Determination of thallium in urine, blood, and hair in illicit opioid users in Iran.

CONTEXT: Heavy metals, including thallium and lead, are introduced to illicit drug users' body as a result of using drugs such as cocaine and heroin. OBJECTIVE: This study aimed to determine urine, blood, and hair thallium (Tl) concentrations in illicit opioid users along with the relevant clinical signs and symptoms consistent with thallotoxicosis and to compare them with the corresponding variables in the control non-opioid user group. MATERIALS AND METHODS: This case-control study was conducted on 50 illicit opioid users who had abused opioids continuously for more than a year, referred to Amirie Drug Abuse Treatment Clinic in Kashan, Iran. The control group included 50 non-opioid users. Thallium concentrations in urine, blood, and hair were assessed in both groups (n = 100) using electrothermal (graphite furnace) atomic absorption spectrometry (ET AAS, GF AAS). RESULTS: In the studied group, the median (interquartile range) concentrations of thallium in urine, blood, and hair were 54.8 ± 79.9 µg/L, 14.5 ± 11.1 µg/L, and 5.4 ± 3.7 µg/g, respectively; these values were 4.8 ± 5.2 µg/L, 2.5 ± 2.4 µg/L, and 1.4 ± 1.1 µg/g, respectively, in the control group. There were significant differences in urine, blood, and hair thallium concentrations between the study group and the control group (p < 0.001). There were significant correlations between duration of illicit opioid use and urine thallium concentrations (r = 0.394, p = 0.005) and hair thallium concentrations (r = 0.293, p = 0.039), but not with blood thallium concentrations (r = 0.246, p = 0.085). Urine and blood thallium concentrations of illicit opioid users with clinical signs and symptoms consistent with thallotoxicosis of weakness (p = 0.01), depression (p = 0.03), and headache (p = 0.03) were higher than users without these problems. DISCUSSION AND CONCLUSION: The results of the study showed that thallium concentrations in urine, blood, and hair in illicit opioid users were significantly higher than the comparable concentrations in the control group. This can be due to the use of illicit opioids adulterated with thallium. Also, this study showed long-term illicit opioid use may lead to thallium exposure. In addition, cigarette smoking was associated with increased thallium exposure.

Non-Opioid Neurotransmitter Systems that Contribute to the Opioid Withdrawal Syndrome: A Review of Preclinical and Human Evidence.

Opioid misuse and abuse is a major international public health issue. Opioid use disorder (OUD) is largely maintained by a desire to suppress aversive opioid withdrawal symptoms. Opioid withdrawal in patients seeking abstinence from illicit or prescribed opioids is often managed by provision of a µ-opioid agonist/partial agonist in combination with concomitant medications. Concomitant medications are administered based on their ability to treat specific symptoms rather than a mechanistic understanding of the opioid withdrawal syndrome; however, their use has not been statistically associated with improved treatment outcomes. Understanding the central and/or peripheral mechanisms that underlie individual withdrawal symptom expression in humans will help promote medication development for opioid withdrawal management. To support focused examination of mechanistically supported concomitant medications, this review summarizes evidence from preclinical (N = 68) and human (N = 30) studies that administered drugs acting on the dopamine, serotonin, cannabinoid, orexin/hypocretin, and glutamate systems and reported outcomes related to opioid withdrawal. These studies provide evidence that each of these systems contribute to opioid withdrawal severity. The Food and Drug Administration has approved medications acting on these respective systems for other indications and research in this area could support the repurposing of these medications to enhance opioid withdrawal treatment. These data support a focused examination of mechanistically informed concomitant medications to help reduce opioid withdrawal severity and enhance the continuum of care available for persons with OUD.

Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome.

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms, and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance, and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that an n-3-PUFA-enriched diet ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and n-3 PUFA supplementation. We demonstrate that the withdrawal of opioids led to a significant depletion in specific microbiota genera, whereas n-3 PUFA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that n-3 PUFA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in n-3 PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

Clinical and metabolic responses to crocin in patients under methadone maintenance treatment: A randomized clinical trial.

Patients under methadone maintenance treatment (MMT) programs are susceptible to several complications including metabolic and clinical disorders. This study was designed to determine the effect of crocin supplementation on mental health parameters and metabolic profiles in subjects under MMT. The current randomized, double-blind, placebo-controlled, clinical trial was conducted among 53 patients under MMT to receive either 15 mg/day of crocin (n = 26) or placebo (n = 27) twice a day for 8 weeks. Crocin administration significantly decreased Beck Depression Inventory score (P = 0.01) and Beck Anxiety Inventory score (P = 0.008) compared with the placebo. In addition, crocin administration resulted in a significant reduction in fasting glucose (P = 0.003), insulin levels (P = 0.01), insulin resistance (P = 0.008), triglycerides (P = 0.001), very low-density lipoprotein (P = 0.001), total cholesterol levels (P = 0.03), and a significant increase in insulin sensitivity (.003) compared with the placebo. Additionally, crocin intake was associated with a significant reduction in high-sensitivity C-reactive protein (p < .001) and malondialdehyde (P = 0.001) and a significant rise in total antioxidant capacity levels (P = 0.01) compared with the placebo. The findings of this clinical trial indicate that taking crocin for 8 weeks by patients under MMT had beneficial effects on their mental health and improved their metabolic profiles.

Kratom and Future Treatment for the Opioid Addiction and Chronic Pain: Periculo Beneficium?

Kratom (Mitragyna speciosa), a naturally existing plant found in South-East Asia, is traditionally used as a herb to help elevate a person's energy and also to treat numerous medical ailments. Other than the analgesic property, kratom has been used as an agent to overcome opioid withdrawal as it contains natural alkaloids, i.e. mitragynine, 7-hydroxymitragynine, and MGM-9, which has agonist affinity on the opioid receptors, including mu (µ) and kappa (κ). The role of neural reward pathways linked to µ-opioid receptors and both dopaminergic and gamma-Aminobutyric acid (GABA)-ergic interneurons that express µ-opioid receptors were deliberated. However, kratom has been reported to be abused together with other illicit substances with high risk of potential addiction. There are also anecdotes of adverse effects and toxicity of kratom, i.e. tremor, fatigue, seizure, and death. Different countries have distinctive regulation and policy on the plantation and use of this plant when most of the countries banned the use of it because of its addiction problems and side effects. The aim of this review is to highlight on the potential use of kratom, unique 'herbs" as a substitution therapy for chronic pain and opioid addiction, based on the neurobiological perspective of pain and the underlying mechanism of actions of drug addiction.

DARK Classics in Chemical Neuroscience: Morphine.

As the major psychoactive agent in opium and direct precursor for heroin, morphine is a historically critical molecule in chemical neuroscience. A structurally complex phenanthrene alkaloid produced by Papaver somniferum, morphine has fascinated chemists seeking to disentangle pharmacologically beneficial analgesic effects from addiction, tolerance, and dependence liabilities. In this review, we will detail the history of morphine, from the first extraction and isolation by Sertürner in 1804 to the illicit use of morphine and proliferation of opioid use and abuse disorders currently ravaging the United States. Morphine is a molecule of great cultural relevance, as the agent that single-handedly transformed our understanding of pharmacognosy, receptor dynamics, and substance abuse and dependence disorders.

Impact of opioids on oxidative status and related signaling pathways: An integrated view.

BACKGROUND: Opioids produce reactive oxygen species (ROS) which are highly reactive molecules that damage cells and tissues, and are suggested to contribute to the opioid use disorders. Thus, antioxidant supplementation might improve the disturbance in redox (oxidation-reduction) homeostasis. However, randomized trials on antioxidant therapy have not shown beneficial effects. OBJECTIVES: The purpose of this review is to shed lights on the oxidative changes resulting from opioid use and to highlight the unanswered questions regarding oxidative profile in an effort to provide a comprehensive view of different aspects of an efficient antioxidant therapy in clinical settings. METHODS: The studies were identified and gathered from the PubMed database over the past 16 years (2000-2016). Our search results were limited to articles in English, both animals and human and in vitro and in vivo studies. A total of 50 full text articles were reviewed and summarized. RESULTS: Opioids elevate the level of ROS and decrease the function of enzymatic antioxidants such as superoxide dismutase, catalase, and glutathione peroxidase. They increase the risk of vitamin deficiency and modify gene expression of target cells through ROS production. The effects of opioids on their target cells are exerted through different way and various mechanisms. CONCLUSION: Opioids modulate the redox homeostasis; therefore, understanding the profile of oxidative changes in individuals with opioid use disorder could be of significant benefits in the clinical setting, to help with selection of an efficient antioxidant therapy and diminishing oxidative damage.

Spironolactone decreases the somatic signs of opiate withdrawal by blocking the mineralocorticoid receptors (MR).

Pharmacological evidence has accumulated showing that glucocorticoids and glucocorticoid receptor (GR) facilitate several responses to different drugs of abuse. Recent findings have attributed a prominent role to the mineralocorticoid receptor (MR) in modulating behavior during the addictive process. The purpose of this study was to investigate the effects of MR blockade on: brain stress system responses to naloxone-induced morphine withdrawal, the somatic signs of abstinence; the effects of morphine withdrawal on noradrenaline (NA) turnover in the paraventricular nucleus (PVN), c-Fos expression and tyrosine hydroxylase (TH) phosphorylated at Ser31 levels in the nucleus tractus solitarius noradrenergic cell group (NTS-A2); and finally, hypothalamus-pituitary-adrenocortical (HPA) axis activity. The role of MR signaling was assessed with i.p. pretreatment with the MR antagonist, spironolactone. Rats were implanted with two morphine (or placebo) pellets. Six days later rats were pretreated with spironolactone or vehicle 30min before naloxone. The physical signs of abstinence, NA turnover, TH activation, c-Fos expression and the HPA axis activity were measured using HPLC, immunoblotting and RIA. Spironolactone attenuated the somatic signs of withdrawal that were seen after naloxone administration to chronic morphine treated animals. On the other hand, pretreatment with spironolactone resulted in no significant modification of the increased NA turnover, TH activation, c-Fos expression or HPA axis activity that occurred during morphine withdrawal. These results suggest that somatic signs of opiate withdrawal are modulated by MR signaling. However, blockade of MR did not significantly alter the brain stress system response to morphine withdrawal.

[Biochemical diagnostics of fatal opium intoxication].

Biochemical diagnostics of fatal opium intoxication remains a topical problem in forensic medical science and practice. We investigated materials obtained in the course of forensic medical expertise of the cases of fatal opium intoxication. The study revealed significant differences between myoglobin levels in blood, urine, myocardium, and skeletal muscles. The proposed approach to biochemical diagnostics of fatal opium intoxication enhances the accuracy and the level of evidence of expert conclusions.

New approach to the neurobiological mechanisms of addiction.

Much progress has been made in the last decade in the understanding the neural substrates of drug addiction, transmitters involved, epigenetic background and their relation to learning and memory but much remains to be elucidated and strong effort is necessary to integrate the rich information at the molecular, cellular systems, and behavioral levels to further clarify the mechanisms and therapy of this complex disease. The aim of this review is to collect and interpret the latest opinions in the development, the underlying mechanisms and therapy of addiction as a disease of central nervous system. The neurocircuitry, the transmitters and the epigenetics of addiction are discussed.

Protective effect of Nigella sativa oil against tramadol-induced tolerance and dependence in mice: role of nitric oxide and oxidative stress.

Nigella sativa seed extracts and its oil have been exploited for their various health benefits. In this study, the effects of N. sativa oil on tramadol-induced tolerance and dependence and possible mechanism(s) of these effects were investigated, for the first time, in mice. Repeated administration of N. sativa oil (4 ml/kg, p.o.) along with tramadol (50mg/kg, s.c.) inhibited the development of tramadol tolerance, as measured by the hot plate test, and dependence as assessed by naloxone (5mg/kg, i.p.)-precipitated withdrawal manifestations. Concomitantly, nitric oxide overproduction and increase in brain malondialdehyde level induced by repeated administration of tramadol to mice or by administration of naloxone to tramadol-dependent mice were inhibited by co-administration of the oil. Also, the decrease in brain intracellular reduced glutathione level and glutathione peroxidase activity induced by both treatments was inhibited by co-administration of the oil. The increase in brain glutamate level induced by both treatments was not inhibited by concurrent administration of the oil. The inhibitory effect of N. sativa oil on tramadol-induced tolerance and dependence was enhanced by concurrent i.p. administration of the NMDA receptor antagonist, dizocilpine (0.25mg/kg). Also, the inhibitory effect of the oil on naloxone-induced biochemical alterations in tramadol-dependent mice was enhanced by concurrent administration of dizocilpine. Similarly, concurrent i.p. administration of the NO synthase inhibitor, L-N(G)-nitroarginine methyl ester (10mg/kg) or the antioxidant, N-acetylcysteine (50mg/kg) enhanced these inhibitory effects of N. sativa oil. On the other hand, these effects were antagonized by concurrent i.p. administration of the NO precursor, L-arginine (300 mg/kg). These results provide evidence that N. sativa oil appears to have a therapeutic potential in tramadol tolerance and dependence through blockade of NO overproduction and oxidative stress induced by the drug.

Impact of opium on the serum levels of TGF-ß in diabetic, addicted and addicted-diabetic rats.

BACKGROUND: Several cells of immune system such as regulatory T cells and macrophages secrete transforming growth factor-ß (TGF-ß) in response to different stimuli. This cytokine has inhibitory effect on immune system and diminished production of this cytokine is associated with autoimmune disorders. OBJECTIVE: The aim of this study was to evaluate the influence of opium addiction on serum level of TGF-ß in male and female diabetic and non-diabetic Wistar rats. METHODS: This experimental study was performed on normal, opium addicted, diabetic and addicted-diabetic male and female rats. Serum level of TGF-ß was measured by ELISA. RESULTS: The results of our study indicated that the mean serum level of TGF-ß in female addicted rats was significantly increased compared to control group (p<0.004). Conversely, in male addicted rats the mean serum level of TGF-ß was lower compared with control (p<0.065). CONCLUSION: Our results suggest that opium and its derivatives have differential inductive effects on the cytokine expression in male and female rats.

Effect of opium addiction on lipid profile and atherosclerosis formation in hypercholesterolemic rabbits.

In some Asian and Middle Eastern societies, opium consumption has traditionally been regarded as a way to lower blood lipids and to prevent heart diseases. This could eventually lead to addiction. In this study, the effect of oral opium consumption on serum lipids and atherogenesis in rabbits was investigated. Twenty-eight male New Zealand white rabbits were divided into control, hypercholesterolemic, addicted, and hypercholesterolemic-addicted groups and were studied for 3 months. Serum lipid profile was determined at the beginning of the study and at 1 month intervals thereafter. At the end of the study period, aortic plaque formation was assessed. Compared with control, in the hypercholesterolemic and hypercholesterolemic-addicted groups, cholesterol, triglycerides, and low-density lipoprotein cholesterol levels were significantly increased (P<0.01). The increases in lipids and lesion areas in the aorta were higher in hypercholesterolemic-addicted than hypercholesterolemic group (P<0.05). Our findings suggest that opium consumption can have aggravating effects in atherosclerosis formation related with hypercholesterolemia, mainly affecting lipid profile.

Duration of spinal anesthesia with bupivacaine in chronic opium abusers undergoing lower extremity orthopedic surgery.

BACKGROUND: It has been demonstrated that chronic opium abusers have lower thresholds for pain. Spinal anesthesia is a common procedure in anesthesia, which is performed through administration of drugs (usually local anesthetics) in the intrathecal space, to produce temporary pain relief. The aim of this study was to determine whether chronic opium abuse could have any possible effect on the duration of spinal block by bupivacaine. METHODS: In a case-control study, 50 opium abusers and 50 nonabusers undergoing lower extremity orthopedic operations were selected from the patients admitted in Taleghani Hospital in Tehran for elective surgery. The study parameters were assimilated as much as possible, including the method of anesthesia. RESULTS: No statistically significant difference was noted between the two groups regarding the age, sex, and duration of surgery; while, the duration of sensory block was much shorter in the opium abusers (86.6+/-15.7 minutes) compared with the nonabusers (162+/-22.1 minutes) (P<0.0001). CONCLUSION: The study suggests a shortened duration of spinal block with bupivacaine in opium abusers. The results can propose a number of possible mechanisms including cross-tolerance mechanisms between local anesthetics and opioid compounds at the level of spinal neurons. Further molecular studies at the level of spine are suggested.

A combined spectroscopic and functional MRI investigation of the dorsal anterior cingulate region in opiate addiction.

Converging neuropsychological and functional neuroimaging evidence indicates that the dorsal anterior cingulate cortex (dACC) is dysfunctional in drug-addicted populations. Few studies, however, have investigated the biochemical and physiological properties of the dACC in such populations. We used proton magnetic resonance spectroscopy ((1)H-MRS) together with functional magnetic resonance imaging (fMRI) to probe dACC biochemistry and physiological activity during performance of a behavioural control task in 24 opiate-dependent individuals (maintained on a stable dose of methadone or buprenorphine at the time of study) and 24 age, gender, intelligence and performance-matched healthy subjects. While both groups activated the dACC to comparable levels, the opiate-using group displayed relatively increased task-related activation of frontal, parietal and cerebellar regions, as well as reduced concentrations of dACC N-acetylaspartate and glutamate/glutamine. In addition, the opiate-using group failed to show the expected correlations between dACC activation and behavioural measures of cognitive control. These findings suggest that the dACC is biochemically and physiologically abnormal in long-term opiate-dependent individuals. Furthermore, opiate addicts required increased, perhaps compensatory, involvement of the fronto-parietal and cerebellar behavioural regulation network to achieve normal levels of task performance/behavioural control. These neurobiological findings may partly underpin key addiction-related phenomena, such as poor inhibitory control of drug-related behaviour in the face of adverse consequences, and may be of relevance to the design of future treatment studies.

Multiple aspects of hair analysis for opiates: methodology, clinical and workplace populations, codeine, and poppy seed ingestion.

Levels of morphine, 6-monoacetylmorphine (MAM) and codeine in hair in both clinical and workplace subjects are presented. Aggressive wash procedures, consisting of 1 isopropanol wash, three 30-min, and two 1-h buffer washes, followed by digestion, extraction and confirmation of digested samples, resulted in values from the cutoff of 2 ng morphine/10 mg hair to greater than 200 ng/10 mg hair. Both morphine and MAM were present above the cutoff in all hair samples from 69 clinical subjects. Only 39 of the 69 heroin-using subjects had urine tests positive for 6-MAM. In a study of morphine in hair following poppy seed consumption, ten subjects ingested 150 g of poppy seed over 3 weeks. Urine samples were collected on the days of poppy seed ingestion and hair samples were taken in the 5th week of the study. The range among the 10 subjects of the highest urine value for each subject was 2929 to 13,827 ng morphine/mL. Hair morphine levels were 0.05-0.48 ng/10 mg hair (average 0.17 ng/10 mg hair). Hair opiate levels of workplace subjects ranged somewhat lower than those of clinical subjects. While all clinical hair samples contained MAM, many workplace samples did not. From workplace samples, a maximum amount of morphine likely to be present from codeine use was 0-3.7% of the codeine in the hair.

Cerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenance.

This study evaluated cerebral phosphorus metabolites in opiate-dependent polydrug abusers in methadone maintenance therapy (MMT) and determined whether metabolite profiles differed based on treatment duration. Phosphorus magnetic resonance spectroscopy (31P-MRS) data were acquired with the ISIS volume localization method from a 50-mm thick axial brain slice through the orbitofrontal and occipital cortices. Study subjects included 15 MMT subjects, seven having undergone treatment for an average of 39 +/- 23 weeks (mean +/- S.D.) and eight having undergone treatment for 137 +/- 53 weeks, as well as an age matched comparison group (n = 16). The methadone dose administered on the study day averaged 70.5 +/- 17.1 mg and was statistically equivalent in short- and long-term subgroups. MMT subjects (n = 15) differed from control subjects in percent phosphocreatine (%PCr) levels (-13%), and in both phosphomonoester (%PME, +13%) and phosphodiester (%PDE, +10%) levels, which likely reflect abnormalities in energy and phospholipid metabolism, respectively. There were no sex effects or group by sex interaction effects on these measures. In short-term MMT treatment subjects, abnormal %PCr (-18%), %PME (+20%) and %PDE (+17%) levels were found compared with control subjects. The only metabolite abnormality detected in long-term MMT subjects was decreased %PCr (-9%), in spite of continued illicit drug abuse. From these data, we conclude that polydrug abusers in MMT have 31P-MRS results consistent with abnormal brain metabolism and phospholipid balance. The nearly normal metabolite profile in long-term MMT subjects suggests that prolonged MMT may be associated with improved neurochemistry.

Presence of a reduced opioid response in interleukin-6 knock out mice.

Cytokines are known to influence neuronal functions. The purpose of this study was to investigate the putative role of the cytokine interleukin-6 (IL-6) in the pathways involved in opioid-mediated responses, by using IL-6-deficient mice. We reported that with a thermal stimulus IL-6-knock-out (IL-6KO) mice presented nociceptive thresholds similar to those measured in their controls. However, they showed a reduced analgesic response both to the restraint stress and to the administration of low doses of morphine. Hypothalamic levels of the opioid peptide beta-endorphin were significantly higher in IL-6KO mice than they were in their controls. The development of tolerance to the analgesic effect of morphine was more rapid in IL-6-deficient mice than in wild-type controls. Binding experiments showed that the number of opioid receptors in the midbrain, but not in the hypothalamus, decreased in IL-6KO mice. Autoradiographic binding analysis revealed that the density of mu receptors diminished while the delta-opioid receptors did not. These results suggest that IL-6 is necessary for a correct development of neuronal mechanisms involved in the response to both endogenous and exogenous opiates.

[Lipid peroxidation and status of the antioxidant system in opiate addiction, chronic alcoholism, or substance abuse caused by inhaling solvent vapors]. / Perekisnoe okislenie lipidov i sostoianie antioksidantnykh sistem pri opiinoi narkomanii, khronicheskom alkogolizme, toksikomanii, obuslovlennoi vdykhaniem parov organicheskikh rastvoritelei.

Patterns of lipid peroxidation and the state of antioxidant systems were studied in 30 healthy volunteers (control), 18 patients with toxicomania developed as a result of inspiration of organic solvent vapors, 21 patients with chronic alcoholism and in 27 patients with opium narcomania within 4-6 years after withdrawal. The data obtained suggest that activation of lipid peroxidation and decrease in the rate of antioxidant response, which were detected in the patients with narcomania, correlated with severity of the psychopathological failures induced by chronic toxic effect of the narcotics or toxic preparations applied.