non-interventional studies in Germany and Canada. METHODS: Here, we report on analyses of pooled data from the two non-interventional studies. Patients were treated with AOM under real-life conditions. Data were analyzed for a timeframe of 6 months. We analyzed data on Brief Psychiatric Rating Scale (BPRS) domains and items, BPRS total scores in various patient subgroups (male vs. female patients, patients with disease duration ≤ 5 years and > 5 years, patients with different levels of disease severity at baseline), Clinical Global Impression - Improvement (CGI-I) ratings for the total population and subgroups, and comorbidities for the total population. RESULTS: Data from 409 patients were included. 65.5% of the patients had comorbidities. Improvements were found in all BPRS domains and items. Furthermore, improvements were similar for male and female patients, patients with disease duration ≤ 5 years and > 5 years, and across different levels of disease severity at baseline. Numerically, more favorable results were found for younger patients, female patients, and those with shorter disease duration. CONCLUSIONS: AOM can be an effective treatment in the broad range of patients, across sexes, regardless of patient age and duration of disease, independently of disease severity, and across symptoms. TRIAL REGISTRATION: NCT02131415 (May 6, 2014), vfa non-interventional studies registry 15960N.

Improvement of functioning in patients with schizophrenia: real-world effectiveness of aripiprazole once-monthly (REACT study).

BACKGROUND: Functional impairment affects many patients with schizophrenia. Treatment with the long-acting injectable antipsychotic aripiprazole once-monthly (AOM) may help improve functioning. OBJECTIVES: To explore changes in functioning in patients with schizophrenia who received AOM treatment in observational studies. METHODS: Here we report functional outcomes in the form of Global Assessment of Functioning (GAF) scores in a pooled analysis of data from two observational studies from Canada (NCT02131415) and Germany (vfa non-interventional studies registry 15960N). Data from 396 patients were analyzed. RESULTS: At baseline, the mean GAF score was 47.7 (SD 13.4). During 6 months of treatment with AOM, the mean GAF score increased to 59.4 (SD 15.8). Subgroups stratified by patient age (≤35 years/>35 years), sex, disease duration (≤5 years/>5 years) and disease severity at baseline had all significantly improved their GAF at month 6. 51.5% of the patients showed a GAF score increase of at least 10 points, which was regarded as clinically meaningful, and were considered responders. CONCLUSIONS: These data show that treatment with AOM may help improve patient functioning in a routine treatment setting. TRIAL REGISTRATION: NCT02131415 (May 6, 2014), vfa non-interventional studies registry 15960N.

Immune signature of multiple sclerosis-associated depression.

Multiple neurobiological pathways have been implicated in the pathobiology of major depressive disorder (MDD). The identification of reliable biological substrates across the entire MDD spectrum, however, is hampered by a vast heterogeneity in the clinical presentation, presumably as a consequence of heterogeneous pathobiology. One way to overcome this limitation could be to explore disease subtypes based on biological similarity such as "inflammatory depression". As such a subtype may be particularly enriched in depressed patients with an underlying inflammatory condition, multiple sclerosis (MS) could provide an informative disease context for this approach. Few studies have explored immune markers of MS-associated depression and replications are missing. To address this, we analyzed data from two independent case-control studies on immune signatures of MS-associated depression, conducted at two different academic MS centers (overall sample size of n = 132). Using a stepwise data-driven approach, we identified CD4+CCR7lowTCM cell frequencies as a robust correlate of depression in MS. This signature was associated with core symptoms of depression and depression severity (but not MS severity per se) and linked to neuroinflammation as determined by magnetic resonance imaging (MRI). Furthermore, exploratory analyses of T cell polarization revealed this was largely driven by cells with a TH1-like phenotype. Our findings suggest (neuro)immune pathways linked to affective symptoms of autoimmune disorders such as MS, with potential relevance for the understanding of "inflammatory" subtypes of depression.

Acute stress leaves fear generalization in healthy individuals intact.

Because threatening situations often occur in a similar manner, the generalization of fear to similar situations is adaptive and can avoid harm to the organism. However, the overgeneralization of fear to harmless stimuli is maladaptive and assumed to contribute to anxiety disorders. Thus, elucidating factors that may modulate fear (over)generalization is important. Based on the known effects of acute stress on learning, which are at least partly due to noradrenergic arousal, we investigated whether stress may promote fear overgeneralization and whether we could counteract this effect by reducing noradrenergic arousal. In a placebo-controlled, double-blind, between-subjects design, 120 healthy participants underwent a fear-conditioning procedure on Day 1. Approximately 24 hours later, participants received orally either a placebo or the beta-adrenergic receptor antagonist propranolol and were exposed to a stress or control manipulation before they completed a test of fear generalization. Skin conductance responses as well as explicit rating data showed a successful acquisition of conditioned fear on Day 1 and a pronounced fear generalization 24 hours later. Although physiological data confirmed the successful stress manipulation and reduction of noradrenergic arousal, the extent of fear generalization remained unaffected by stress and propranolol. The absence of a stress effect on fear generalization was confirmed by a second study and a Bayesian analysis across both data sets. Our findings suggest that acute stress leaves fear generalization processes intact, at least in a sample of healthy, young individuals.

Autoantibody-associated psychiatric syndromes in children: link to adult psychiatry.

Studies show that psychiatric symptoms in adults and children are sometimes associated with serum neural autoantibodies. The significance of serum neural autoantibodies associated with psychiatric symptoms in children remains often unclear, but might be relevant for the extent and occurrence of psychiatric disease manifestation in later life, as well as therapy and outcome. For this narrative review, we sought articles listed in PubMed and published between 1988 and 2020 addressing the maternal-fetal transfer of neural autoantibodies and psychiatric disorders associated with serum neural autoantibodies. We identified six major subgroups of psychiatric disorders in children that are associated with serum neural autoantibodies: patients with attentional deficit hyperactivity disorder, autism spectrum disorder, obsessive compulsive disorder, Gilles de la Tourette syndrome, psychosis and catatonia. Furthermore, we summarized study findings from maternal-fetal transfer of Contactin-associated protein-like 2, N-methyl-D-aspartate receptor and fetal brain autoantibodies associated with behavioral effects in animals and humans. We hypothesize that the maternal transfer of serum neuronal autoantibodies during or after birth could result (1) in the ignition of an autoimmune-mediated inflammation having neurodevelopmental consequences for their children (autoimmune-priming-attack hypothesis) and (2) has a potential impact on the later manifestation of psychiatric disorders. Through this narrative review, we propose a diagnostic pathway for the clinical diagnosis of a potentially autoimmune origin of psychiatric symptoms in children while considering recent guidelines.

BDNF influences neural cue-reactivity to food stimuli and food craving in obesity.

There is increasing evidence that brain-derived neurotrophic factor (BDNF) impacts on the development of obesity. We are the first to test the hypothesis that BDNF levels might be associated with neural reactivity to food cues in patients suffering from obesity and healthy controls. We assessed visual food cue-induced neural response in 19 obese patients and 20 matched controls using functional magnetic resonance imaging and analyzed the associations between BDNF levels, food cue-reactivity and food craving. Whole-brain analysis in both groups revealed that food cues elicited higher neural activation in clusters of mesolimbic brain areas including the insula (food > neutral). Patients suffering from obesity showed a significant positive correlation between plasma BDNF levels and visual food cue-reactivity in the bilateral insulae. In addition, patients suffering from obesity with positive food cue-induced insula activation also reported significantly higher food craving than those with low cue-reactivity-an effect that was absent in normal weight participants. The present findings implicate that BDNF levels in patients suffering from obesity might be involved in food craving and obesity in humans. This highlights the importance to consider BDNF pathways when investigating obesity and obesity treatment.

Leptin predicts cortical and subcortical gray matter volume recovery in alcohol dependent patients: A longitudinal structural magnetic resonance imaging study.

The neuroprotective effects of leptin and its role in addictive disorders has been highlighted by several recent studies. However, its potential effects on morphological alterations in alcohol dependence are yet to be investigated. Associations between leptin and the longitudinal courses of gray matter volume (GMV) and cortical thickness (CT) were investigated in N = 62 alcohol-dependent patients that underwent structural magnetic resonance imaging after a mean abstinence of 12 (baseline) and 27 days (follow-up) respectively. Blood samples were collected at baseline to determine leptin levels. A cohort of N = 74 healthy individuals served as a reference sample. At baseline, alcohol-dependent patients compared to healthy controls displayed smaller GMV in the insula, parts of the superior, middle and inferior frontal gyri and hippocampal regions and thinner CT in the insula, parts of the superior and middle frontal cortices, the lateral orbitofrontal cortex and parts of the occipital and lingual cortices that partially recovered during abstinence (pFWE < 0.05). In alcohol-dependent patients, leptin was a significant predictor of GMV and CT recovery in the areas that showed the strongest whole-brain effects, specifically GMV in the right insula (R2 = 0.070, pFDR = 0.040) and left inferior frontal triangular gyrus (R2 = 0.076, pFDR = 0.040), as well as CT in the left insula (R2 = 0.158, pFDR = 0.004) and right superior frontal cortex (R2 = 0.180, pFDR = 0.004). Present results support the role of leptin in predicting GMV and CT recovery during the first month of abstinence in alcohol-dependent patients.

The use of long-acting Aripiprazole in a multi-center, prospective, uncontrolled, open-label, cohort study in Germany: a report on global assessment of functioning and the WHO wellbeing index.

BACKGROUND: In this non-interventional study, the functionality and well-being of patients with schizophrenia with aripiprazole once-monthly (AOM) was evaluated under real-life conditions in a naturalistic population. METHODS: This non-interventional, prospective, multicenter 6-month study included 242 predominantly symptomatically stable patients (mean age 43.1 ± 15.1 years, 55% male) who switched their treatment to AOM after 9.7 (± 22.3) months of oral treatment. Outcome parameters included functionality (Global Assessment of Functioning, GAF), patient's wellbeing (WHO-5 Well-Being Index, WHO-5), and both patient's and clinician's assessment of efficacy and tolerability of AOM. Treatment emergent adverse events (TRAE) were also recorded. RESULTS: At baseline, the mean GAF score was 47.0 (±13.9), indicating that patients experienced serious impairment in functioning. A continuous increase to 60.2 (±17.0) during treatment was found, with a robust and significant increase already after 4 weeks. At study start, patients reported diminished wellbeing, with a mean score of 10.6 (±5.6) on the WHO-5 scale. During treatment, patient wellbeing increased continuously with strong and significant improvements even after 4 weeks and an overall improvement of 4.8 (±6.9) over the course of 6 months with an endpoint of 15.4 (±5.5). Stratification of these results showed that more pronounced effects were achieved in younger patients ≤35 years (p<0.05 for GAF). The effectiveness and tolerability of AOM was rated good/very good by most patients (89.2 and 93.7%) and physicians (91.4 and 96.8%). Only few TRAEs occurred. CONCLUSIONS: Our results show a significant positive effect after initiation of AOM treatment in predominantly stable patients with schizophrenia on their functioning and wellbeing, which was even more pronounced in patients aged ≤35 years, thereby supporting previous randomized controlled findings under routine conditions in clinical practice.

HPA axis stress reactivity and hair cortisol concentrations in recently detoxified alcoholics and healthy controls with and without childhood maltreatment.

Childhood maltreatment (CM) is a strong risk factor for alcohol dependence (AD) and is associated with a more severe course of the disease. Alterations of the hypothalamic-pituitary-adrenal (HPA) axis may play an important role in this relationship. The aim of the present study was to systematically investigate potential alterations in HPA functioning associated with AD diagnosis and CM. Four study groups were recruited: AD patients with (n = 29; 10♀) and without (n = 33; 8♀) CM and healthy controls with (n = 30; 20♀) and without (n = 38; 15♀) CM. Cumulative cortisol secretion was measured by hair cortisol concentration (HCC). To measure HPA axis response to the Trier social stress test (TSST), saliva and blood samples were analysed for adrenocorticotropic hormone (ACTH) and cortisol. In the AD groups, the period of hair growth covered acute alcohol consumption and withdrawal. The TSST was scheduled after completion of withdrawal. Irrespective of CM, higher HCCs and reduced ACTH and cortisol levels before and after TSST were observed in AD patients. The analyses did not reveal any differences between AD patients with and without CM. Healthy controls with CM had lower plasma cortisol levels compared with those without CM. The results suggest that AD is strongly related to HPA axis functioning, which may superimpose possible differences between AD patients with and without CM. Future studies should investigate whether biologically different subtypes of AD with and without CM can be identified in earlier stages or before the development of AD.

Glucocorticoids, Noradrenergic Arousal, and the Control of Memory Retrieval.

Glucocorticoids and noradrenaline can enhance memory consolidation but impair memory retrieval. Beyond their effects on quantitative memory performance, these major stress mediators bias the engagement of multiple memory systems toward "habitual" control during learning. However, if and how glucocorticoids and noradrenaline may also affect which memory system is recruited during recall, thereby affecting the control of retrieval, remain largely unknown. To address these questions, we trained healthy participants in a probabilistic classification learning task, which can be supported both by cognitive and habitual strategies. Approximately 24 hr later, participants received a placebo, hydrocortisone, yohimbine (an α2-adrenoceptor antagonist increasing noradrenergic stimulation), or both drugs before they completed a recall test for the probabilistic classification learning task. During training, all groups showed a practice-dependent shift toward more habitual strategies, reflecting an "automatization" of behavior. In the recall test, after a night of sleep, this automatization was even more pronounced in the placebo group, most likely due to offline consolidation processes and with beneficial effects on recall performance. Hydrocortisone or yohimbine intake abolished this further automatization, preventing the shift to a more efficient memory system and leading, in particular in the hydrocortisone group, to impaired recall performance. Our results suggest that glucocorticoids and noradrenergic stimulation may modulate the engagement of different strategies at recall and link the well-known stress hormone-induced retrieval deficit to a change in the system controlling memory retrieval.

Hypothalamic-Pituitary-Adrenocortical Axis Activity in Alcohol-Dependent Patients During Treatment with High-Dose Baclofen.

AIMS: Activity of the hypothalamic-pituitary-adrenocortical (HPA) axis has been reported to be affected in alcohol use disorder (AUD). It has been suggested that pharmacological relapse prevention in AUD might exert its effects partly by modulation of HPA axis activity. Here, we assessed the effects of high-dose treatment with baclofen on HPA axis activity in alcohol-dependent patients within a 24-week randomized, placebo-controlled trial (BACLAD study). METHODS: Plasma levels of copeptin, adrenocorticotropic hormone (ACTH), and cortisol were measured at 3 timepoints in alcohol-dependent patients during the study. Corresponding plasma levels in healthy controls were assessed once. RESULTS: ACTH blood levels were significantly higher in the group of alcohol-dependent patients compared to controls. In patients receiving individually titrated high-dose baclofen, plasma cortisol levels decreased significantly, whereas no significant alterations were found in the placebo group. CONCLUSIONS: Our study underlines again the role of HPA axis alterations in AUD. Furthermore, a decrease in hormonal stress levels during treatment with high-dose baclofen might contribute to the relapse preventive effects of this compound.

Therapeutic Drug Monitoring of Naltrexone and 6ß-Naltrexol During Anti-craving Treatment in Alcohol Dependence: Reference Ranges.

AIMS: Aim of this study was to associate concentration of naltrexone and its major active metabolite 6ß-naltrexol in blood with therapeutic outcome during treatment with naltrexone in subjects with alcohol dependence. Treatment with the µ-opiate receptor antagonist naltrexone has been shown to reduce craving for alcohol and alcohol intake in patients suffering from alcohol dependence. SHORT SUMMARY: This article shows the use of therapeutic drug monitoring in alcohol dependent patients, who are treated with naltrexone. The plasma concentrations of naltrexone and 6ß-naltrexol showed high inter-individual variability. They were predictive for treatment response, as they correlated significantly with the reduction of alcohol craving. METHODS: Naltrexone and 6ß-naltrexol were analysed by high performance liquid chromatography with column switching and spectrophotometric detection. Alcohol craving was assessed with the Obsessive-Compulsive Drinking Scale (OCDS). RESULTS AND CONCLUSIONS: The study included 43 patients who were treated with naltrexone with a dose of 50 mg/day. Blood was taken for drug analysis 8 h after the last dose of the day at Week 4, 8 and 12. The plasma concentrations of naltrexone and 6ß-naltrexol showed high inter-individual variability. They were predictive for treatment response, as they correlated significantly with the reduction of alcohol craving. Defining patients with OCDS reduction of 70% or higher as responders, the mean±SD concentration of naltrexone plus naltrexol was 22 ± 13 ng/ml compared to 15 ± 8 ng/ml in patients with score reductions of 1-69%. Further analyses indicated that concentrations of 17-50 ng/ml at 8 h and 7-20 ng/ml at 24 h after drug intake were required for treatment response. CONCLUSIONS: Since plasma concentration of naltrexone plus 6ß-naltrexol was found to be predictive for reduction of alcohol craving, it is concluded that therapeutic drug monitoring has the potential to enhance naltrexone's moderate therapeutic efficiency in patients with alcohol dependence.

Ghrelin modulates mesolimbic reactivity to alcohol cues in alcohol-addicted subjects: a functional imaging study.

Ghrelin has been shown to be involved in the pathophysiology of alcohol dependence, affecting alcohol self-administration and craving. However, the mechanism of action in alcohol dependence still has to be determined. We thus investigated whether ghrelin is associated with mesolimbic cue reactivity to alcohol cues and alcohol craving in recently detoxified alcohol-addicted subjects. We included 41 recently detoxified alcohol-dependent individuals. Functional magnetic resonance imaging (fMRI) was used to study mesolimbic cue reactivity during the presentation of alcohol-related pictures. Additionally, we assessed patients' alcohol craving using the Alcohol Urge Questionnaire and a visual analogue scale. Plasma concentrations of total and acylated (activated) ghrelin were measured in parallel to the fMRI session. The association between ghrelin plasma concentrations, mesolimbic cue reactivity and alcohol craving was assessed by performing correlation and mediation analyses. Alcohol-induced brain response in a network of brain clusters, including the right and left ventral striatum, showed a significant positive association with acylated ghrelin plasma concentration. Additionally, acylated ghrelin was significantly associated with craving. Mediation analyses showed that the association between acylated ghrelin plasma concentration and alcohol craving is mediated by a cue-induced brain response in the ventral striatum. Based on the finding that ghrelin modulates mesolimbic reactivity to alcohol cues, the following should be considered: If alcohol craving and the appetitive status were interrelated, this has to be taken into account when implementing fMRI studies for addictive disorders. Moreover, appetite regulation seems to represent a valid treatment target for reducing cue reactivity in addictive disorders.

Correction to: Effectiveness of aripiprazole once-monthly in schizophrenia patients pretreated with oral aripiprazole: a 6-month, real-life non-interventional study.

Following publication of the original article.

Effectiveness of aripiprazole once-monthly in schizophrenia patients pretreated with oral aripiprazole: a 6-month, real-life non-interventional study.

BACKGROUND: In this study, the treatment of schizophrenia patients with aripiprazole once-monthly (AOM) was evaluated under real-life conditions in a naturalistic setting. METHODS: This multicenter, prospective, non-interventional study included 242 patients (age = 43.1 ± 15.1 years, 55.0% male) who were monitored during 6 months of AOM treatment. Endpoints included measurements of psychopathology (Brief Psychiatric Rating Scale, BPRS) and severity of illness scales (Clinical Global Impressions-Severity, CGI-S, and -Improvement, CGI-I). Furthermore, treatment-related adverse events (TRAEs) were recorded. RESULTS: At baseline, the mean BPRS total score was 54.1 ± 15.6, the mean CGI-S was 4.8 ± 0.8 and the most frequent illness category was 'markedly ill' (41.7%). Patients had been pretreated with oral aripiprazole for a mean duration of 9.7 months (SD: 22.3) and 87.9% were deemed by their clinician as "clinically stable" and for a mean of 5.9 months. The difference in global BPRS after 6 months was - 13.8 (SD: 16.0; 95% CI: [- 15.9; - 11.7]; p < 0.001). The proportion of patients with high CGI-S scores decreased and the proportion of patients with low scores increased significantly (p < 0.001, respectively). BPRS scores improved numerically especially well in younger patients ≤35 years, CGI-S scores decreased significantly more in this population. TRAEs were rare, with low incidences of extrapyramidal symptoms (2.9%) or weight increase (0.4%). CONCLUSIONS: Treatment with AOM showed satisfying effectiveness in outpatients with further improvement of psychopathology after oral aripiprazole treatment for a considerable duration and even after having achieved clinically judged "stability". Our findings indicate a robust therapeutic effect of AOM and substantiate previous results from randomized controlled trials under real-world routine conditions.

An elevated plus-maze in mixed reality for studying human anxiety-related behavior.

BACKGROUND: A dearth of laboratory tests to study actual human approach-avoidance behavior has complicated translational research on anxiety. The elevated plus-maze (EPM) is the gold standard to assess approach-avoidance behavior in rodents. METHODS: Here, we translated the EPM to humans using mixed reality through a combination of virtual and real-world elements. In two validation studies, we observed participants' anxiety on a behavioral, physiological, and subjective level. RESULTS: Participants reported higher anxiety on open arms, avoided open arms, and showed an activation of endogenous stress systems. Participants' with high anxiety exhibited higher avoidance. Moreover, open arm avoidance was moderately predicted by participants' acrophobia and sensation seeking, with opposing influences. In a randomized, double blind, placebo controlled experiment, GABAergic stimulation decreased avoidance of open arms while alpha-2-adrenergic antagonism increased avoidance. CONCLUSION: These findings demonstrate cross-species validity of open arm avoidance as a translational measure of anxiety. We thus introduce the first ecologically valid assay to track actual human approach-avoidance behavior under laboratory conditions.

Noradrenergic Stimulation Impairs Memory Generalization in Women.

Memory generalization is essential for adaptive decision-making and action. Our ability to generalize across past experiences relies on medial-temporal lobe structures, known to be highly sensitive to stress. Recent evidence suggests that stressful events may indeed interfere with memory generalization. Yet, the mechanisms involved in this generalization impairment are unknown. We tested here whether a pharmacological elevation of major stress mediators-noradrenaline and glucocorticoids-is sufficient to disrupt memory generalization. In a double-blind, placebo-controlled design, healthy men and women received orally a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine that leads to increased noradrenergic stimulation, or both drugs, before they completed an associative learning task probing memory generalization. Drugs left learning performance intact. Yohimbine, however, led to a striking generalization impairment in women, but not in men. Hydrocortisone, in turn, had no effect on memory generalization, neither in men nor in women. The present findings indicate that increased noradrenergic activity, but not cortisol, is sufficient to disrupt memory generalization in a sex-specific manner, with relevant implications for stress-related mental disorders characterized by generalization deficits.

Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans.

BACKGROUND: Endocannabinoids are critical for rewarding behaviors such as eating, physical exercise, and social interaction. The role of endocannabinoids in mammalian sexual behavior has been suggested because of the influence of cannabinoid receptor agonists and antagonists on rodent sexual activity. However, the involvement of endocannabinoids in human sexual behavior has not been studied. AIM: To investigate plasma endocannabinoid levels before and after masturbation in healthy male and female volunteers. OUTCOMES: Plasma levels of the endocannabinoids 2-arachidonoylglycerol (2-AG), anandamide, the endocannabinoid-like lipids oleoyl ethanolamide and palmitoyl ethanolamide, arachidonic acid, and cortisol before and after masturbation to orgasm. METHODS: In study 1, endocannabinoid and cortisol levels were measured before and after masturbation to orgasm. In study 2, masturbation to orgasm was compared with a control condition using a single-blinded, randomized, 2-session crossover design. RESULTS: In study 1, masturbation to orgasm significantly increased plasma levels of the endocannabinoid 2-AG, whereas anandamide, oleoyl ethanolamide, palmitoyl ethanolamide, arachidonic acid, and cortisol levels were not altered. In study 2, only masturbation to orgasm, not the control condition, led to a significant increase in 2-AG levels. Interestingly, we also found a significant increase of oleoyl ethanolamide after masturbation to orgasm in study 2. CLINICAL TRANSLATION: Endocannabinoids might play an important role in the sexual response cycle, leading to possible implications for the understanding and treatment of sexual dysfunctions. STRENGTHS AND LIMITATIONS: We found an increase of 2-AG through masturbation to orgasm in 2 studies including a single-blinded randomized design. The exact role of endocannabinoid release as part of the sexual response cycle and the biological significance of the finding should be studied further. Cannabis and other drug use and the attainment of orgasm were self-reported in the present study. CONCLUSION: Our data indicate that the endocannabinoid 2-AG is involved in the human sexual response cycle and we hypothesize that 2-AG release plays a role in the rewarding consequences of sexual arousal and orgasm. Fuss J, Bindila L, Wiedemann K, et al. Masturbation to Orgasm Stimulates the Release of the Endocannabinoid 2-Arachidonoylglycerol in Humans. J Sex Med 2017;14:1372-1379.

The Effect of Nicotine on HPA Axis Activity in Females is Modulated by the FKBP5 Genotype.

Tobacco smoking modulates activity in the hypothalamic-pituitary-adrenal (HPA) axis and is used to cope with stress, especially by females. The single nucleotide polymorphism (SNP) rs1360780, linked to FK506-binding protein 51 (FKBP5), has been shown to affect HPA axis functioning, and has thus been suggested as a promising candidate for indicating vulnerability to stress-related disorders. The aim of this study was to investigate the interaction between nicotine consumption and rs1360780 on cortisol plasma levels in females. A total of 296 female smokers (assessed by the Fagerström Test for Nicotine Dependence; FTND) were genotyped for the SNP rs1360780. We measured participants' cortisol plasma concentration in blood plasma collected 3 h after standardized tobacco smoking exposure. In the 36 TT-homozygotes, we found a significant negative correlation between the FTND sum score and cortisol plasma concentrations. Using linear regression analysis, we found that the FTND sum score accounted for 12.4% of the variance of cortisol plasma levels. This association was not detected in C-allele carriers. Our results suggest that nicotine is an important confounder in the modulation of HPA axis activity by FKBP5. In light of these findings, future studies on FKBP5 should seek to include data on nicotine consumption as a covariate.

Effects of Cigarette Smoking on Plasma Concentration of the Appetite-Regulating Peptide Ghrelin.

BACKGROUND: Weight gain is a common but only a partially understood consequence of smoking cessation. Existing data suggest modulating effects of the orexigenic peptide ghrelin on food intake. The aim of the present study was to investigate the effect of tobacco withdrawal on plasma concentration of acetylated and total ghrelin. METHODS: Fifty four normal-weighted smokers and 30 non-smoking healthy controls were enrolled in our study. Concentrations of acetylated and total ghrelin were measured in blood plasma drawn two hours after a standardized meal and three hours after the smokers smoked their last cigarette. The severity of tobacco addiction was assessed based on cotinine plasma concentration, the Fagerström Test for Nicotine Dependence (FTND) and the number of cigarettes smoked per day. RESULTS: The plasma concentration of acetylated ghrelin, but not total ghrelin, was significantly higher in smokers than in non-smokers. Moreover, we found significant negative correlations between acetylated ghrelin and all measures of the severity of nicotine dependence. CONCLUSIONS: Early abstinence from tobacco smoking seems to be associated with increased plasma concentration of the orexigenic peptide acetylated ghrelin. This could be one reason for increased food craving during nicotine withdrawal and subsequent weight gain. Smokers might compensate these effects by increasing tobacco intake.