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Official websites use. Share sensitive information only on official, secure websites. Correspondence to: P. Tel: , Fax: Correspondence to: R. Tel: Fax: More must be learned about metabolic and biochemical alterations that contribute to the development and expression of drug dependence. Experimental opioid administration influences mechanisms and indices of oxidative stress, such as antioxidant compounds and purine metabolism. We examined perturbations of neurotransmitter-related pathways in opioid dependence OD. Other drug use in addition to opioids was associated with partly different biochemical changes. This is a preliminary investigation using metabolomics and showing multiple peripheral alterations of metabolic pathways in OD. Further studies should explore the metabolic profile of conditions of opioid abuse, withdrawal and long-term abstinence in relation to agonist and antagonist treatment and investigate biochemical signatures of opioid substances and medications. Keywords: metabolomics, metabonomics, addiction, metabolic profiling, opioid detoxification, methadone. Substance misuse is commonly associated with health risks and increased susceptibility to organ damage, as in the case of alcohol abuse and liver injury Zakhari and Li, Less is known on the nature of biochemical changes and their contribution to the development of chronic toxicity and drug dependence. The metabolome defines a metabolic state as regulated by a net of interactions between genes and environment and provides useful information to bridge the gap between genotype and phenotype. Opioid substances are known to induce biochemical alterations Jiang et al. In experimental conditions, opioid administration has been associated with changes in oxidative stress mechanisms Sharma et al. Oxidative damage, known as oxidative stress, is the result of accumulation of free radicals insufficiently neutralized by antioxidant agents Sies, Reliable indices of oxidative stress include modifications of glutathione and tocopherol levels. Experimental changes in oxidative status induced by opioid substances affect cell energy, involve nucleotide metabolism and may influence purine compounds levels Chen et al. The initial objective is to recognize whether these changes are associated with opioid abuse and dependence. In this preliminary study, we analyzed oxidation—reduction activity and purine metabolites in plasma of opioid dependent OD patients during methadone detoxification, using a liquid chromatography electrochemical array detection LCECA metabolomics platform that has been employed to map biochemical changes and identify monoaminergic signatures of several CNS disorders, including amyotrophic lateral sclerosis and Parkinson Bogdanov et al. Fourteen participants were recruited among OD individuals 18 years of age or older enrolled in a methadone detoxification study described in detail elsewhere Mannelli et al. The sample size was deemed sufficient based on previous investigations. We identified initial signatures of psychiatric and neurologic disorders using the same metabolomics platform in comparable samples Rozen et al. All subjects provided oral and written informed consent and the study was conducted according to the principles expressed in the Declaration of Helsinki of , as revised in Individuals received medical and psychiatric evaluation with routine clinical laboratory tests at screening. The condition of current dependence on substances other than opioids or nicotine was excluded. Individuals who used or abused other substances were included only if their primary drug was an opioid drug. Subjects were also excluded in case of pregnancy, history or presence of medical or neurological disorder, suicide risk, DSM IV diagnosis of psychotic disorder, major depression and bipolar disorder. OD patients were participating in a 6-day inpatient detoxification and received oral methadone daily between 9 and 10 a. Control subjects did not receive study treatment. Alcohol use was self-reported and confirmed by breathalyzer. Blood samples for analysis were collected on days 2 or 3 of treatment from OD participants, to reduce the influence of pre-treatment differences in opioid or other drug use. All samples were collected between 10 and 11 a. Collection was completed over 18 months. Plasma was extracted, centrifuged, and stored frozen before shipping. Briefly, the LCECA metabolomics platform contains 16 coulometric electrode array systems, allowing differential detection and quantification of small molecules on the basis of their oxidation—reduction potentials. The platform used for this metabolic profiling has been used for the study of the tryptophan and tyrosine pathways Beal et al. The robustness of the platform, its reproducibility, and sensitivity have been well documented Rozen et al. During the preparation of the samples, pools were created from equal volume subaliquots of all samples. Pooled samples represent the maximum analytical complexity expected from among sample variation in the study. Aliquots of the pool were analyzed after each seven samples in the run sequence. All samples and pools were analyzed against the middle pool in the run sequence. By this criterion, we identified approximately peaks, of which 39 matched known compounds in our component library of standard electrochemical signatures Kristal et al. Compounds are grouped by metabolic pathway. Data represent means of values relative to the entire pool values for that metabolite. In the case of OD, biochemical differences between patients and controls might reveal differences in key reactions and suggest mechanisms of disease. We accounted for multiple hypothesis testing by estimating cumulative false discovery rates Q -values based on the nominal p -values qvalue package in R; www. Characteristics of the sample are shown in Table 2. Three OD individuals Six OD patients One or two days later, at the time of sample collection, they received either 20 or 25 mg of methadone and showed mild or less than mild withdrawal discomfort. No other pharmacological treatment beside methadone was recorded at the time of biological sampling. Differences were found between treated OD patients and non-drug dependent volunteers in the concentration of compounds involved in the process of oxidation and reduction. The measures of redox activity that were significantly different between drug abusers and controls are shown in Figure 1. Measures of oxidation—reduction activity that were significantly different between opioid dependent subjects Op and controls Ctrl. In the Op group, open circles indicate patients with recent use of only opioids, while filled circles indicate individuals with other drug use in addition to opioids see Methods. Horizontal lines indicate medians. Significant changes were revealed by the analysis of purine metabolites in OD patients. Figure 2 shows purine metabolites and the ratios of purine metabolites that were significantly different between drug abusers and controls. Purine metabolites that were significantly different between opioid dependent patients Op and controls Ctrl. There were no significant differences between OD patients in treatment and controls in a variety of monoamines and precursors from the tryptophan, tyrosine and phenylalanine pathways. This group showed a pattern of oxidation—reduction activity and purine metabolites not dissimilar from the whole group of drug abusers. Figure 1. Comparisons of all metabolites and metabolite ratios between OO and control groups are available upon request. OD patients undergoing methadone detoxification showed different peripheral levels of antioxidant activity and purine metabolites when compared with non-drug users. Whether any of these changes can serve as a biological marker of disease or response to methadone treatment needs to be studied in prospective longitudinal studies. Heroin or morphine administration and withdrawal are associated with reduced antioxidant defenses in animals Guzman et al. Opioid-induced oxidative stress is inconsistently modified by the administration of antioxidant agents, including tocopherol and glutathione Mori et al. Accordingly, indices of oxidation such as reactive oxygen species were reduced in OD patients undergoing short detoxification or controls, compared with active abusers Pereska et al. Although in our OD sample, the rapidly reduced withdrawal discomfort following methadone administration Table 2 may be consistent with improved redox status, the influence of treatment cannot be determined with a single evaluation. Preclinical investigations have identified multiple roles of purines in the brain, including energy metabolism, trophic functions, signaling, and neuromodulation Boucsein C et al. Acute administration of morphine enhances purine catabolism lowering cell energy, a condition that reverts following drug discontinuation, but not with chronic administration in rodents Di Francesco et al. In type I diabetes, a model of chronic metabolic disease, increased mithochondrial purine catabolism is reactive to antioxidant offenses and has been measured by changes in hypoxanthine, guanine, guanosine, and xanthosine, similar to what found in plasma of OD patients Kristal et al. Uric acid and hypoxanthine levels in OD subjects were comparable or significantly lower than in controls. Diabetes, alcohol abuse, or acute cardiovascular disorders are initially associated with higher plasma levels of the final bio-products of purine pathways, which decrease in severe or chronic conditions Kristal et al. Plasma guanine and xanthosine were elevated in OD patients. This could mean a potential gain of energy, through a conversion to their corresponding nucleotides via salvage pathways Barsotti et al. However, accumulation can occur also in case of reduced elimination following an excessive metabolic workload, similar to what is observed in patients with chronic renal failure Niwa et al. Within the multi-dimensional frame of drug-dependence, metabolomics analysis can follow patterns of biochemical changes and lead to formulate pathogenetic hypotheses at different levels. One example is offered by the neurotrophic and modulatory effects of guanine-based purines. The combination of high guanine—low guanosine levels we found in OD patients is commonly associated with brain toxic insult and increased dopamine turnover in experimental models Ciccarelli et al. Elevated peripheral guanine binding protein levels were previously found in OD patients receiving methadone Linseman and Loucks, ; Manji et al. Guanine and guanine-based purines also participate in the regulation of the Gabaergic and Glutamatergic transmission, affecting motivation, learning, memory, and anxiety Majumder et al. This raises questions on whether increased guanine levels are equivalent to enhanced central purinergic transmission in response to oxidative damage, confirming hypotheses of purinergic neuromodulation of withdrawal and drug-seeking behaviors Capasso and Loizzo, ; Majumder et al. To this end, future investigations should initially characterize peripheral purines patterns associated with treatment and recovery, as opposed to those modifications that accompany opioid abuse and withdrawal. Although dopamine, serotonin, and noradrenaline contribute to the expression of OD Espejo et al. Similar results adopting different evaluations methods were previously explained with the development of adaptive changes following chronic opioid use Macedo et al. Only, N -methylserotonin levels were found elevated in drug abusers. N -methylserotonin is a congener of serotonin and with its derivative bufotenine has shown psychotropic and hallucinogenic effects Takeda, Both compounds are elevated in psychiatric disorders characterized by altered perceptions and hallucinations Takeda, ; Takeda et al. Polydrug abuse is a common clinical observation and was investigated for the ability to affect metabolic pathways. Recent use of other drugs was not associated with increased drug or alcohol use severity, or more intense withdrawal discomfort in our sample Table 2. This is consistent with the hypothesis that the co-use of different drugs may reflect different patterns of intensity of neurobiological responses to oxidative stress Parrott et al. N -methylserotonin was found more elevated when OD patients who abused non-opioid drugs were included in the analysis. Given the relatively small number of subjects, we could not determine if the effect was associated with non-opioid drug use. Although OD patients and controls were carefully characterized and the biological differences found were strong and significant, the rather small sample reduced the ability to control for confounding factors and the results should be viewed as preliminary. Besides the discussed influence of non-opioid drug use, the number of smokers was not significantly different between groups, however individual smoking patterns were not investigated and their influence cannot be excluded. Confounding by nutritional factors has been suggested in metabolomics studies Lenz, ; Walsh et al. The metabolomic platform we used was successfully employed to identify biochemical changes in neurologic disorders without controlling for dietary factors Rozen et al. Future investigations and more stringent inclusion criteria will help determine whether diverse dietary habits and other individual factors, such as age, lifestyle, or ethnic background, constitute confounds in populations of drug abusers. Notwithstanding the caveats, we provide evidence that metabolomics can be a valuable tool to assess biochemical changes in OD. This is a preliminary report on multiple metabolome modifications of antioxidant activity and purine pathways in a small sample of drug-dependent individuals. Findings suggest the possibility of measuring biochemical alterations associate with the disease and its response to treatment. Further studies should characterize metabolite profiles for the conditions of opioid abuse, withdrawal and long-term abstinence in relation to different treatments and different drugs of abuse. A long-term goal is to associate metabolic perturbations with etiologic, pathogenetic, and prognostic aspects of drug dependence. The application of these principles will help formulate classification of the disease based on metabolomic profiles and identify biomarkers for drug response phenotypes, valuable tools in the process of discovering new medications, and developing new approaches to treatment. The authors thank Dr Ting Kai Li for his insightful comments and suggestions in the preparation of this paper. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. In addition, he is an inventor on patents in the metabolomics field. These patents do not address directly the area of addiction or the results of the study reported here. Dr Kaddurah-Daouk is an equity holder in Metabolon Inc. No author has declared potential conflict of interest with the present work. As a library, NLM provides access to scientific literature. Hum Psychopharmacol. Published in final edited form as: Hum Psychopharmacol. Find articles by Paolo Mannelli. Find articles by Ashwin Patkar. Find articles by Steve Rozen. Find articles by Wayne Matson. Find articles by Ranga Krishnan. Find articles by Rima Kaddurah- Daouk. The publisher's version of this article is available at Hum Psychopharmacol. Metabolic comparisons between opioid dependent OD individuals and controls. Open in a new tab. Drs Rozen and Matson have no financial disclosures at this time. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel. Urine tests c.

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