Integration of Molecular Inflammatory Interactome Analyses Reveals Dynamics of Circulating Cytokines and Extracellular Vesicle Long Non-Coding RNAs and mRNAs in Heroin Addicts During Acute and Protracted Withdrawal.

Heroin addiction and withdrawal influence multiple physiological functions, including immune responses, but the mechanism remains largely elusive. The objective of this study was to investigate the molecular inflammatory interactome, particularly the cytokines and transcriptome regulatory network in heroin addicts undergoing withdrawal, compared to healthy controls (HCs). Twenty-seven cytokines were simultaneously assessed in 41 heroin addicts, including 20 at the acute withdrawal (AW) stage and 21 at the protracted withdrawal (PW) stage, and 38 age- and gender-matched HCs. Disturbed T-helper(Th)1/Th2, Th1/Th17, and Th2/Th17 balances, characterized by reduced interleukin (IL)-2, elevated IL-4, IL-10, and IL-17A, but normal TNF-α, were present in the AW subjects. These imbalances were mostly restored to the baseline at the PW stage. However, the cytokines TNF-α, IL-2, IL-7, IL-10, and IL-17A remained dysregulated. This study also profiled exosomal long non-coding RNA (lncRNA) and mRNA in the plasma of heroin addicts, constructed co-expression gene regulation networks, and identified lncRNA-mRNA-pathway pairs specifically associated with alterations in cytokine profiles and Th1/Th2/Th17 imbalances. Altogether, a large amount of cytokine and exosomal lncRNA/mRNA expression profiling data relating to heroin withdrawal was obtained, providing a useful experimental and theoretical basis for further understanding of the pathogenic mechanisms of withdrawal symptoms in heroin addicts.

Plasma metabolites changes in male heroin addicts during acute and protracted withdrawal.

BACKGROUND: Heroin addiction and withdrawal have been associated with an increased risk for infectious diseases and psychological complications. However, the changes of metabolites in heroin addicts during withdrawal remain largely unknown. METHODS: A total of 50 participants including 20 heroin addicts with acute abstinence stage, 15 with protracted abstinence stage and 15 healthy controls, were recruited. We performed metabolic profiling of plasma samples based on ultraperformance liquid chromatography coupled to tandem mass spectrometry to explore the potential biomarkers and mechanisms of heroin withdrawal. RESULTS: Among the metabolites analyzed, omega-6 polyunsaturated fatty acids (linoleic acid, dihomo-gamma-linolenic acid, arachidonic acid, n-6 docosapentaenoic acid), omega-3 polyunsaturated fatty acids (docosahexaenoic acid, docosapentaenoic acid), aromatic amino acids (phenylalanine, tyrosine, tryptophan), and intermediates of the tricarboxylic acid cycle (oxoglutaric acid, isocitric acid) were significantly reduced during acute heroin withdrawal. Although majority of the metabolite changes could recover after months of withdrawal, the levels of alpha-aminobutyric acid, alloisoleucine, ketoleucine, and oxalic acid do not recover. CONCLUSIONS: In conclusion, the plasma metabolites undergo tremendous changes during heroin withdrawal. Through metabolomic analysis, we have identified links between a framework of metabolic perturbations and withdrawal stages in heroin addicts.

Modulation of neuropeptide Y levels is impaired in crack withdrawal patients

Abstract Introduction The dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has a key role in drug addiction susceptibility. In addition to the well-known relationship between cortisol and the HPA axis, other molecules are involved with stress response and could modify the HPA activation, such as the neuropeptide Y (NPY), which has anxiolytic proprieties. There are few studies evaluating the effect of NPY levels on addiction, especially in crack cocaine dependence. Objective To evaluate NPY in crack users during early withdrawal to determine its relationship with drug use and cortisol levels. Methods We analyzed 25 male inpatient crack users. Serum NPY levels were measured at admission and discharge (mean of 24 days). Morning salivary cortisol was measured at admission. Results Serum NPY levels at admission and discharge were very similar. Lower NPY levels at discharge were associated with higher lifetime crack use. Also, a negative correlation was found between morning cortisol and delta NPY (NPY discharge - NPY admission). Conclusion These preliminary findings indicate that crack use influences the modulation of NPY levels and modifies stress response. The NPY pathway may play an important role in the pathophysiology of crack addiction, and the anxiolytic effect of NPY may be impaired in crack users. Future studies should consider NPY as a measurable indicator of the biological state in addiction.

The association between interleukin-8 levels and the development of withdrawal symptoms during methamphetamine abstinence.

OBJECTIVE: Withdrawal symptoms are common during methamphetamine (METH) abstinence. This study aimed to explore the association between serum interleukins and withdrawal symptoms during METH abstinence. METHODS: This study recruited 120 METH users, and 94 of them completed the 2-week follow-up. Serum interleukin-1ß, 6,8,10 were tested at admission. Withdrawal symptoms were assessed by the Methamphetamine Withdrawal Questionnaire (MAWQ). RESULTS: Serum IL-8 levels were positively correlated with MAWQ scores at the 2-week endpoint (r = .257, p = .013). The variation of the MAWQ scores during the 2-week follow-up was negatively correlated with serum IL-8 levels at admission (r = -.249, p = .026). Serum IL-8 levels remained associated with the severity of METH withdrawal symptoms (ß = .363, p = .023), after adjusting for potential confounders. LIMITATIONS: This study did not include normal controls. Most patients were male and cigarette smokers. Patients were only followed up for 2 weeks, and their toxicology data were not collected. Interleukins were only measured at admission, and were tested in serum, not in the cerebrospinal fluid. CONCLUSIONS: Our study demonstrated that higher serum IL-8 levels may predict more severe withdrawal symptoms at 2 weeks after METH abstinence.

Effects of childhood trauma on BDNF and TBARS during crack-cocaine withdrawal

Objective: To evaluate the association between childhood trauma (CT) and serum levels of brain-derived neurotrophic factor (BDNF) and thiobarbituric acid-reactive substances (TBARS) during crack-cocaine withdrawal. Method: Thirty-three male crack-cocaine users were recruited at admission to a public addiction treatment unit. Serum BDNF and TBARS levels were evaluated at intake and discharge. Information about drug use was assessed by the Addiction Severity Index-6th Version (ASI-6); CT was reported throughout the Childhood Trauma Questionnaire (CTQ). CTQ scores were calculated based on a latent analysis model that divided the sample into low-, medium-, and high-level trauma groups. Results: There was a significant increase in BDNF levels from admission to discharge, which did not differ across CT subgroups. For TBARS levels, we found a significant time vs. trauma interaction (F2,28 = 6.357, p = 0.005,ηp 2 = 0.312). In participants with low trauma level, TBARS decreased, while in those with a high trauma level, TBARS increased during early withdrawal. Conclusion: TBARS levels showed opposite patterns of change in crack-cocaine withdrawal according to baseline CT. These results suggest that CT could be associated with more severe neurological impairment during withdrawal.

Nicotine e-cigarette vapor inhalation effects on nicotine & cotinine plasma levels and somatic withdrawal signs in adult male Wistar rats.

RATIONALE: Non-contingent chronic nicotine exposure procedures have evolved rapidly in recent years, culminating in electronic nicotine delivery systems (ENDS or e-cigarettes) to deliver vaporized drugs to rodents in standard housing chambers. OBJECTIVES: The aim of the current work was to use ENDS to test concentration-dependent effects of nicotine e-cigarette vapor inhalation on blood-nicotine concentrations, blood-cotinine concentrations, and somatic withdrawal signs over time in rats. METHODS: Male Wistar rats were exposed to vapor containing various concentrations of nicotine (20, 40, 80 mg/mL) for 11 days through ENDS, and blood concentrations of nicotine and cotinine, the major proximate metabolite of nicotine, as well as spontaneous and precipitated somatic withdrawal signs, were measured over time (across days of exposure and over hours after termination of vapor exposure). RESULTS: Exposing male Wistar rats to non-contingent nicotine vapor inhalation through ENDS produces somatic withdrawal symptoms and measurable blood-nicotine and blood-cotinine levels that change according to (1) concentration of nicotine in vape solution, (2) number of days of nicotine vapor exposure, (3) time since termination of nicotine vapor exposure, and (4) relative to the withdrawal signs, whether withdrawal was spontaneous or precipitated (by mecamylamine). CONCLUSIONS: The data presented here provide parameters that can be used as a reasonable starting point for future work that employs ENDS to deliver non-contingent nicotine vapor in rats, although many parameters can and should be altered to match the specific goals of future work.

Neuro-Immuno-Endocrine Interactions in Early Life Stress and Heroin Withdrawal Timeline.

Both heroin abuse and early life stress (ELS) affect the immune system and the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, accelerated aging due to mild inflammation has been indicated in these conditions. The present study aims to compare plasma levels of apoptosis markers, inflammatory markers, and stress hormones during early heroin abstinence period. Thirty-one individuals with heroin/opioid use disorder who had heroin-ELS and 26 of their siblings who were not abusing substances (ELS), and 32 individuals with heroin/opioid use disorder without a history of ELS (heroin-no ELS) were included in the study. The levels of interleukin-6, C-reactive protein, erythrocyte sedimentation rate, albumin, alanine transaminase, aspartate transaminase, and white blood cell count were assessed as the inflammatory and biochemistry markers. Also, apoptosis markers including tumor necrosis factor (TNF)-related weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, soluble tumor necrosis factor receptor type I as apoptosis markers were detected by enzyme-linked immunosorbent assay. ELS was simultaneously evaluated using the Childhood Trauma Questionnaire, Minnesota Multiphasic Personality Inventory, and beck depression inventory scales. Besides, heroin craving was assessed by Daily Drinking/Drug Questionnaire score in individuals with heroin use disorder. This is the first study to evaluate the inflammatory, stress, and apoptosis markers during heroin abstinence, supporting the association between ELS and peripheral pro-inflammatory markers' levels and HPA axis.

Predictive factors for abiraterone withdrawal syndrome. / Factores predictivos del síndrome de retirada de abiraterona.

INTRODUCTION AND OBJECTIVE: Abiraterone withdrawal syndrome (AWS) is characterized by a transient decrease in the PSA after abiraterone acetate (AA) treatment discontinuation in patients diagnosed with metastatic castration-resistant prostate cancer (mCRPC). The aim of our study is to identify the possible predictive factors of AWS at diagnosis. MATERIALS AND METHODS: We performed a retrospective study of 70 patients treated with AA at the Institut Català d'Oncologia - L'Hospitalet between 2015 and 2017. RESULTS: 11 patients presented AWS. The mean age at diagnosis was 65.73 years and the mean age of presentation was 74.18 years. Patients were in the ninth treatment cycle. The median PSA was: 30.5ng/ml at diagnosis, 33.24ng/ml in the AWS, and 15.78ng/ml before starting another treatment. The median follow-up period after AWS was 8.2 months. The predictive factors of AWS would be: high PSA (p=.002), ISUP≥4 (p=.002) and stage IV at diagnosis (p<.001). Patients with a T stage present high risk, but without statistical significance. An AUC of 0.84 was obtained, with a 95% CI between 0.77 and 0.92 (p<.001). CONCLUSIONS: The incidence of AWS is not negligible, describing prolonged responses after AA withdrawal, including the possibility of increased overall survival. These results could entail new treatment schemes for mCRPC.

Estrogen receptor 1 gene variants and estradiol activities in alcohol dependence.

OBJECTIVE: Alcohol use disorders inflict a great individual and societal burden. Although sex hormone effects have been implicated in alcohol dependence, research has mostly neglected estrogen activities and female alcohol-dependent patients. Here, we investigated associations of estrogen receptor 1 (ESR1) genetics and serum estradiol activities with aspects of alcohol dependence. METHOD: Serum estradiol activities of early-abstinent alcohol-dependent in-patients (n[♂] = 113, n[♀] = 87) were followed for at median 5 days and compared with healthy controls (n[♂] = 133, n[♀] = 107). All participants were genotyped for five ESR1 single nucleotide polymorphisms (rs6902771, rs11155819, rs6557171, rs2982683, rs2982712). RESULTS: Bioavailable estradiol levels decreased during withdrawal treatment (P[♂] < .001, P[♀] = .011). Male patients with an increase of bioavailable estradiol during withdrawal showed fewer days to (P = .033) and more alcohol-related readmissions (P < .05) during the 12-month follow-up. Higher estradiol and estradiol-to-testosterone activities were significantly related to liver, muscle, and cell count damage in male patients. Estradiol-to-testosterone activities in female patients were lower compared to female controls (total P = .013, bioavailable P = .009). Moreover, the ESR1 genotypes jointly separated alcohol-dependent patients from controls (P = .037). CONCLUSION: Our findings support the role of ESR1 genetics in alcohol dependence and show for the first time that estradiol activities may sex-specifically predict alcohol-related sequelae and outcome following in-patient withdrawal treatment.

Influences of the Menstrual Phase on Cortisol Response to Stress in Nicotine Dependent Women: A Preliminary Examination.

INTRODUCTION: Evidence indicates that menstrual cycle phase plays a role in smoking withdrawal symptoms and craving. Stress increases these symptoms. Whether the stress regulatory mechanism is associated with menstrual phase and withdrawal symptoms is not well understood. METHODS: Thirty-seven female smokers and 16 female nonsmokers were asked to complete a laboratory session. In each group, approximately half of the participants were tested when they were in the follicular phase and the other half was tested in the luteal phase. The session included resting baseline, stress, and recovery periods. Saliva samples for the measurement of cortisol and subjective measures of craving and withdrawal symptoms were collected at the end of each period. RESULTS: A series of repeated measures analysis of covariance found a significant smoking group × menstrual phase × sampling time interaction in cortisol levels (p < .05). Follow-up analyses indicated a reduced cortisol stress response in the luteal group relative to the follicular group in smokers (p < .02). This difference was not found in nonsmokers. CONCLUSIONS: Menstrual cycle phase is related to hormonal stress response and smoking withdrawal symptomatology. IMPLICATIONS: We show influences of the menstrual cycle phase on stress response among smokers. This is demonstrated by a reduced cortisol response to stress in the luteal group relative to the follicular group among smokers. This menstrual phase difference was not found in nonsmokers.

Circulating orexin changes during withdrawal are associated with nicotine craving and risk for smoking relapse.

We examined the extent to which orexin measured during smoking and the early phase of abstinence was related to craving, withdrawal, stress hormones, and risk for smoking relapse in men and women. Considering its role in modulating nicotine-related reward, we predicted that a reduction in circulating orexin during withdrawal would be associated with increased craving and risk for smoking relapse. Two hundred and eighty five participants provided biological samples and self-report information to identify predictors of smoking relapse. All participants attended two laboratory sessions, which were before and after a period of required abstinence from smoking. After quitting, participants also attended four weekly sessions to track smoking relapse. Only smokers who relapsed within the follow-up period exhibited reduced orexin levels during the initial withdrawal period; ACTH, but not craving nor cortisol, increased across the abstinence period for successful abstainers but not for relapsers. Sex differences in orexin and craving or withdrawal associations also emerged. Adding sex, HPA hormones, and self-reported measures of craving and withdrawal as potential mediators had minimal effects on the above abstinence and orexin effects. These results provide the first evidence that circulating orexin may be a useful marker of risk for relapse; and sex, adrenal hormones, and self-reported craving and withdrawal were not mediators of this effect. The results point to a promising pathway to investigate objective biological markers for craving and smoking relapse and highlight the complexity of the neurobiology of relapse.

Smoking-induced changes in leptin serum levels and c/EBPalpha-related methylation status of the leptin core promotor during smoking cessation.

Previous studies have provided evidence of an association between serum leptin levels and smoking as well as craving during smoking cessation. As promoter methylation also regulates leptin expression, we investigated the leptin gene promoter region of smokers before and after smoking cessation. Since leptin's core promoter region contains an essential c/EBPalpha transcription binding site, we narrowed our investigation to C-300 (-300 base pairs from the transcription start site) of that binding site. Female smokers showed hypermethylation of C-300 compared to non-smokers. Global methylation status is associated with higher craving and the degree of dependence in female smokers. Serum leptin levels in female smokers were significantly higher than in non-smokers. These findings support previous results and, for the first time, point to a pathophysiological role of c/EBPalpha-related C-300 methylation in tobacco dependence.

Epigenetic alterations of the POMC promoter in tobacco dependence.

Impaired regulation of the hypothalamic-pituitary-adrenal (HPA) axis is substantially involved in several psychiatric disorders. Smoking interferes with HPA axis by activating proopiomelanocortin (POMC) neurons and thus stimulating the expression of POMC. The POMC transcript is processed into several peptide hormones, such as adrenocorticotropic hormone (ACTH) and alpha-melanocyte-stimulating hormone (alpha-MSH), that play a role in stress response and weight control. In alcohol dependence, POMC promoter methylation is associated with craving. Here, we describe evidence of altered POMC promoter methylation in smoking. To determine how tobacco dependence and its withdrawal affect POMC promoter-specific DNA methylation, we assessed blood samples of 36 tobacco dependent individuals at day 1, 7 and 14 of withdrawal compared to 41 healthy controls using direct bisulfite sequencing. We found that POMC promoter methylation is significantly higher in smokers than in non-smokers. Moreover, this methylation difference does not readapt within 14 days of abstinence. We offer two explanatory models: Smokers could have a higher methylation state before the onset of smoking and this premorbid status might be acquired by environmental factors in early life. Alternatively, smoking may activate POMC neurons and its protein expression. Therefore, increasing methylation status of its promoter might be an adjustment to keep homeostasis. In either way, altered POMC methylation in smokers seems to indicate an adaptation of stress signaling, thereby potentially serving as a marker for stress-related functions that support the addiction.

The Association between the Level of Plasma Oxytocin and Craving among Former Heroin Users.

BACKGROUND: Animal studies have demonstrated that oxytocin can influence addiction behaviors and might interact with the dopaminergic system, which is a key component of addiction behaviors. However, related evidence from clinical studies is scarce. The aim of our study was to explore the relationship between plasma oxytocin level and heroin craving among patients receiving methadone maintenance treatment, and to ascertain whether this relationship is moderated by novelty-seeking. METHODS: The study was conducted in a methadone maintenance therapy clinic of a medical center in Taiwan. Seventy-seven patients with heroin addiction were enrolled. Plasma oxytocin was measured using an ELISA kit. Craving was assessed using an established instrument, the Chinese Craving Scale. RESULTS: A significant negative association was found between the plasma oxytocin level and craving score, which remained robust after controlling the effects of social support and low-density lipoprotein cholesterol. An interaction between oxytocin and novelty-seeking indicated that this relationship was stronger among patients with a lower level of novelty-seeking. CONCLUSION: This finding may be taken into account in future studies and may provide a basis for the development of potential treatment for addiction. The effect of oxytocin for the treatment of opioid dependence might be modulated by some psychological factors.

Evaluation of oxidative stress and brain-derived neurotrophic factor levels related to crack-use detoxification.

Crack is a central nervous system stimulant extracted from the Erythroxylum coca plant. It is considered the most potent and addictive form of cocaine, and its euphoric effects are attained within a few seconds after consumption. Alteration of biological markers of oxidative stress and brain-derived neurotrophic factor (BDNF) could be related to the severity of crack withdrawal symptoms in patients undergoing rehabilitation. Thus, the objective of this study was to evaluate if the crack consumption and the drug detoxification process during 14 days in hospitalization regime was able to modify the oxidative status and BDNF levels, in male crack-abstinent patients. The crack detoxification process increased the glutathione (GSH), total thiol content (GST), nitric oxide (NO), and superoxide dismutase (SOD) levels, and reduced the mean BDNF levels. Moreover, a positive correlation was found between the number of hospital admission days and SOD values and between the GST levels and crack-use time after 14 days of detoxification. Furthermore, a negative correlation between the frequency of crack use and NO levels on the first day of hospitalization was also found. In conclusion, the results of this study indicated that crack consumption causes increased oxidative stress in drug users and that the detoxification process during 14 days was sufficient to improve oxidative parameters and antioxidant defenses of the patients, which could positively contribute to rehabilitation process. In addition, we also observed a great variability in the BDNF levels of the patients during the detoxification process, resulting in a reduction in the mean values of this neurotrophin.

Early life adversity influences stress response association with smoking relapse.

RATIONALE: We examined the hypothesis that stress-related blunting of cortisol in smokers is particularly pronounced in those with a history of severe life adversity. OBJECTIVES: The two aims of this study were first to examine hormonal, craving, and withdrawal symptoms during ad libitum smoking and after the first 24 h of abstinence in smokers who experienced high or low levels of adversity. Second, we sought to examine the relationship between adversity and hypothalamic-pituitary-adrenal (HPA) hormones to predict relapse during the first month of a smoking cessation attempt. METHODS: Hormonal and self-report measures were collected from 103 smokers (49 women) during ad libitum smoking and after the first 24 h of abstinence. HPA hormones were measured during baseline rest and in response to acute stress in both conditions. All smokers were interested in smoking cessation, and we prospectively used stress response measures to predict relapse during the first 4 weeks of the smoking cessation attempt. RESULTS: The results showed that high adversity was associated with higher distress and smoking withdrawal symptoms. High level of early life adversity was associated with elevated HPA activity, which was found in both salivary and plasma cortisol. Enhanced adrenocorticotropic hormone (ACTH) stress response was evident in high-adversity but not in low-adversity relapsers. CONCLUSIONS: This study demonstrated that early life adversity is associated with stress-related HPA responses. The study also demonstrated that, among smokers who experienced a high level of life adversity, heightened ACTH and cortisol responses were linked with increased risk for smoking relapse.

Peripheral immune system suppression in early abstinent alcohol-dependent individuals: Links to stress and cue-related craving.

BACKGROUND: Peripheral immune system cytokines may play an integral role in the underlying sensitized stress response and alcohol craving during early alcohol withdrawal. To date, the nature of these immune changes during early abstinence have not been examined. METHODS: A total of 39 early abstinent, treatment-seeking, alcohol-dependent individuals and 46 socially drinking controls were exposed to three guided imageries: stress, alcohol cue and neutral. These were presented randomly across consecutive days. Plasma measures of tumor necrosis factor alpha (TNFα), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), and interleukin-10 (IL-10), were collected at baseline, immediately after imagery and at various recovery time-points. Ratings of alcohol craving, negative mood and anxiety were also obtained at the same time-points. RESULTS: The alcohol group demonstrated decreased basal IL-10 compared with controls particularly following exposure to alcohol cue. They also showed a dampened TNFα and TNFR1 response to stress and cue, respectively, and a generalized suppression of IL-6. In the alcohol group, these immune system adaptations occurred alongside significant elevations in anxiety, negative mood and alcohol craving. CONCLUSIONS: Findings demonstrate that broad immunosuppression is still observed in alcohol-dependent individuals after 3 weeks of abstinence and may be linked to motivation for alcohol.

Prenatal and adult androgen activities in alcohol dependence.

OBJECTIVE: Alcohol dependence is more prevalent in men than in women. The evidence for how prenatal and adult androgens influence alcohol dependence is limited. We investigated the effects of prenatal and adult androgen activity on alcohol dependence. Moreover, we studied how the behaviours of pregnant women affect their children's prenatal androgen load. METHOD: We quantified prenatal androgen markers (e.g., second-to-fourth finger length ratio [2D : 4D]) and blood androgens in 200 early-abstinent alcohol-dependent in-patients and 240 controls (2013-2015, including a 12-month follow-up). We also surveyed 134 women during pregnancy (2005-2007) and measured the 2D : 4D of their children (2013-2016). RESULTS: The prenatal androgen loads were higher in the male alcohol-dependent patients compared to the controls (lower 2D : 4D, P = 0.004) and correlated positively with the patients' liver transaminase activities (P < 0.001) and alcohol withdrawal severity (P = 0.019). Higher prenatal androgen loads and increasing androgen levels during withdrawal predicted earlier and more frequent 12-month hospital readmission in alcohol-dependent patients (P < 0.005). Moreover, stress levels (P = 0.002), alcohol (P = 0.010) and tobacco consumption (P = 0.017), and lifetime stressors (P = 0.019) of women during pregnancy related positively to their children's prenatal androgen loads (lower 2D : 4D). CONCLUSION: Androgen activities in alcohol-dependent patients and behaviours of pregnant women represent novel preventive and therapeutic targets of alcohol dependence.

Severity of Withdrawal Symptoms, Plasma Oxytocin Levels, and Treatment Outcome in Heroin Users Undergoing Acute Withdrawal.

Pre-clinical studies show that, following chronic opioid exposure, oxytocin neurons exhibit over-excitation upon withdrawal, causing an increase in oxytocin brain and plasma levels. Relevant clinical data on humans are scarce. This study investigates the opioid withdrawal stress effect on oxytocin plasma levels in humans. We evaluated 57 male chronic heroin users in a residential detoxification program. We determined plasma oxytocin levels by ELISA and measured the stress effects of withdrawal using the COWS scale for opioid withdrawal, the VAS scale for craving, and the Hamilton scales for anxiety and depression on the second day of admission. Out of the 57 patients enrolled in the study, 27 completed the 21-day program, while the remaining 30 dropped out prior to completion. Plasma oxytocin levels were significantly higher in those individuals who dropped out than in those who completed the program. Participants who dropped out at some stage scored higher in the COWS, VAS-Craving, and Hamilton-anxiety scales, indicating a higher stress and explaining the higher oxytocin levels. In addition, plasma oxytocin levels correlated positively with the scores achieved in the COWS and Hamilton-anxiety scales. Higher withdrawal stress levels are associated with higher plasma oxytocin levels and early treatment discharge.