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Dopamine functioning is an essential mechanism underlying addictive behaviors. This paper evaluates the association of Internet gaming disorder (IGD) with the catechol‐O‐methyltransferase (COMT) val158met polymorphism and examines the roles of impulsivity and reinforcement sensitivity in this association. Using diagnostic interviews, this study recruited 69 participants with IGD and 138 participants without. All participants underwent diagnostic interviews for IGD and an evaluation for the COMT val158met polymorphism, impulsivity, and reinforcement sensitivity. Among participants with the Val/Val genotype, the odds ratio (95% confidence interval) for IGD was 2.09 (1.15–3.80). The IGD–Val/Val genotype association was mediated by impulsivity and fun‐seeking. The Val/Val genotype is indicative of low frontal functioning and is a predictive factor of IGD, with this effect being confounded by impulsivity and fun‐seeking. Interventions targeting impulsivity and fun‐seeking might attenuate the risk of IGD, particularly among individuals with the Val/Val genotype. Additional studies are necessary to elucidate the possible role of dopamine functioning.

Background: Genetic factors were suggested to have influence on the development of post-traumatic stress disorder (PTSD). The possible association between catechol-O-methyltransferase (COMT) Val158Met polymorphism and PTSD has been evaluated in several studies. But the results were still controversial. Therefore, we conduct this meta-analysis to address these issues. Methods: The PubMed, EMBASE, Cochrane Library, and Web of Science databases were searched for eligible studies. The pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to estimate the association between COMT Val158Met polymorphism and PTSD. Results: Five articles including 6 studies with 893 cases and 968 controls were finally included in the present meta-analysis. The pooled analyses did not demonstrate a significant association between the COMT Val158Met polymorphism and PTSD in any of the selected genetic models: allele model (OR = 1.13, 95% CI: 0.97–1.31), dominant model (OR = 1.17, 95% CI: 0.93–1.46), recessive model (OR = 1.44, 95% CI: 0.78–2.66), and additive model (OR = 1.54, 95% CI: 0.85–2.80). Subgroup analyses suggested that the Hardy-Weinberg equilibrium status of genotype distributions could influence the relationship of COMT Val158Met polymorphism and PTSD. Conclusions: The present meta-analysis suggested that the COMT Val158Met polymorphism may not be associated with the PTSD risk. Further large-scale and population-representative studies are warranted to evaluate the impact of the COMT Val158Met polymorphism on the risk of PTSD.

Hypertension is a preventable risk factor of cardiovascular diseases. It is considered a major cause of CVD-morbidity and mortality worldwide. Some risk factors and prevention strategies related to hypertension were studied intensively, however, with growing the burden of this disorder and genetic has become the dominant field of treating diseases, still, specific genes involved in increasing blood pressure remain to be identified. This meta-analysis was conducted to assess the relationship of COMT Val158/Met variation to high systolic and diastolic blood pressure. PubMed and Web of Science (WOS) were intensively searched for the genetic association on the link of COMT Val158/Met to hypertension. The search was done up to October 15th 2020 and updated on November 22nd 2020. Two investigators were independently extracting data and evaluating the risk of bias using the Cochrane risk of bias tool. Q-genie tool was used to assess the quality of all included articles. Met-dominant model (Met/Met + Val/Met vs Val/Val) showed a significant association to systolic and diastolic blood pressure with a pooled standardized mean difference of -0.215 and 95%CI [-0.399 to -0.0300] and -0.205, 95%CI [-0.390 to -0.0197], respectively. Met allele was significantly related to high systolic and diastolic blood pressure. However, high-quality, case-control studies are lacking.

Polymorphisms of the catechol-O-methyl transferase (COMT) or monoamine oxidase B (MAO-B) genes may affect the occurrence of dyskinesia in Parkinson’s disease (PD) patients. However, the findings are inconsistent. Thus, we performed a meta-analysis to assess whether COMT and MAO-B genetic variants are associated with an increased incidence of levodopa-induced dyskinesia (LID) in PD patients. A literature search of PubMed, Embase, and Cochrane Library was conducted to identify relevant studies published up to January 2021. The strength of the association between the polymorphisms and LID susceptibility was estimated by odds ratio (OR) and associated 95% confidence interval (CI). The pooled ORs were assessed in different genetic models. Ten studies involving 2385 PD patients were included in the meta-analysis. Analysis of pooled ORs and 95% CIs suggested that the AA genotype of COMT(rs4680) was associated with LID (OR = 1.39, 95%CI: 1.02–1.89, P = 0.039) in the recessive model, and this correlation was more obvious in Brazilian samples in the analysis stratified by ethnicity. For the AG genotype of MAO-B(rs1799836), the pooled OR was 1.66 (95% CI: 1.04–2.65, P = 0.03) in patients with LID versus those without LID in the heterozygote model. Our meta-analysis implicates the AA genotype of the COMT rs4680 polymorphism as potentially increasing the risk of LID in a recessive genetic model for PD patients. Furthermore, the AG genotype of the MAO-B rs1799836 polymorphism may influence the prevalence of LID in PD patients in the heterozygote model. However, further well-designed studies with larger PD patient cohorts are required to validate these results after adjusting for confounding factors.

Aim We analyzed the association between SLC6A4, DRD2, COMT and MAOA genes and suicide attempt (SA) in Mexican adolescent patients with major depressive disorder (MDD). Methods The sample included 197 adolescents (127 females and 70 males) with principal diagnosis of MDD. Among them, 63 patients had SA at least once and 134 had not SA. The mean age of patients with and without SA was 15 ± 1.4 and 14 ± 1.5 years, respectively. We analyzed the genotype and allele distribution between patients with and without SA of SLC6A4 (5HTTLPR/rs25531), DRD2 (rs6275), COMT (rs4680), and MAOA (uVNTR). Results We did not find genotype or allele association between SA and SLC6A4 (χ2=0.67, p = 0.71; χ2=0.07, p = 0.77, respectively), DRD2 (χ2=0.05, p = 0.97; χ2=0.003, p = 0.95), and MAOA (females: χ2=0.86, p = 0.64; χ2=0, p = 1/males: χ2=0.008, p = 0.92) genes. However, there were differences in genotype frequencies of COMT/rs4680 between patients with SA and without SA (χ2=11.17, p = 0.003). Also, we observed a high frequency of Met158 allele showing an increased risk of having presented at least one SA (χ2=10.6, p = 0.001; OR = 1.43; 95% CI, 1.17-1.74). Conclusions Our findings showed an association between low activity genotype and allele of Val158Met polymorphism of COMT gene and SA in Mexican adolescents with MDD.

IMPORTANCE: Adapting one’s gait speed to external circumstances is critical for safe ambulation. Dopamine (DA), critical for adapting to increased task demands, predicts usual gait speed and may exert a greater role in complex tasks like rapid gait speed. OBJECTIVE: We hypothesized that a genotypic proxy indicator of greater prefrontal DA signaling would predict significantly faster rapid gait. DESIGN: Longitudinal cohort study over 8 years SETTING: Community-dwelling adults with no baseline mobility disability PARTICIPANTS: N = 2,353 participants from the Health ABC Study MEASUREMENTS: Repeated measures of walking speed (meters/sec) were obtained in response to: “walk as fast as possible… (rapid gait) or “walk at your usual pace (usual gait).” Catechol-O-methyltransferase (COMT) val158met polymorphism indicated DA signaling (val/val=higher metabolism, lower DA signaling; met/met=lower metabolism, higher DA signaling). RESULTS: Participants declined in rapid gait from 1.55 (SD=.33) to 1.35 m/s (SD=0.34). Across the full follow-up period, the met/met genotype was associated with significantly greater rapid gait slowing. In mixed effect models, between-group differences were independent of covariates, and remained similar after adjustment for sensorimotor function, cognition, depressive symptoms, and energy. Follow-up analyses indicated the met/met genotype had a significantly faster rapid gait speed compared to the val/val genotype for the first 3 years (p < .01) but not years 4–8 (p > .05). CONCLUSION: Greater prefrontal DA measured with COMT polymorphism may facilitate short-term adaptation to rapid walking demands that are lost over time. Studies should examine whether these effects are long-term and the underlying mechanistic pathways.

Post-traumatic stress disorder (PTSD) is one of the prevalent neurological disorder which is drawing increased attention over the past few decades. Major risk factors for PTSD can be categorized into environmental and genetic factors. Among the genetic risk factors, polymorphisms in the catechol-O-methyltransferase (COMT) gene is known to be associated with the risk for PTSD. In the present study, we analysed the impact of deleterious single nucleotide polymorphisms (SNPs) in the COMT gene conferring risk to PTSD using computational based approaches followed by molecular dynamic simulations. The data on COMT gene associated with PTSD were collected from several databases including Online Mendelian Inheritance in Man (OMIM) search. Datasets related to SNP were downloaded from the dbSNP database. To study the structural and dynamic effects of COMT wild type and mutant forms, we performed molecular dynamics simulations (MD simulations) at a time scale of 300 ns. Results from screening the SNPs using the computational tools SIFT and Polyphen-2 demonstrated that the SNP rs4680 (V158M) in COMT has a deleterious effect with phenotype in PTSD. Results from the MD simulations showed that there is some major fluctuations in the structural features including root mean square deviation (RMSD), radius of gyration (Rg), root mean square fluctuation (RMSF) and secondary structural elements including α-helices, sheets and turns between wild-type (WT) and mutant forms of COMT protein. In conclusion, our study provides novel insights into the deleterious effects and impact of V158M mutation on COMT protein structure which plays a key role in PTSD.

Objective : to investigate the association of the polymorphic marker Val158Met in the catechol-O-methyl transferase (COMT) gene with depression in an open population aged 25–44 years. Patients and methods . A representative sample of the population living in Oktjabr'skij district of Novosibirsk aged 25– 44 years (427 men, median age – 34±0.4 years, response rate – 71%; 548 women, median age 35±0.4 years, response rate – 72%) was screened in 2013–2016 (budget framework № 0324- 2018-0001, Reg. № AAAA-A17-117112850280-2). In addition to the standard epidemiological examination, screening participants underwent psychological testing, which determined the level of depression. Study participants who underwent COMT Val158Met (rs4680) polymorphism genotyping were randomly assigned to a cohort of 224 men and 217 women. Pearson's χ2 test was used to test the statistical significance of differences between these groups; p≤0.05 was considered statistically significant in all types of analysis. Results and discussion . In an open population aged 25–44 years, the prevalence of severe depression (SD) was 13.2%, moderate depression – 24.4%. SD was more prevalent in COMT G/G genotype carriers (61.8%), compared to A/A genotype carriers (38.2%; χ 2 =6.097; df=2, p=0.047); the G allele carriers also had a higher prevalence of SD (55.3%), compared to A allele carries (44.7%; χ 2 =5.408; df=1; p=0.02). SD was less prevalent among male COMT A/A genotype carriers (15.8%), compared to G/A genotype carriers (84.2%; χ 2 =4.603; df=1; p=0.032). SD was more prevalent in female G/G genotype carriers (65.5%), compared to A/A genotype carriers (34.5%; χ 2 =4.769; df=1; p=0.029). The G allele was more common among women with SD (58.2%) than the A allele (41.8%; χ 2 =6.658; df=2; p=0.01). In a logistic regression model, COMT Val/Val genotype in the studied population [Relative risk (RR) 1.594], as well as G (Val) allele in the studied population (RR=1.378) and women (RR=1.557), significantly increased the risk of depression. Conclusion. The data allows us to assume that COMT G/G polymorphism may be linked to a high depression level.

Objective Catechol-O-methyltransferase (COMT), the product of the COMT gene, detoxifies the carcinogenic catechol estrogens. The aim of the present study was to examine the relationship between COMT Val158Met polymorphism and the risk of ovarian cancer. Material and methods The study groups consist of 94 individuals as a patients group with ovarian cancer (n=47) and control group (n=47). The allele and genotype frequencies were determined according to Hardy-Weinberg equilibrium (HWE). The allele and genotype frequencies. determined according to HWE. Genetic analysis were performed by real-time-polymerase chain reaction instrument, and the statistical analysis were performed by SPSS program. Results Although no significant relationship was obtained among groups (p=0.413) regarding COMT gene Val158Met polymorphism, the genotype frequencies for COMT Val158Met (rs4860) polymorphism in groups was homozygote wild type GG genotype 25.5%, heterozygote GA genotype 46.8%, homozygote mutant AA genotype 27.7%. Conclusion This study is the first to investigate the relationship between ovarian cancer and the Val158Met polymorphism in the COMT gene in a Turkish population. No statistically significant relationship was identified among genotypes belonging to the patient and control groups although sample sizes were relatively small and the analysis should be repeated in a larger cohort.

Catechol O-methyltransferase (COMT) is an enzyme that transfers a methyl group to the catechol-derivative substrates using S-adenosyl-l-methionine (SAM) and Mg2+. We report the biochemical and structural analysis of COMT from Niastella koreensis (NkCOMT). NkCOMT showed the highest activity with Mg2+, although the enzyme also showed a significant level of activity with Cu2+ and Zn2+. NkCOMT structures complexed with SAH and Mg2+ elucidated how the enzyme stabilized the cosubstrate and the metal ion and revealed that the region near the SAM binding site undergoes conformational changes upon the binding of the cosubstrate and the metal ion. We also identified the catechol binding pocket of the enzyme and explained a broad substrate specificity of the bacterial enzyme and its ability to accommodate the catechol derivatives. In addition, we developed the NkCOMTE211R and NkCOMTE211K variants that showed both enhanced activities and regiospecificity for the production of the para-forms. Our study provides a structural basis for regiospecificity of NkCOMT, which is related with the conformational change upon binding of SAM and Mg2+.

Peiyan Ni,1– 3 Manli Liu,1– 3 Dequan Wang,1– 3 Yang Tian,1– 3 Liansheng Zhao,1– 3 Jinxue Wei,1– 3 Xueli Yu,1– 3 Xueyu Qi,1– 3 Xiaojing Li,1– 3 Hua Yu,1– 3 Rongjun Ni,1– 3 Xiaohong Ma,1– 3 Wei Deng,1– 3 Wanjun Guo,1– 3 Qiang Wang,1– 3 Tao Li1– 4 1The Psychiatric Laboratory, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 2Mental Health Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 3Huaxi Brain Research Center, West China Hospital, Sichuan University, Chengdu, 610041, People’s Republic of China; 4Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, People’s Republic of ChinaCorrespondence: Tao LiThe Psychiatric Laboratory, West China Hospital, Sichuan University, 28 Dian Xin Nan Road, Chengdu, Sichuan, 610041, People’s Republic of ChinaTel/Fax +86-28-85423561Email litaohx@scu.edu.cnIntroduction: Schizophrenia, bipolar disorder (BD), and major depressive disorder are three common mental disorders. Although their diagnosis and treatment differ, they partially overlap.Methods: To explore the similarities and characteristics of these three psychiatric diseases, an intelligence quotient (IQ) assessment was performed to evaluate cognitive deficits. Relative catechol-O-methyltransferase (COMT) expression in peripheral blood mononuclear cells was examined in all three groups compared with healthy controls (HCs).Results: The results indicated that patients with any of the three psychiatric diseases presented IQ deficits, and that the first-episode schizophrenia (FES) group had even lower cognitive function than the other two groups. The relative COMT expression decreased in the FES group and increased in the BD group compared with the HC group. The correlation analysis of COMT expression level and IQ scores showed a positive correlation between relative COMT expression and full-scale IQ in the HC group. However, this correlation disappeared in all three psychiatric diseases studied.Conclusion: In conclusion, this cross-disease strategy provided important clues to explain lower IQ scores and dysregulated COMT expression among three common mental illnesses.Keywords: first-episode schizophrenia, FES, bipolar disorder, BD, first-episode major depressive disorder, MDD, catechol-O-methyltransferase, COMT, intelligence quotient, IQ

Catechol-O-methyl transferase (COMT) enzyme catalyzes the metabolism of dopamine and other catechols in the brain. Several articles investigated catechol-O-methyltransferase (COMT) Val158Met polymorphism as risk factor for alcohol dependence (AD) but the results were inconclusive. The aim of present meta-analysis was to evaluate the association of Val158Met (COMT) polymorphism with AD. Authors performed keyword search of the four electronic databases- Pubmed, Google Scholar, Springer Link and Science Direct databases up to December 31,2019 . Total eighteen studies that investigated the association of Val158Met polymorphism with AD were retrieved. The pooled results from the meta-analysis (2,278 AD cases and 3717 healthy controls) did not show association with AD using all five genetic models (allele contrast model: OR = 1.02, 95% CI= 0.90-1.14, p= 0.03; homozygote model: OR = 1.06, 95% CI= 0.81-1.38, p= 0.69; dominant model: OR = 0.99, 95% CI= 0.85-1.14, p= 0.87; co-dominant model: OR = 0.97, 95% CI= 0.86-1.11, p= 0.71; recessive model: OR = 1.05;95% CI= 0.85-1.29, p=0.61). Results of subgroup analysis showed that Val158Met is not risk for AD in Asian and Caucasian population. In conclusion, COMT Val158Met is not a risk factor for alcohol dependence.

Human catechol-O-methyltransferase (hCOMT) is considered a therapeutic target due to its crucial roles in the metabolic inactivation of endogenous neurotransmitters and xenobiotic drugs. There are nevertheless few safe and effective COMT inhibitors and there lacks a diversity in structure. To discover novel safe and effective hCOMT inhibitors from herbal products, in this study, 53 herbal products were collected and their inhibitory effects against hCOMT were investigated. Among them, Scutellariae radix (SR) displayed the most potent inhibitory effect on hCOMT with an IC50 value of 0.75 μg mL−1. To further determine specific chemicals as COMT inhibitors, an affinity ultrafiltration coupled with liquid chromatography-mass spectrometry method was developed and successfully applied to identify COMT inhibitors from SR extract. The results demonstrated that scutellarein 2, baicalein 9 and oroxylin A 12 were potent COMT inhibitors, showing a high binding index (>3) and very low IC50 values (32.9 ± 3.43 nM, 37.3 ± 4.32 nM and 18.3 ± 2.96 nM). The results of inhibition kinetics assays and docking simulations showed that compounds 2, 9 and 12 were potent competitive inhibitors against COMT-mediated 3-BTD methylation, and they could stably bind to the active site of COMT. These findings suggested that affinity ultrafiltration allows a rapid identification of natural COMT inhibitors from a complex plant extract matrix. Furthermore, scutellarein 2, baicalein 9 and oroxylin A 12 are potent inhibitors of hCOMT in SR, which could be used as promising lead compounds to develop more efficacious non-nitrocatechol COMT inhibitors for biomedical applications.

In the pharmacotherapy of patients with Parkinson's disease (PD), entacapone reduces the peripheral metabolism of L-dopa to 3-O-methyldopa (3-OMD), thereby prolonging the half-life (t1/2) of L-dopa and increasing the area under the concentration curve (AUC). The effect of entacapone on the pharmacokinetics of L-dopa differs between patients with high-activity (H/H) and low-activity (L/L) catechol-O-methyltransferase (COMT) Val158Met polymorphisms, but the effects are unclear in heterozygous (H/L) patients. 3-OMD has a detrimental effect and results in a poor response to L-dopa treatment in patients with PD; however, the influence of this polymorphism on the production of 3-OMD remains unknown. Therefore, the present study aimed to clarify the effect of the COMT Val158Met polymorphism on the concentrations of L-dopa and 3-OMD in the presence of entacapone. We performed an open-label, single-period, single-sequence crossover study at two sites in Japan. The study included 54 Japanese patients with PD, who underwent an acute L-dopa administration test with and without 100 mg entacapone on two different days. Entacapone increased L-dopa AUC0-infinity by 1.59 ± 0.26-fold in the H/H group, which was significantly higher than that in the H/L (1.41 ± 0.36-fold) and L/L (1.28 ± 0.21-fold) groups (p < 0.05). The concurrent administration of L-dopa with entacapone suppressed the increase in 3-OMD levels compared with L-dopa alone in all genotypes. Our results suggest that the COMT Val158Met polymorphism may be an informative biomarker for individualized dose adjustment of COMT inhibitors in the treatment of PD.

The goal of the study was to explore the influence of single-nucleotide polymorphisms of the COMT gene on the formation and features of pain syndrome, the level of anxiety, and the need for narcotic analgesics in patients with breast cancer. Materials and methods. The intensity of pain and opioid consumption in the postoperative period were evaluated in 58 patients who met the inclusion criteria of the study and were operated for breast cancer. The frequency of chronic pain syndrome after mastectomy was studied in the same group of patients after a year by using short pain questionnaires, McGill Pain Questionnaire and PainDetect. The anxiety level was assessed by using the HADS questionnaire. Genotyping was performed for single-nucleotide polymorphisms, rs4680, rs740603, rs2097603 = rs2070577, rs4633, of the COMT gene localized in the 22q11.21 region in the studied group of patients. The relationship between the carrier of different genotypes and the intensity of acute and chronic pain, the severity of the pain rating index for sensory and affective characteristics, the presence of a neuropathic component of pain, and the severity of anxiety were studied in the entire sample. The use of narcotic analgesics was evaluated in the postoperative period (IU/day and IU/course) and for the relief of chronic pain. Results. It is shown that the intensity of postoperative pain and the severity of anxiety do not depend on the presence of a mutant allele for the studied polymorphisms of the COMT gene, while the postoperative consumption of opioids in patients with the rs4680 missense mutation in the exon of this gene is significantly less. The dependence of the intensity of chronic pain syndrome and the severity of anxiety on the presence of a mutant allele for the polymorphic locus rs4680 localized in the exon of the COMT gene was established. No significant relationship was observed between the mutant alleles and the use of opioids for chronic pain relief after mastectomy. Conclusion. Genotyping for the COMT gene polymorphisms can be useful for choosing the optimal tactics of pain management in patients with breast cancer.

Catechol-O-methyltransferase (COMT) methylates both endogenous and exogenous catechol compounds to inactive and safe metabolites. We first optimised conditions for a convenient and sensitive continuous fluorescence-based 6-O-methylation assay of esculetin, which we used for investigating the COMT activity in human, mouse, rat, dog, rabbit, and sheep liver cytosols and microsomes and in ten different rat tissues. Furthermore, we compared the inhibition potencies and mechanisms of two clinically used COMT inhibitors, entacapone and tolcapone, in these species. In most tissues, the COMT activity was at least three times higher in cytosol than in microsomes. In the rat, the highest COMT activity was found in the liver, followed by kidney, ileum, thymus, spleen, lung, pancreas, heart, brain, and finally, skeletal muscle. Entacapone and tolcapone were characterised as highly potent mixed type tight-binding inhibitors. The competitive inhibition type dominated over the uncompetitive inhibition with entacapone, whereas uncompetitive inhibition dominated with tolcapone. Rats, dogs, pigs, and sheep are high COMT activity species, in contrast to humans, mice, and rabbits; COMT activity is highest in the liver. Both entacapone and tolcapone are potent COMT inhibitors, but their inhibition mechanisms differ.

Objective Leadership styles can influence subordinates' health. We investigated how the gene encoding the Catechol-O-Methyltransferase (COMT) enzyme (i.e. COMT rs4680 Val158Met) influenced effects of abusive supervision and transformational leadership on subordinates' headache and neck pain. Methods Multiple group structural equation modeling (SEM) was employed to test associations of leadership with subordinates' pain six months after in a representative sample of the Norwegian working population (n = 996). Genotyping was performed by TaqMan technology. Results Abusive supervision was associated with increased risk, and transformational leadership with decreased risk, of headache and neck pain. Both leadership styles exhibited more pronounced effects in individuals with the Met/Met genotype. Conclusion Met/Met employees were relatively vulnerable to adversity, but also relatively responsive to constructive leadership. Many workers may benefit more from constructive leadership than population-averaged associations might suggest.

In the pharmacotherapy of patients with Parkinson’s disease (PD), entacapone reduces the peripheral metabolism of l-dopa to 3-O-methyldopa (3-OMD), thereby prolonging the half-life (t1/2) of l-dopa and increasing the area under the concentration curve (AUC). The effect of entacapone on the pharmacokinetics of l-dopa differs between patients with high-activity (H/H) and low-activity (L/L) catechol-O-methyltransferase (COMT) Val158Met polymorphisms, but the effects are unclear in heterozygous (H/L) patients. 3-OMD has a detrimental effect and results in a poor response to l-dopa treatment in patients with PD; however, the influence of this polymorphism on the production of 3-OMD remains unknown. Therefore, the present study aimed to clarify the effect of the COMT Val158Met polymorphism on the concentrations of l-dopa and 3-OMD in the presence of entacapone. We performed an open-label, single-period, single-sequence crossover study at two sites in Japan. The study included 54 Japanese patients with PD, who underwent an acute l-dopa administration test with and without 100 mg entacapone on two different days. Entacapone increased l-dopa AUC0–infinity by 1.59 ± 0.26-fold in the H/H group, which was significantly higher than that in the H/L (1.41 ± 0.36-fold) and L/L (1.28 ± 0.21-fold) groups (p

Catechol-O-methyltransferase (COMT) has been shown to be a key regulator of pregnancy outcomes in mouse, and its deficiency is causative in the development of a preeclampsia-like disease process. Preeclampsia is a human pregnancy disorder associated with failure of intrauterine trophoblast cell invasion and trophoblast-guided uterine spiral artery remodeling, which are not well-developed in mouse. The purpose of this study was to investigate COMT in rat, a species with deep intrauterine trophoblast invasion. To accomplish this task, we used clustered regularly interspaced short palindromic repeats/Cas9-mediated genome editing of the rat Comt gene. A Comt null rat model was established and its fertility characterized. Comt null male and female rats were viable and fertile. COMT deficiency did not significantly impact pregnancy outcomes, including litter size, placental and fetal weights, Mendelian and sex ratios, or pregnancy-dependent adaptations to hypoxia. Collectively, our findings indicate that pregnancy-associated phenotypic outcomes of COMT deficiency are not equivalent in mouse and rat. In rat, COMT is not required for a successful pregnancy outcome.

Visuospatial working memory (WM) impairments in Parkinson's disease (PD) are more prominent and evolve earlier than verbal WM deficits, suggesting some differences in underlying pathology. WM is regulated by dopaminergic neurotransmission in the prefrontal cortex, but the effect of dopamine on specific processes supporting visuospatial WM are not well understood. Dopamine therapeutic effects on different WM processes may also differ given the heterogeneity of cognitive changes in PD. The present study examined the effect of dopamine therapy on memory load and distraction during visuospatial WM. Exploratory analyses evaluated whether individual differences in medication effects were associated with a gene, catechol-O-methyltransferase (COMT), which regulates prefrontal cortex dopamine levels. Cognitively normal PD participants (n=28) and controls (n=25) performed a visuospatial WM task, which manipulated memory load and the presence/absence of distractors. PD participants performed the task on and off medication. PD COMT groups were comprised of Met homozygote (lower COMT activity) and heterozygote and Val homozygote carriers (higher COMT activity, Het/Val). The results showed that handling higher memory loads and suppressing distraction were impaired in PD off, but not on medication. Medication improved distraction resistance in Met, but not Het/Val group. COMT did not modulate medication effects on memory load. These findings demonstrate that dopaminergic therapy restores visuospatial WM processes in patients without cognitive impairment and suggest that COMT variants may partly explain the mixed effects of medication on specific processes governed by distinct brain systems. Future investigations into gene-modulated effects of medication could lead to individualized strategies for treating cognitive decline.

22q11.2 deletion is a common microdeletion that causes an array of developmental defects including 22q11.2 deletion syndrome (22q11DS) or DiGeorge syndrome and velocardiofacial syndrome. About 30% of patients with 22q11.2 deletion develop schizophrenia. Mice with deletion of the ortholog region in mouse chromosome 16qA13 exhibit schizophrenia-like abnormal behaviors. It is suggested that the genes deleted in 22q11DS are involved in the pathogenesis of schizophrenia. Among these genes, COMT, ZDHHC8, DGCR8, and PRODH have been identified as schizophrenia susceptibility genes. And DGCR2 is also found to be associated with schizophrenia. In this review, we focused on these five genes and reviewed their functions in the brain and the potential pathophysiological mechanisms in schizophrenia, which will give us a deeper understanding of the pathology of schizophrenia.

Objective We sought to determine if the links between and within the default mode network (DMN) and dorsal attention network (DAT) exhibited different conditions according to catechol-O-methyltransferase (COMT) gene polymorphism in relationship to attention-deficit hyperactivity disorder (ADHD) symptoms.Methods Fifty-seven children with ADHD and 48 healthy controls (HCs) were administered an intelligence test, the Children’s Depression Inventory, the Korean ADHD rating scale, and continuous performance test. Resting-state brain functional MRI scans were obtained, and COMT genotyping was performed to distinguish valine carriers and methionine homozygotes.Results Compared to controls, children with ADHD showed increased ADHD scale scores, increased visual commission errors, and increased functional connectivity (FC) within the DMN and DAT. Compared to all children with ADHD, children with the methionine homozygote and those who were valine carriers showed increased FC within the DMN and DAT and decreased FC between the DMN and DAT. FC within the DMN was also increased in HC valine carriers compared to HC children with the methionine homozygote, and in children with ADHD who were valine carriers compared to HC valine carriers.Conclusion We observed increased brain connectivity within the DMN and DAT and altered brain connectivity within and between the DMN and DAT associated with COMT polymorphism in children with ADHD.

Background: Lactoferrin (bLF) is an iron-binding multifunctional protein that is abundant in milk. In mice, it inhibits catechol-O-methyltransferase (COMT) activity and increases blood levodopa levels. However, the clinical effects are unknown.Objective: The objective of this study was to determine the effect of bLF on the kinetics of levodopa in blood.Design: The effects of the concomitant administration of a combined formulation of levodopa and an aromatic amino acid decarboxylase inhibitor and bLF on the concentration of levodopa in blood and its metabolism were assessed in eight healthy subjects. In addition, we analyzed the association with clinical factors and evaluated whether clinical factors affected the COMT inhibitory activity of bLF in vitro.Results: Although not statistically significant, the peak plasma concentration (Cmax) of levodopa increased by 18.5%. From the results of the stratified analysis of total cholesterol, a relationship with ΔCmax was predicted. Therefore, bLF was reacted with cholesterol in the presence of lecithin and sodium deoxycholate in vitro to evaluate COMT inhibitory activity, and an increase in inhibitory activity was observed. By contrast, the ester compound cholesteryl oleate had no effect. The inhibitory activity of free fatty acids, which are known to interact with bLF, was also enhanced.Conclusion: The COMT inhibitory activity of bLF is not effective in elevating blood levodopa levels. However, in humans with high lipid levels, such as cholesterol, interactions may enhance the inhibitory effect, resulting in the enhanced absorption of levodopa.Trial registration: ID, UMIN000026787, registered 30 March 2017; URL, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000030749Trial registration: UMIN Japan identifier: UMIN000026787.

The aim of this systematic review was to qualitatively synthesise the available research that investigated the influence of COMT genotype at SNP rs4680 on both task-based and resting-state connectivity in healthy adults. Thirty-five studies were identified that met inclusion criteria. Of the included studies, 20 studies reported resting-state findings and 16 studies reported task-based findings (emotion-processing, memory, working memory, reward-based learning and executive function). Studies were highly heterogeneous but an overall trend towards an association of the Val allele with greater resting-state connectivity and the Met allele with greater task-based connectivity is reported. A possible interpretation of current findings is discussed, whereby the Val allele is associated with improved cognitive flexibility allowing integration of novel relevant stimuli, and the Met allele allows improved sustained attention and targeted neural processing, particularly between limbic regions and prefrontal cortex. The most promising brain regions implicated in a COMT genotype influence on functional connectivity include prefrontal regions, amygdala and hippocampus.

Catechol O-methyltransferase (COMT) is known as an important drug-target protein in the field of Parkinson's disease. All clinically approved COMT inhibitors bring a 5-substituted-3-nitrocatechol ring as a pharmacophore, and they bind to COMT with S-adenosylmethionine (SAM) and an Mg2+ ion to form a quaternary complex (COMT/SAM/Mg2+/inhibitor). However, structural information about such quaternary complexes is only available for a few inhibitors. Here, a new crystal structure of COMT complexed with nitecapone (5), SAM and Mg2+ is revealed. Comparison of the structures of these complexes indicates that conformation of the catechol binding pocket is almost constant regardless of structure of the inhibitors. The only restriction of the side chain of inhibitors (i.e., the substituent at the 5-position of 3-nitrocatechol) seems to be that it does not make steric repulsion with COMT. However, recent crystallographic and biochemical studies suggest that COMT is a flexible protein, and its conformational flexibility seems crucial for its catalytic process. Based on this information, implications of these quaternary inhibitor complexes were investigated. Met 40 in the α2α3-loop makes atomic contacts with SAM or S-adenosylhomocysteine and the 3-position of the catechol inhibitor. This interaction seems to play a critical role in the affinity of the inhibitor and to stabilize the COMT/SAM/Mg2+/nitrocatechol inhibitor complex by fixing the flexible α2α3-loop.

The aim of this study was to evaluate the possible association between polymorphisms in the catechol- O -methyltransferase ( COMT ) and β2-adrenergic receptor ( ADRB2 ) genes and muscular temporomandibular disorders (TMD). This was a case–control study. Individuals were evaluated using the Research Diagnostic Criteria for Temporomandibular Disorders and were divided into three groups: unaffected (no TMD) ( n = 154); exclusively muscular TMD ( n = 49); exclusively articular TMD ( n = 49). Genomic DNA was obtained from saliva samples, and single nucleotide polymorphisms in the COMT (rs165774, rs6269, rs9332377) and ADRB2 (rs2053044, rs1042713, rs1042714) genes were investigated. The TT genotype for the COMT rs9332377 gene was highly associated with the presence of muscular TMD ( P = 0.03). With respect to the ADRB2 gene, the non-polymorphic AA genotype in the rs1042713 region was more prevalent in the articular TMD group than in the muscular TMD group ( P = 0.05). This study supports the hypothesis that alterations in the COMT and ADRB2 genes influence the muscular pathophysiology.

The dorsal striatum coordinates input-output processing of numerous functions including those related to motor activity, motivation, and learning. Considerable anatomical and biochemical heterogeneity across striatal subregions has long been known to result in distinct functional outcomes, and for imbalances in these pathways to contribute to many complex disorders. Here we highlight the study of Hörtnagl et al. (2019) who utilize precision dissection of human caudate nucleus and putamen for detailed measurement of major neurochemical markers to address the question of anatomical heterogeneity of neurotransmitter distribution and turnover in these regions. The findings identify gradients of neurotransmitter markers in rostro-caudal, dorso-lateral, and anterior-posterior directions with a precision that has not been previously determined in humans. Correlative analyses of the results also suggest tentative links between content of various neurotransmitters in specific subregions, raising the intriguing possibility that neurotransmitter quantity in one territory may correlate with the quantity of the same or different transmitter from another territory. This suggests the presence of a functional anatomy over extensive brain regions and networks that can be studied through multiple correlative analyses, and identify a possible basis for a new approach for postmortem analysis of neurotransmitter distribution and function.

Negative symptoms in schizophrenia have been associated with functional changes in frontostriatal pathways. Dysregulation of the dopamine signal in frontostriatal pathways leads to the symptomology observed in schizophrenia. Although the catechol-O-methyltransferase (COMT) gene, one of the susceptibility genes for schizophrenia, has been associated with dopamine activities in prefrontal and striatal regions, it is still unclear whether the disease state and COMT val158 met genotype have an interaction effect on the functional connectivity of frontostriatal pathways. In this study, we evaluated the possible interactions between COMT val158 met variations and the disease state on the resting-state functional connectivity (RSFC) of frontostriatal pathways in fifty-one first episode schizophrenia (FES) patients (val/val: 29, met +: 22) with prominent negative symptoms and forty-eight healthy controls (val/val: 31, met +: 17). Regions of interest were defined by the result of a meta-analysis of frontostriatal pathways using the Neurosynth database. We found a significant genotype × disease interaction effect on the RSFC between the bilateral anterior cingulate (ACC) and right caudate, which overlapped with the main effect of the disease state. Behavioural regression analysis suggested that RSFC between the right ACC and right caudate correlated with the severity of SANS avolition-apathy scores in patients who were met carriers but not in patients who were val homozygous. Our findings suggest that the RSFC of frontostriatal pathways may differentially affected by an individual's COMT val158 met genotype.

A decrease in the light in autumn and winter causes depression like seasonal affective disorders (SAD) in sensitive patients, in which the serotonin (5-HT) and dopamine (DA) brain mediator systems are involved. We studied the interaction of the 5-HT and DA brain systems in an experimental SAD model in sexually mature male mice of the congenic B6-1473C and B6-1473G lines with high and low activity of tryptophan hydroxylase 2, a key enzyme of 5-HT synthesis in the brain. Mice of each line (divided into two groups of eight individuals) were kept for 30 days in standard (14 h light/10 h dark) and short (4 h light/20 h dark) daylight. The presence of the C1473G variant in the tryptophan hydroxylase 2 gene did not affect the expression of key genes of DA system: Drd1, Drd2, Scl6a3, Th, and Comt, that encode the D1 and D2 receptors, dopamine transporter, tyrosine hydroxylase, and catechol-o-methyltransferase, respectively. A decrease in the level of DA in the midbrain, as well as of its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, was detected in B6-1473G mice. Keeping mice in short daylight did not affect expression of the Drd1 gene in all brain structures nor the expression of the Slc6a3 and Th genes in the midbrain. Drd2 expression increased in the midbrain and decreased in the hippocampus, where Comt expression increased. An increase in DA level in the midbrain and DOPAC in the striatum was detected in mice kept in short daylight. This indicates the involvement of the brain’s DA system in the reaction to a decrease in daylight duration. No statistically significant effect of the interaction between the presence of the C1473G variant and daylight length on indicators of the activity of DA system was detected. No reasons were found to assert that this polymorphism determines the observed reaction of the brain DA system in keeping of animals under short daylight conditions.

Background: In the treatment of morbid obesity bariatric surgery has become the method of choice. Dopamine is the primary modulator of the brain’s reward system and plays an essential role in the regulation of food intake. The role of dopamine is well documented in weight regulation and food intake in both animal models and humans. Still, the role of dopamine has not been well studied for weight loss. Catechol-O-methyltransferase (COMT) degrades catecholamines and estrogens are both known to be important risk factors for cardiovascular diseases and consequently obesity. The gene coding for COMT contains a Val108/158Met polymorphism that exerts a considerable influence on enzymatic activity. We hypothesized that this polymorphism might influence weight loss in obese patients, who previously underwent gastric banding surgery. In obesity research, it is known that women tend to lose more weight than men, and weight before surgery might also affect the outcome of weight loss efforts. Several studies have shown that physical activity (PA) plays an important role in maintaining weight as well as in both non-surgical and surgical weight loss. Therefore, we examined whether gender, age, weight before surgery and PA are good predictor variables for the outcome of surgical weight loss. Methods: One to six years after bariatric surgery 74 adults underwent a semi-structured interview. In a second step data on the post-surgical PA level were collected with the Moorehead-Ardelt Quality of Life Questionnaire. Finally, mouth swabs were used for genotyping. Results: 54 women and 20 men were enrolled between January 2004 and September 2009. Short-term EWL in the mid-activity genotype dopamine group (GA) was significantly higher (p = 0.007) than was short-term EWL in the low-activity genotype dopamine group (AA) or in the high-activity genotype dopamine group (GG). However, there were no significant differences between the COMT groups with respect to long-term EWL. Long-term we determined that EWL is significantly positively influenced by PA and negatively by gender. The effect of EWL was more pronounced in female than in male subjects. Conclusion: Various individual genotypes of the COMT polymorphism (Val108/158Met) make an impact only on short-term EWL, but not on long-term EWL. However, gender and PA proved to be good surgical weight loss predictors for long-term EWL.

The low level of dopamine at substantia nigra (mid-brain) has been considered to be one of the reasons for Parkinson’s disease (PD). This dopamine deficit is due to the influence of Catechol-O-Methyltransferase (COMT). A recent report outline that the flavonoid family of molecules are able to inhibit the COMT enzyme. To identify a potential molecule from the flavonoid family, we performed molecular screening over a group of flavonoid molecules using glide method. Among the screened molecules, morin molecule shows, relatively larger binding affinity (−7.90 kcal/mol) towards COMT enzyme. Further, an Induced Fit Docking (IFD) has been carried out for morin with COMT enzyme; the corresponding docking score value is −8.17 kcal/mol. To understand the conformational flexibility of morin in the active site of COMT, its conformation has been compared with the corresponding gas phase conformation. Further, molecular dynamics (MD) simulation has been performed to understand the dynamical behavior and the stability of morin molecule in the active site of COMT enzyme. The morin strongly binds with the catalytic triad and gatekeeper residues and these interactions have been maintained during the 50 ns MD simulation. Notably, the O(1) atom of morin forms interaction with Glu198, Mg ion and catalytic residue Asn169; in which, Glu198 is more stable during the simulation. The O(11) atom blocks the ionization process through the interaction with Lys143. Both of these interactions are essential to inhibit the enzymatic function of COMT enzyme. The binding free energy study shows morin molecule exhibit good binding towards COMT enzyme. Communicated by Ramaswamy H. Sarma

Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.

Summary Chronic post-surgical pain (CPSP) is a debilitating condition affecting 10–50% of surgical patients. The current treatment strategy for CPSP is not optimal, and the identification of genetic variation in surgical patients might help to improve prediction and treatment of CPSP. The neurotransmitter dopamine (DA) has been associated with several chronic pain disorders. This narrative review focuses on DA neurotransmission as a potential target in the treatment of CPSP. The current knowledge on genetic variation within DA neurotransmission and its role in CPSP susceptibility are reviewed. Three genes involved in DA neurotransmission (COMT, GCH1, and DRD2) have been associated with variability in pain sensitivity, development of CPSP, and analgesic requirement. The direction of the effect of the association is sometimes inconclusive because of contradictory results, but ample evidence suggests a modulatory role of DA. Because of this modulatory role, DA is an excellent pharmacological target in the treatment of pain. Pharmacotherapy focused on DA neurotransmission has potential in both prevention (via D1-like receptors) and treatment (via D2-like receptors and DA reuptake inhibitors) of CPSP. The development of prediction models including genetic risk factors is necessary to better identify patients at risk.

Cognitive flexibility has been hypothesized to be neurochemically rooted in dopamine neurotransmission. Nonetheless, underpowered sample sizes and contradictory meta-analytic findings have obscured the role of dopamine genes in cognitive flexibility and neglected potential gene–gene interactions. In this largest neurocognitive-genetic study to date (n = 1400), single nucleotide polymorphisms associated with elevated prefrontal dopamine levels (catechol-O-methyltransferase; rs4680) and diminished striatal dopamine (C957T; rs6277) were both implicated in Wisconsin Card Sorting Test performance. Crucially, however, these genetic effects were only evident in low-IQ participants, suggesting high intelligence compensates for, and eliminates, the effect of dispositional dopamine functioning on flexibility. This interaction between cognitive systems may explain and resolve previous empirical inconsistencies in highly educated participant samples. Moreover, compensatory gene–gene interactions were discovered between catechol-O-methyltransferase and DRD2, such that genotypes conferring either elevated prefrontal dopamine or diminished striatal dopamine—via heightened striatally concentrated D2 dopamine receptor availability—are sufficient for cognitive flexibility, but neither is necessary. The study has therefore revealed a form of epistatic redundancy or substitutability among dopamine systems in shaping adaptable thought and action, thus defining boundary conditions for dopaminergic effects on flexible behavior. These results inform theories of clinical disorders and psychopharmacological interventions and uncover complex fronto-striatal synergies in human flexible cognition.

The catechol-O-methyltransferase (COMT) is a candidate gene to provide promising evidence of psychiatric disorders, but there is a knowledge gap between the genetic factor and multiple physical activity-related injuries (PARIs). The aim of this study was to explore the contribution of COMT to the risk of PARIs among university students in the Chinese Han population. We can further search for the intrinsic risk factors for the occurrence of multiple physical activity injuries and provide a scientific basis for early screening and precise intervention for the high-risk group of college students with multiple PARIs. A 1:1 matched case-control study of 61 PARIs cases and 61 healthy controls were carried out. DNA samples of the participants were isolated from saliva and genotyped on eight SNPs of the COMT gene (rs9265, rs4680, rs6269, rs4818, rs4633, rs165655, rs165656, and rs165722) using the MALDI-TOF MS method. We found that rs6269 and rs4818 were significantly associated with PARIs, and rs6269-GG and rs4818-GG contributed to the reduced risk of PARIs. Further haplotype analysis showed a four-marker C-G-C-G haplotype (rs165722-rs6269-rs4633-rs4818) acted with a protective role in the development of PARIs (p = 0.037, OR: 0.474, 95% CI: 0.269 to 0.834). However, the interactions between club membership and rs6269 or rs4818 would significantly increase the risk of PARIs (both p &lt, 0.001, OR: 5.121 and 4.977, respectively). This is the first study to find the contribution of COMT to PARIs occurrence, suggesting that the COMT polymorphisms and the gene–environment interactions may alter the risk of PARIs.

Objective. To explore the mechanism of catechol-O-methyltransferase (COMT) in tooth movement pain. Methods. The experimental groups were randomly allocated into the healthy control, sham operation, model, model+shCOMT experimental, model+shCOMT control, and model+COMT antagonist groups. A tooth movement pain model was established. The pain stimulation and behavior test were performed. The duration of grooming behavior was determined. The appropriate experimental force and duration for application were selected. COMT shRNA vector was constructed and packaged as adenovirus. The shCOMT adenovirus was injected into the left infraorbital foramen. Seven days later, the trigeminal ganglia of all treatment groups were obtained. The COMT and IL-17 expressions were detected by western blot. The appropriate COMT antagonist concentration was selected. The pathological results of each group were detected by HE staining. The tooth movement distance was determined. The COMT gene expression was detected by FISH. The COMT and IL-17 expressions in the right trigeminal ganglion tissue of each group were detected by western blot. Results. The 60 g force and 14-day duration required the lowest stimulus intensity, the duration of grooming behavior was the longest, and the effect on COMT and IL-17 was the most significant. In the model group, formation of digestive cavity was seen in the trigeminal ganglion tissue, with infiltration of inflammatory cells, upregulation of the COMT and IL-17 expressions, and significant increase in the tooth movement distance. Compared with the model group, the shCOMT experimental group and the COMT antagonist group significantly improved the trigeminal ganglion tissue injury, significantly decreased the tooth movement distance, and significantly inhibited the COMT and IL-17 expressions. Conclusion. The efficiency of tooth movement can be influenced by interfering the COMT-related gene expression. This proves that the COMT system can regulate the orthodontic tooth movement pain.

The abuse of performance-enhancing catecholamine-based stimulants, such as levodopa, is controlled in horse racing through the application of a regulatory threshold for the common major metabolite. However, catechol-O-methyltransferase (COMT) enzyme inhibitors can be used to restrict the catalysis of the stimulant, and so the concurrent administration of both substances would be a viable strategy to enhance racing performance while removing the risk of exceeding the threshold. A 200 mg dose of nitecapone, a COMT inhibitor, was administered to a Thoroughbred horse, and we have analysed the blood (≤24 h) and urine (≤48 h) samples that were collected. The extracts, analysed by UHPLC coupled to a high-resolution accurate mass spectrometer, were consistent with the presence of nitecapone glucuronide in all the samples collected. An in-depth examination of the samples was then carried out using targeted accurate mass extracted ion chromatograms to identify whether the metabolites that have been found in other species were also present in the extracts. Once these were tentatively identified, MS/MS experiments were conducted on some of the metabolites (M1-M5), as well as decomposition products (DP1 and DP2), to verify that spectrum included MS fragments were consistent with their proposed structures. The accumulated data provided evidence that is consistent with this drug having been converted into many metabolites and a few decomposition products. An unexpected finding was that O-methylation was a very minor pathway until after the reduction of the 2,4-pentanedione side chain had occurred.

The article's abstract is not available.