Fentanyl abuse proportion in methadone maintenance treatment, and patients' knowledge about its risks.

INTRODUCTION: Fentanyl is not yet routinely monitored among methadone maintenance treatment (MMT) patients in Israel. We aimed 1. to evaluate urine fentanyl proportion changes over 3 years and characterize patients' characteristics 2. To study patients' self-report on fentanyl usage, and compare knowledge about fentanyl risk, before and following brief educational intervention. METHODS: Fentanyl in the urine of all current MMT patients was tested every 3 months year between 2021 and 2023, and patients with positive urine fentanyl were characterized. Current patients were interviewed using a fentanyl knowledge questionnaire (effects, indications, and risks) before and following an explanation session. RESULTS: Proportion of fentanyl ranged between 9.8 and 15.1%, and patients with urine positive for fentanyl (September 2023) were characterized as having positive urine for pregabalin, cocaine, and benzodiazepine (logistic regression). Of the current 260 patients (87% compliance), 78(30%) self-reported of fentanyl lifetime use ("Ever"), and 182 "never" use. The "Ever" group had higher Knowledge scores than the "Never", both groups improved following the explanatory session (repeated measure). The "Ever" group patients were found with urine positive for cannabis and benzodiazepine on admission to MMT, they were younger, did not manage to gain take-home dose privileges and had a higher fentanyl knowledge score (logistic regression). CONCLUSIONS: In the absence of routine fentanyl tests, a high knowledge score, shorter duration in MMT, benzodiazepine usage on admission, and current cannabis usage, may hint of the possibility of fentanyl abuse.

Predictors of treatment retention and survival among methadone-maintained patients: A possible role for a functional delta opioid receptor gene variant.

BACKGROUND: Variants in the delta opioid receptor gene, OPRD1, were associated with opioid use disorder and response to treatment. The study goal was to assess whether OPRD1 variants predict survival and retention in methadone maintenance treatment (MMT). METHODS: Retention and survival time since admission (June 1993 - June 2022) until leaving treatment (for retention), or at the end of follow-up (Dec 2022) (for retention and survival) were analyzed in 488 patients. Vital data was taken from a national registry. Predictors were estimated using Kaplan-Meier and Cox regression models. RESULTS: Longer retention and survival were found for carriers of the T allele of SNP rs204076. This SNP is associated with OPRD1 expression in cortex (GTEx). Carriers of the T allele (n = 251) survived longer compared to non-carriers (24.7 vs. 20.2 years, p = 0.005) and had longer retention (11.2 vs. 8.8 years, p = 0.04). Multivariate analysis identified the T allele as an independent predictor of longer survival time (p = 0.003) and retention (p = 0.009). Additional predictors for survival were no benzodiazepine use after one year in MMT, no hepatitis C, <20 years of opioid usage, and admission at age < 30. Additional predictors for longer retention were no use of other drugs except opioids on admission, and no drugs at one year, as well as methadone dose ≥ 100mg/d at one year and axis I & II DSM-5 psychiatric diagnosis. CONCLUSIONS: The OPRD1 SNP rs204076 and non-genetic predictors contribute to survival time and retention in MMT patients.

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (rg > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

Hepatitis C Virus Elimination in Methadone-treated Patients: Implementation of Hepatology Clinic in a Methadone Treatment Program.

OBJECTIVES: Patient ignorance and bureaucratic obstacles prevent initiation of hepatitis C virus (HCV) treatment in patients participating in methadone treatment program. Despite high safety and efficacy of currently available oral medications, the rate of patient-initiated treatment remains low. We evaluated the impact of an interventional program on treatment success rate and factors associated with treatment engagement. METHODS: An intervention performed from 2018 to 2020 included an on-site Fibroscan and hepatologist evaluation, anti-viral HCV treatment initiation, and close support and follow-up by a dedicated team. Demographic and medical data were collected and comparison between patients who completed vs. patients who did not complete HCV treatment was done. RESULTS: Fifty-nine out of 74 HCV polymerase chain reaction-positive patients (79.7%) were willing and capable of undergoing on-site hepatologist and Fibroscan evaluations. Twelve (25%) of the participants had cirrhosis, 2 of whom were decompensated. Fifty of the 57 patients that got an anti-viral medication prescription (87%) initiated the treatment. Premature treatment discontinuation was rare (3 patients), intention-to-treat sustain virologic response (SVR) rate was 81% and per-protocol SVR rate was 97%. The rate of treatment initiation during the intervention was significantly higher than the patients' self-initiation rate (44 vs 12 patients). The main factors associated with successful completion of the care cascade was full abstinence from street drugs for 6 months before treatment initiation. CONCLUSIONS: Installing a hepatology clinic in an methadone treatment program center was associated with a 3-fold increase in the HCV treatment, with high adherence to treatment levels, and a high SVR rate. The main factor associated with low engagement to treatment was ongoing street drug use.

Cannabis use is associated with lower retention in methadone maintenance treatment, but not among schizophrenic- and other chronically psychotic patients.

The findings of studies on cannabis use and retention in methadone maintenance treatment (MMT) are inconsistent.To study cannabis use and its relationship to patients' outcomes in MMT with/without lifetime DSM-IV-TR schizophrenia/chronic-psychosis diagnosis.Since June 1993, 877 patients with available lifetime DSM-IV-TR psychiatric diagnosis were followed-up until December 2017. Urine drug screens on admission and after one year were analyzed.Lifetime schizophrenia/psychosis was diagnosed in 50 (5.7%) patients. They did not differ from the other 827 by admission cannabis use (18.0% vs. 12.3%) and had similar 1-year retention rates (76.0% vs.77.0%, respectively). Cumulative retention of the cohort excluding schizophrenia/chronic-psychosis was longer for the 667 patients who did not use cannabis after 1-year (9.1 years, 95%CI 8.4-9.9) compared with the 118 cannabis-users after 1-year (6.0 years, 95% CI 4.8-7.2, p<.001). Among the schizophrenia/chronic-psychosis group, cannabis was not related to retention (38 non-users, 7.9 years 95%CI 5.2-10.5 vs. 9 cannabis-users, 9.9 years, 95% CI 3.8-16.0, p=.5). Survival was shorter for the 41 schizophrenia/chronic-psychosis non-users (15.2 years, 95% CI 12.8-17.7) than for the 719 non-schizophrenia/chronic-psychosis non-users (18.5, 95%CI 17.9-19.2, p = 0.009). However, survival was comparable among the 9 cannabis-users with schizophrenia/chronic-psychosis (20.1, 95% CI 16.2-24.1) and 101 other cohort users (18.6, 95% CI 16.9-20.4).Cannabis use is associated with decreased retention among MMT patients, however the effects of cannabis on schizophrenia/psychosis patients on retention and survival cannot be verified due to the small sample size and the limited data regarding chronicity of cannabis use. Future larger, prospective studies are needed.

The prevalence of constipation and its relation to sweet taste preference among patients receiving methadone maintenance treatment.

BACKGROUND: Preference for sweet-tasting foods, weight gain, and constipation characterize patients receiving methadone maintenance treatment (MMT). The prevalence of constipation in MMT and its relation to preference for sweet taste and body mass index (BMI) are undetermined. METHODS: A random sample of 83 patients was interviewed for constipation with the Patient Assessment Constipation Quality of Life (PAC-QOL) questionnaire. They rated taste intensity and reward of sweet, salty, and sour solutions by means of a nine-point Likert scale. Data on their BMI, drugs in urine, methadone dose, and serum levels were analyzed. RESULTS: Forty-two patients reported minimum to severe constipation. They characterized as having longer durations of opioid usage before MMT and worse sleep quality than non-constipated patients (logistic regression). Constipation intensity was inversely correlated with duration in MMT and linearly correlated with the Patient Assessment Constipation Quality of Life score. Patients with constipation rated reward to sweet taste significantly higher with no differences in taste intensity compared to non-constipated patients. Patients with high methadone serum levels (≥750 ng/mL) rated taste intensity significantly lower compared to those with normal methadone serum levels (<750 ng/mL), and the lowest rates were reported among patients with no constipation and high methadone serum levels. CONCLUSIONS: Constipation was highly prevalent among MMT patients and associated with poor sleep and lower quality of life. The relation to preference for sweets, as reflected by higher reward rating, strongly supports the need for nutritional intervention to alleviate constipation symptoms and improve quality of life and sleep.

OPRD1 SNPs associated with opioid addiction are cis-eQTLs for the phosphatase and actin regulator 4 gene, PHACTR4, a mediator of cytoskeletal dynamics.

Several OPRD1 intronic variants were associated with opioid addiction (OD) in a population-specific manner. This follow-up study aims to further characterize the OPRD1 haplotype pattern of the risk variants in different populations and apply in silico analysis to identify potential causal variants. A population-specific haplotype pattern was revealed based on six OPRD1 eQTL SNPs and five common haplotypes were identified in a sample of European ancestry (CEU). A European-specific haplotype ('Hap 3') that includes SNPs previously associated with OD and is tagged by SNP rs2236861 is more common in subjects with OD. It is quite common (10%) in CEU but is absent in the African sample (YRI) and extends upstream of OPRD1. SNP rs2236857 is most probably a non-causal variant in LD with the causal SNP/s in a population-specific manner. The study provides an explanation for the lack of association in African Americans, despite its high frequency in this population. OD samples homozygous for 'Hap 3' were reanalyzed using a denser coverage of the region and revealed at least 25 potentially regulatory SNPs in high LD. Notably, GTEx data indicate that some of the SNPs are eQTLs for the upstream phosphatase and actin regulator 4 (PHACTR4), in the cortex, and others are eQTLs for OPRD1 and the upstream lncRNA ENSG00000270605, in the cerebellum. The study highlights the limitation of single SNP analysis and the sensitivity of association studies of OPRD1 to a genetic background. It proposes a long-range functional connection between OPRD1 and PHACTR4. PHACTR4, a mediator of cytoskeletal dynamics, may contribute to drug addiction by modulating synaptic plasticity.

Post-traumatic stress disorder due to sexual abuse and its relation to pain sensitivity among patients in methadone maintenance treatment.

We studied whether post-traumatic stress disorder (PTSD) due to sexual abuse is related to pain indices among methadone maintenance treatment (MMT) patients. Pain threshold was determined, and suprathreshold pain levels were rated among 18 patients with PTSD and sexual abuse, and 38 patients without PTSD (20 with and 18 without sexual abuse). Patients with PTSD had higher proportion of chronic pain and high-perceived stress, and lower pain threshold, with similar supra-threshold ratings. Patients with benzodiazepine in urine had higher pain thresholds and they rated supra-threshold stimuli lower. However, the analgesic effect was not observed among PTSD patients.

Trend differences over 20 years between two methadone maintenance clinics, one with and one without cannabis legalization.

BACKGROUND: Although methadone maintenance treatment (MMT) guidelines are well established, patients' characteristics and outcome change over time may be affected by the legality of cannabis. OBJECTIVE: To study trend changes between two clinics over 20 years from Las Vegas (LV) and 27 years from Tel Aviv (TA). METHODS: Patients' characteristics at admission, including drugs in urine at first and 13th month were obtained from their medical charts. Changes by year of admission and cumulative retention were analyzed. RESULTS: The LV MMT clinic (1724 patients) had a lower one-year retention rate compared to the TA MMT clinic (1014 patients) (46.4% vs. 74.4%, respectively, p < 0.0005), and a higher rate of opioid stop after one year (75.9% vs. 68.8%, respectively, p = 0.003). The age at MMT admission and the retention rates decreased in LV and increased in TA. The prevalence of cannabis and benzodiazepine misuse on MMT admission increased in LV with no change recorded in TA. Cocaine on MMT admission decreased in LV and increased in TA, while amphetamine use increased in LV and decreased in TA. Cox models multivariate analyses found cannabis on admission to predict shorter retention in LV (as younger age male and amphetamines), and cannabis after one year in TA (as did cocaine and opiates after one year and BDZ on admission). CONCLUSION: Although cannabis prevalence increased only in LV where it was legalized, it was associated with poor outcomes in both clinics. Younger age, a known poor outcome predictor, may be related to decreased retention in LV.

Polymorphisms in Stress-Related Genes Are Associated with Reduced Cocaine Abuse and Longer Retention in Methadone Maintenance Treatment for Opioid Use Disorder.

BACKGROUND: As CRH-binding protein (CRHBP) SNP rs1500 was associated with reduced cocaine abuse after 1 year in methadone maintenance treatment (MMT) for heroin addiction, we evaluated the association of additional 28 selected SNPs, in 17 stress-related genes, with MMT outcome. METHODS: The distribution of genotypes of each SNP by cocaine abuse after 1 year in MMT was assessed under the dominant and recessive models using χ2. Cumulative retention (up to 26.5 years) was studied using Kaplan-Meier analyses. Logistic regression and Cox model were used for multivariate analyses. RESULTS: Of a nonselective sample of 404 patients, 25 patients with <50% Europeans/Middle Eastern ancestry were excluded. Of the remaining 379 patients, 330 (87.1%) stayed at least 1 year in treatment. Four SNPs were associated with cocaine abuse after 1 year in MMT. A lower proportion of cocaine abusers was found in the groups of subjects with the following genotypes: arginine vasopressin (AVP) SNP rs2282018 CC, CRHBP rs7728378 TT, galanin rs3136541 TT/TC, and neuropeptide Y receptor Y1 (NPY1R) rs4518200 AA. The following independent variables were associated with lack of cocaine in urine after 1 year (multivariate analyses): CRHBP rs7728378 TT, NPY1R rs4518200 AA, no cocaine in urine on admission, as well as opiate and benzodiazepine use after 1 year in MMT. Cumulative retention (n = 379) was longer in carriers of AVP rs2282018 CC (13.7 years, 95% CI 11.1-16.2) versus TT/TC genotypes (10.5, 95% CI 9.4-11.5) (p = 0.0230) Conclusions: The study suggests that a reduction in cocaine abuse and longer retention among MMT patients is mediated in part by variants in stress-related genes and is a step toward precision medicine.

Pregabalin Misuse: Motives, Pattern, and Knowledge about Its Risks among Patients in Methadone Maintenance Treatment.

We examined motives for pregabalin misuse and the relation with knowledge on its risks among patients receiving MMT. A questionnaire was used to assess patients' knowledge before and after an explanatory session. Responses were either "never-use" or "ever-use" (past, occasional, chronic). Pregabalin in urine was tested during 1 month, 4 months before, and 24 months after the explanatory session. Of 231 participants, 72 (31.2%) responded "ever-use" while 46 (19.9%) tested positive for pregabalin (42 (58.3%) of the "ever-use" and 4 (2.5%) of the "never-use" group). The 'occasional' subgroup had the highest proportion of non-prescribed pregabalin (75%), used it for recreational purpose (16.7%) and non-orally (41.7%). A faster dropout (shorter retention in MMT) was observed among patients who used pregabalin not orally (1.4 years, 95%CI 1.2-1.7) vs. (1.7 years, CI 1.6-1.8, p = .02), and those who used it not for pain (p = .024). Knowledge scores were higher among those tested positive for pregabalin (3.5 ± 1.7 vs. 2.9 ± 2.0, p = .04). Pregabalin is highly misused among MMT patients. Those who use it not for its indications, or not orally had a shorter retention in MMT, most likely not as a sole cause. "Ever users" knew more about pregabalin indications and risks. Monitoring and education on pregabalin are recommended.

The Relation between Changes in Vitamin D and Vitamin B12 Levels, Body Mass Index and Outcome in Methadone Maintenance Treatment Patients.

Patients' Body Mass Index (BMI) increase during methadone maintenance treatment (MMT), and both Vitamins D and B12 deficiencies may be associated with BMI. We studied the relations between BMI, these vitamins and treatment outcome in patients with opioid use disorder receiving MMT. Vitamin B12 levels were available for 272 patients and Vitamin D levels were available for 260 patients. Of those 112 and 80 respectively had two measures (at admission or thereafter, and while stabilized or after one year in treatment). Patients' BMI levels and long-term retention were analyzed. Vitamin B12 was lower in patients abusing cocaine/amphetamine on admission. Vitamin D did not change over time, but a significant weight gain could be observed in 38 patients whose vitamin D was elevated compared to 42 whose levels were not, (25.4 ± 4.8 to 28.8 ± 5.2 vs. 24.3 ± 3.7 to 25.5 ± 4.0, p(Time) < 0.0005, p(Group) = 0.03, p(interaction) = 0.02). BMI changes correlated with vitamin D levels change (r = 0.26, p = .04). Longer cumulative retention was observed among the elevated vitamin D group (8.1 years, 95% CI 6.3-9.8) in comparison with the non-elevated group (4.8y 95% CI 3.6-6.1, Kaplan Meier, p = .02). Stimulants misuse was associated with low B12 levels. Vitamin D elevation is associated with weight gain and longer retention in treatment.

Improvement in Cognitive Performance after One Year of Methadone Maintenance Treatment.

Individuals with substance use disorders are known to suffer from stress, poor sleep, and cognitive impairment. We investigated whether individuals with opioid use disorder would improve cognitive performance following a year of methadone maintenance treatment (MMT). Perceived Stress Scale (PSS), the Pittsburgh Sleep Quality Index (PSQI), and a standardized computerized cognitive battery were administered at admission (T0) to 29 patients, and repeatedly following one year of MMT (T1) by 19 patients. Admission measures did not differ between those who studied once or twice. Patients who perceived very high stress levels (PSS ≥24) at T0 (11, 37.9%) had lower computerized global cognitive scores (67.6±16.2 vs. 90.9±12.5 p≤0.0005). At T1, PSS and PSQI scores improved significantly among 11 patients with no substance abuse, but worsened among 8 with substance abuse (PSS p(interaction)=0.009, p(groups)=0.005, PSQI p(interaction)=0.01, p(groups)=0.04). Global cognitive score improved at T1 for the entire sample (81.8±20.1 to 89.2±13.8, p=0.05). Differentiation by high stress at T0 or by substance abuse at T1 subgroups showed that improvement was observed by those with very low cognitive scores at T0. Patients with poor cognition may improve following one year of MMT, due to stress and substance abuse reduction. Interventions for stress reduction are recommended.

Cognitive state, substance use patterns and outcome after discharge from Kfar Izun, a unique rehabilitation facility.

We studied cognitive performance following discharge from a novel rehabilitation facility, treating individuals with psychosis that developed during trips abroad following mandatory military service. Montreal Cognitive Assessment (MoCA), phonetic and semantic fluency, State-Trait Anxiety, and self-Efficiency were administered before discharge, and 3 and 6 months after discharge. Of the 43 participants (30.2% females), 23(54.8%) had cognitive impairment (MoCA <27), and 15(35.7%) had poor phonetic fluency. Anxiety trait and state were high and inversely correlated with self-efficacy (R=-0.48, p = 0.001) and phonetic fluency (R=-0.43, p = 0.004) and was higher among those who experienced physical exposure, females, and those who served in non-combat army units. Six months after discharge, of 32 participants, 28 were working/studying with a 58.1% reduction in smoking and alcohol consumption, and 16 participants stopped substance use. Phonetic fluency improved among the high anxiety state group with no change among the others. High anxiety levels lowered among those who were still using drugs after six months. The anxiety level lowered and 87.1% of the participants were conducting a productive lifestyle at 6 months after discharge, but half still abused cannabis. Bigger sample and longer follow up would be needed to learn more about the impact of rehabilitation.

Stress indices in methadone maintenance treatment - Cross sectional and follow up study.

To study the prevalence of perceived high stress among methadone maintenance treatment (MMT) patients, and whether stress can predict outcome, and whether stress may improve during treatment, we studied a sample of 107 MMT patients using Perceived Stress Scale (PSS) questionnaires. We studied if PSS scores on admission predict long-term retention, and we monitored stress indices (PSS, heart rate variability, saliva cortisol) on admission, 6 and 12 months later, to measure changes. Variables included demographic data, history of adverse events, and urine test. A sample of 79 (73.8%) males and 28 (26.2%) females whose age at opioid use onset was 22.1±7.2 years and age at study onset 50.5±10.8 years was studied for PSS. Both high and very-high PSS patients characterized (logistic regression) as abusing benzodiazepine, and with history of depressive symptoms. The very-high PSS group on admission (n=29) had shorter cumulative retention (1.8 years, 95%%CI 1.2-2.4) compared with 50 others (2.8 years, 95%%CI 2.3-3.3, p=0.03). Monitoring stress indices among 25 patients found that no-benzodiazepine and cocaine use on admission, opioid discontinuation after 6 months, and any substance discontinuation after a year were associated with stress reduction. Conclusion: stress level appears to normalize among MMT patients if no other substance is abused.

Educational lectures enhance knowledge about the human immunodeficiency virus (HIV) and reduce risky behavior and fear among methadone maintenance treatment patients.

Background: The aim of this study was to characterize human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)-related knowledge and stigma among methadone maintenance treatment (MMT) patients and evaluate the contribution of an educational lecture in reducing risky behavior and unjustified overprotective behavior due to fear and stigma among MMT patients. Methods: Patients from an MMT clinic within a tertiary medical center were invited to an educational lecture on HIV/AIDS. Seventy participants (of current 330) were chosen by a random sample (December 2015), plus at-risk patients and HIV patients. Attendee compliance and change in scores of questionnaires on knowledge (modified HIV-K-Q-22) and on sexual and injection behaviors were studied. Results: Forty-six patients (65.7% compliance) attended the lecture, and their knowledge and behavior scores improved 2 weeks post-lecture (knowledge: from 14.2 ± 3 to 19.0 ± 2.2 [P < .0005], sexual behavior: from 12.1 ± 2.9 to 8.8 ± 3.0 [P < .0005], and injection behavior: from 7.3 ± 6.2 to 0.2 ± 1.3 [P < .0005]). The unjustified fear of proximity to HIV carriers reported by 50% attendees fell to 35% post-lecture. Eight months post-lecture, the scores on knowledge and risky behavior of 21 randomly chosen attendees were still better than pre-lecture scores (knowledge: 15.4 ± 2.3 vs. 17.2 ± 1.8 [paired t test, P = .001], sexual behavior: 13.2 ± 2.3 vs. 9.7 ± 2.9 [P < .0005], and injection behavior: 9.3 ± 5.6 vs. 2.8 ± 3.1 [P < .0005]). Drug abuse and treatment adherence were not related to intervention and to risky behavior. Conclusions: More knowledge, less fear, and less risky behavior immediately and at 8 months post-lecture reflect the success and importance of the educational intervention. Future efforts are needed in order to reduce ignorance and fear associated with HIV/AIDS.

Drug Abuse and Behavioral Transgressions during Methadone Maintenance Treatment (MMT) are Related to High Psychopathy Levels.

Introduction: Studies which used the Psychopathy Checklist-Revised (PCL-R) among methadone maintenance treatment (MMT) patients focused mostly on methodological issues, without addressing its relationship to patients' misconduct during treatment. This paper tests the hypothesis that high PCL-R scores are related to high rates of drug abuse, and high numbers of behavioral transgressions in MMT during a 7-year period. Material and Methods: 107 MMT patients were recruited from a MMT clinic in Israel, and were administered the PCL-R. The questionnaires results as well as routine drug test findings were recorded between 7/2007 and 11/2007. Seven years later (7/2014), repeated drug test results were analyzed, and the number of behavioral transgressions during the entire period was computed. Results: High levels of psychopathy were related to drug test results indicating any illicit drug use, cocaine use and benzodiazepines misuse at the beginning of study, and limited to benzodiazepines misuse among patients who stayed in treatment at the 7-year follow-up. However, higher scores on different PCL-R facets were significantly associated with different types of drugs. The PCL-R's total score and all but the antisociality facet were positively correlated with a higher number of behavioral transgressions (such as, threats and/or verbal and physical aggression). Conclusions: Administration of the PCL-R during MMT may help identify patients with high illicit drug use levels and a higher chance of committing behavioral transgressions during treatment.

A 3' UTR SNP rs885863, a cis-eQTL for the circadian gene VIPR2 and lincRNA 689, is associated with opioid addiction.

There is a reciprocal relationship between the circadian and the reward systems. Polymorphisms in several circadian rhythm-related (clock) genes were associated with drug addiction. This study aims to search for associations between 895 variants in 39 circadian rhythm-related genes and opioid addiction (OUD). Genotyping was performed with the Smokescreen® array. Ancestry was verified by principal/MDS component analysis and the sample was limited to European Americans (EA) (OUD; n = 435, controls; n = 138). Nominally significant associations (p < 0.01) were detected for several variants in genes encoding vasoactive intestinal peptide receptor 2 (VIPR2), period circadian regulator 2 (PER2), casein kinase 1 epsilon (CSNK1E), and activator of transcription and developmental regulator (AUTS2), but no signal survived correction for multiple testing. There was intriguing association signal for the untranslated region (3' UTR) variant rs885863 in VIPR2, (p = .0065; OR = 0.51; 95% CI 0.31-0.51). The result was corroborated in an independent EA OUD sample (n = 398, p = 0.0036; for the combined samples). Notably, this SNP is an expression quantitative trait locus (cis-eQTL) for VIPR2 and a long intergenic non-coding RNA, lincRNA 689, in a tissue-specific manner, based on the Genotype-Tissue Expression (GTEx) project. Vasoactive intestinal peptide (VIP) is an important peptide of light-activated suprachiasmatic nucleus cells. It regulates diverse physiological processes including circadian rhythms, learning and memory, and stress response. This is the first report of an association of a VIPR2 variant and OUD. Additionally, analysis of combinations of single nucleotide polymorphisms (SNPs) genotypes revealed an association of PER2 SNP rs80136044, and SNP rs4128839, located 41.6 kb downstream of neuropeptide Y receptor type 1 gene, NPY1R (p = 3.4 × 10-6, OR = 11.4, 95% CI 2.7-48.2). The study provides preliminary insight into the relationship between genetic variants in circadian rhythm genes and long non-coding RNA (lncRNAs) in their vicinity, and opioid addiction.

Outcome of Patients With High Depressive Symptoms on Admission to Methadone Maintenance Treatment.

Objective: Comorbidity of depression among individuals with opioid addiction is highly prevalent, but their outcome in methadone maintenance treatment (MMT) is not well determined.Methods: Characteristics and outcomes (retention until December 2017) of newly admitted and already (5.5 ± 4 years) in MMT patients with available Hamilton Depression Rating Scale (HAM-D) scores on admission were studied.Results: During psychiatric intake on admission, 70 (21.2%) of 330 patients were diagnosed with high depressive symptoms beyond the cutoff (HAM-D scores ≥ 18). Depressed and nondepressed groups had a similar proportion of females (20% and 23.8%) and age at admission (43.0 ± 10.5 and 43.7 ± 10.4 years), but the depressed group had higher Brief Psychiatric Rating Scale (BPRS) scores (21.4 ± 8.6 vs. 7.0 ± 7.3, respectively; p < .0005), a higher proportion of minority (non-Jewish faith; 28.6% vs.15.4%; p =.02), and a higher proportion of positive urine screening results for cocaine (55.7% vs. 34.4%; p = .001) and for benzodiazepines on admission (74.3% vs. 57.5%; p = .01). Retention after 1 year was similar (79% and 80.7%), but depressed patients had higher rates of cocaine (40.8% vs. 25.5%; p = .05) and benzodiazepine use (59.2% vs. 41.8%; p = .04) and a shorter cumulative retention (5.6 years, 95% confidence interval [CI; 4.3, 7.0]) than the nondepressed patients (6.8 years, 95% CI [6.1, 7.5]; p = .05). Of the 263 evaluated while already in MMT, 23.5% were depressed, characterized with more females (43.5% vs. 23.4%) and with a history of rape (34.5% vs. 7.6%).Conclusions: Newly admitted depressed and nondepressed patients succeeded similarly in the first year retention in treatment, despite their cocaine and benzodiazepine co-abuse. The depression was characterized with females and with rape history in those who were already in MMT. Adequate intervention is recommended for both depressed groups to improve long-term retention and outcome.

Genetic Variant in the CRH-binding Protein Gene (CRHBP) is Associated With Cessation of Cocaine Use in Methadone Maintenance Patients With Opioid Addiction.

OBJECTIVES: We have previously shown associations between 4 genetic variants in opioid and stress-related genes (OPRM1, NPYR1/NPYR5, NR3C1, and CRHBP) and prolonged abstinence from heroin without methadone maintenance treatment (MMT). We currently assessed the associations between these variants and MMT patients' characteristics. METHODS: A non-selective group of 351 patients who stayed at least 1 year in their first admission to MMT were genotyped and their characteristics and substance in urine on admission and after 1 year were studied. RESULTS: The proportions of patients with both cocaine and benzodiazepine abuse were reduced significantly after 1 year in MMT; however, cocaine abuse cessation was significantly associated with the non-carriers of the CRHBP (corticotrophin releasing hormone binding protein) SNP rs1500 minor C allele (GG genotype) (P = 0.0009, PBonferroni = 0.0221). More carriers of the 2 C alleles (CC genotype) than carriers of the GC and GG genotypes abused cocaine on admission (32.3% vs 19.7%, respectively, P = 0.0414, recessive model), and more of the C allele carriers (GC and CC genotypes) than non-carriers (GG genotype) abused cocaine after 1 year in MMT (25.7% vs 15.8%, respectively, P = 0.0334, dominant model). Abusers of benzodiazepine were more prevalent among carriers of the C allele compared with non-carriers on admission (60.6% vs 45.9%, respectively, P = 0.0080, dominant model), as well as after 1 year in MMT (50.9% vs 39.1%, respectively, P = 0.0362). CONCLUSIONS: Reduction in cocaine abuse among MMT patients may be mediated by a genetic effect in a stress-related gene (CRHBP SNP rs1500 minor C allele). Evaluations of larger samples, additional SNPs, and different populations are needed to support these findings.