The Study Of Socio-psycho-genetic Susceptibility Characteristics Of Methamphetamine Use Disorder And Related High-risk Psychological And Behavioral Problems

Objective:Methamphetamine(MA)is one of the most abused drugs in the world,which extensively harms human health and life safety.Methamphetamine use disorder(MAUD)is affected by both environmental and genetic factors,but few previous studies have systematically and comprehensively explored the susceptibility characteristics of MAUD from the two aspects in one study.In addition,patients with MAUD are at high risk of psychological and behavioral problems,such as MA-induced paranoia,aggression and suicide,and few studies have comprehensively explored the prevalence and influencing factors of these problems.This study aims to explore the susceptibility characteristics of MAUD from the“socio-psycho-genetic”perspective and to comprehensively investigate the prevalence and influencing factors of three major types of psychological and behavioral problems that are common in MAUD patients:MA-induced paranoia,aggression,and suicidal ideation.The findings of the current study will provide theoretical and practical guidance for follow-up screening,prevention,intervention and management on MAUD and its related high-risk psychological and behavioral problems.Methods:1.Study object:This study was a case-control study.The MAUD case group consisted of adult male MAUD patients in Changsha Compulsory Drug Rehabilitation Center from December 2017 to August2018.They were included in MAUD case questionnaire group and MAUD case blood sample group.According to stimulants use disorder diagnostic criteria of“Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition”(DSM-5),the two case groups were further divided into mild to moderate MAUD group(2-5 criteria)and severe MAUD group(6 or more criteria)/typical severe MAUD group(10 or more criteria)respectively.The healthy control questionnaire group consisted of people without substance use disorders(SUDs)who were matched with the MAUD case questionnaire group by gender,age,and educational level,which came from a national sample collected by a mobile phone survey from January to February 2022.The healthy control blood sample group consisted of healthy people who were matched with the mild to moderate MAUD group and typical severe MAUD group from MAUD case blood sample group by gender and age,which came from healthy population who underwent physical examination in the Health Management Center of The Second Xiangya Hospital of Central South University from May to December 2021.2.Study content:The MAUD patients completed the demographic information sheet,MA-use characteristics sheet,Chinese Version of the Semi-Structure Assessment for Drug Dependence and Alcoholism(SSADDA),Alcohol Use Disorders Identification Test(AUDIT),Fagerstr(?)m Test for Nicotine Dependence(FTND),Childhood Trauma Questionnaire-Short Form(CTQ-SF),Multidimensional Scale of Perceived Social Support(MSPSS),Barratt Impulsiveness Scale-11(BIS-11),Chinese Version of Aggression Questionnaire(AQ-CV),Eysenck Personality Questionnaire-Revised,Short Scale for Chinese(EPQ-RSC)and Beck Scale for Suicide Ideation(BSSI),as well as were collected venous peripheral blood for single nucleotide polymorphism(SNP)polymerase chain reaction(PCR)resequencing and promoters Mass ARRAY deoxyribonucleic acid(DNA)methylation detection and analysis of dopamine reward pathway genes,such as dopamine receptor D2(DRD2)gene,dopamine receptor D4(DRD4)gene,and catechol-o-methyltransferase(COMT)gene.The healthy control questionnaire group completed the basic information sheet,CTQ-SF,MSPSS,BIS-11 and AQ-CV,while the healthy control blood sample group were collected venous peripheral blood for SNP PCR resequencing and promoters Mass ARRAY DNA methylation detection and analysis of dopamine reward pathway genes DRD2,DRD4 and COMT.3.Statistical analyses:Descriptive analyses were used to show the basic characteristics of the samples and normality tests were carried out.Two group comparisons were conducted by independent two-sample t-test,Mann-Whitney U nonparametric test,and Chi-square test.Three group comparisons were conducted by ANOVA test,Kruskal-Wallis H nonparametric test,and Chi-square test,with Bonferroni correction performed.Correlations between variables were analyzed by Pearson or Spearman correlation analysis.Multivariate Logistic regressions or multivariate linear regressions were used to explore the independent influencing factors of MAUD-related high-risk psychological and behavioral problems.Results:1.The study of socio-psycho-genetic susceptibility characteristics of MAUD(1)By comparing the severe MAUD group,mild to moderate MAUD group and the healthy control questionnaire group,the results showed that the severe/mild to moderate MAUD group was unmarried and not full-time employed,only one child in his family(χ~2=33.04,p<0.001),not raised by his parents before adulthood(χ~2=6.57,p=0.010),had more childhood abuse(e.g.,physical abuse,H=-91.42,p<0.001)and less social support(e.g.,family support,H=71.20,p=0.001),compared with the control group.Compared with the control group/the mild to moderate MAUD group,the severe MAUD group showed higher level of impulsivity(e.g.,motor impulsivity,H=89.47,p<0.001),unstable personality tendency(z=-4.82,p<0.001),and a series of MA-use characteristics(i.e.,younger age of first MA use,younger age of MAUD onset,more first use pleasure,longer use time,higher dose per use,higher frequency of use,MA-induced paranoia,current craving,and co-occurring with tobacco use disorder).(2)By comparing the typical severe MAUD group,mild to moderate MAUD group and the healthy control blood sample group,the results showed that the genotypes of 12 SNP loci of dopamine reward pathway genes DRD2,DRD4 and COMT had no statistically significant difference among the three groups.The methylation levels of the promoter region of DRD2 gene in the three groups were low and below 30%,and the methylation levels of single DNA methylation site(-cytosine-phosphate diester bond-guanine,Cp G)Cp G＿26 in the typical severe group(H=22.00,p=0.038)and Cp G＿27 in the control group(H=-26.08,p=0.019)were significantly lower than levels in the mild to moderate group.The methylation levels of the promoter region of DRD4 gene was relatively high,and the methylation levels of 8 Units in the typical severe group(e.g.,Cp G＿32,H=38.70,p<0.001)and 5 Units in the mild to moderate group(e.g.,Cp G＿32,H=42.23,p<0.001)were significantly lower than levels in the control group.The methylation levels of the promoter region of COMT gene fluctuated greatly and was below 25%,and the methylation levels of Cp G＿3.4 in the typical severe(H=-26.06,p=0.041)and mild to moderate group(H=-27.19,p=0.047)were significantly higher than that in the control group.(3)By analyzing the genetic and epigenetic characteristics of MA-induced paranoia,impulsivity,and aggression in MAUD case questionnaire group,the results showed that MA-induced paranoia was associated with the TT genotype of rs1800955 of DRD4 gene(χ~2=4.27,p=0.039)and lower methylation level of Cp G＿2.3 in the promoter region of DRD4 gene(z=-2.27,p=0.023).High level of motor impulsivity of MAUD patients was associated with G+genotype of rs4818 of COMT gene(z=-2.27,p=0.023),lower methylation level of Cp G＿3.4 in promoter region of COMT gene(r=-0.17,p=0.045),and higher methylation level of Cp G＿22.23 in promoter region of DRD2 gene(r=0.17,p=0.044).High level of overall aggression of MAUD patients was associated with GG genotype of rs1800497 of DRD2 gene(z=-2.80,p=0.005),lower methylation level of Cp G＿24.25 in promoter region of DRD2 gene(r=-0.18,p=0.032),lower methylation level of Cp G＿6 in promoter region of DRD4 gene(r=-0.20,p=0.013),and higher methylation level of Cp G＿25.26 in promoter region of COMT gene(r=0.210,p=0.011).2.The study of three types of MAUD high-risk psychological and behavioral problems(1)The detection rate of MA-induced paranoia in MAUD patients was 40.28%,and its independent risk factors were low education level(OR=0.51,p=0.030),severe MAUD(OR=3.31,p=0.002),extroverted(OR=1.03,p=0.033)and unstable personality tendencies(OR=1.06,p<0.001).(2)The levels of overall aggression(z=-10.06,p<0.001)and its five aggressive dimensions in MAUD patients were significantly higher than those of the control group.The independent risk factors of overall aggression were low education level(β=-3.88,p=0.024),young age of MAUD onset(β=-0.43,p=0.002),co-occurring alcohol use disorder(β=3.77,p=0.007),co-occurring TUD(β=4.71,p=0.001),psychoticism(β=0.19,p=0.024)and unstable personality tendencies(β=0.67,p<0.001).In addition,slightly different risk factors were found for its five dimensions.(3)The detection rate of suicidal ideation in MAUD patients was26.67%,and its independent risk factors included high dose of MA per use(β=1.74,p=0.048),introverted(β=-0.07,p=0.018)and unstable personality tendencies(β=0.06,p=0.011),and high level of self-aggression(β=0.07,p=0.001).In addition,slightly different risk factors were found for its two dimensions.Conclusions:1.MAUD may be affected by both social and psychological factors and may closely associated with the methylation levels in promoter regions of DRD2,DRD4 and COMT genes.In addition,MA-induced paranoia,impulsivity,and aggression of MAUD patients may be related to the methylation levels in promoter regions and gene polymorphism of these three genes.The screening,prevention,intervention,and management on MAUD could initiate from these aspects.2.MAUD patients are at high risk of MA-induced paranoia,aggression,and suicidal ideation.Their independent risk factors include low education level,a series of MA-use characteristics,and certain personality tendencies.Special attention should be paid to those with the above risk factors,and timely screening and intervention should be carried out to reduce disease burden and social harm.