Effect of vitamin D supplementation as adjunctive therapy to methylphenidate on ADHD symptoms: A randomized, double blind, placebo-controlled trial.

OBJECTIVES: Previous studies have shown that serum levels of vitamin D were lower in attention deficit hyperactivity disorder (ADHD) children compared to healthy controls. The aim of the study was to determine the effect of vitamin D supplementation as adjunctive therapy to methylphenidate on symptoms of children with ADHD. METHODS: Sixty-two children aged 5-12 years with a diagnosis of ADHD based on DSM-IV criteria were randomly assigned into two groups to receive either 2000IU vitamin D or placebo in addition to methylphenidate for 8 weeks. Symptoms severity was assessed by Conner's Parent Rating Scale-Revised[S] (CPRS), ADHD rating scale-IV (ADHD-RS), and Weekly Parent Ratings of Evening and Morning Behavior (WPREMB) at weeks 0, 4, and 8. Serum levels of 25(OH)D were measured at baseline and after 8 weeks. Anthropometric variables, dietary intake, physical activity, sun exposure, and side effects were assessed. RESULTS: Fifty-four participants completed the trial. After 8 weeks of supplementation, serum levels of 25(OH)D significantly increased in the vitamin D group. ADHD symptoms decreased significantly in both groups (P < 0.05). Evening symptoms and total score of WPREMB scale were significantly different at weeks 4 and 8 between the two groups (P = 0.013, 0.016, respectively), but no differences were found in symptoms by CPRS and ADHD-RS scales. DISCUSSION: Vitamin D supplementation as adjunctive therapy to methylphenidate improved ADHD evening symptoms. Future research is needed to clarify vitamin D effects as monotherapy in ADHD and its mechanism. The trial was registered in www.irct.ir is (IRCT201404222394N10).

Effects of a Single Lyric Analysis Intervention on Withdrawal and Craving With Inpatients on a Detoxification Unit: A Cluster-Randomized Effectiveness Study.

BACKGROUND: For patients hospitalized on inpatient detoxification units, reducing negative symptoms such as withdrawal and craving is a key treatment area. Although lyric analysis is a commonly utilized music therapy intervention for clients in substance abuse rehabilitation, there is a lack of randomized controlled music therapy studies systematically investigating how lyric analysis interventions can affect patients on a detoxification unit. OBJECTIVE: The purpose of this cluster-randomized effectiveness study was to measure the effects of single-session group lyric analysis interventions on withdrawal and craving with patients on a detoxification unit. A secondary purpose of this study was to determine if relationships existed between treatment effects and participants' familiarity with the song. METHODS: Participants (N = 144) were cluster-randomized to experimental (posttest only) or wait-list control (pretest only) conditions to provide treatment to all participants in an inclusive single-session design. RESULTS: Although participants in the experimental condition had lower withdrawal and craving means than participants in the control condition, these differences were not significant. Familiarity of the song in the lyric analysis was not related to withdrawal or craving. CONCLUSION: Group-based lyric analysis interventions may be effective for temporarily relieving withdrawal and craving in patients on a detoxification unit. Familiarity of the song did not affect results. Implications for clinical practice, suggestions for future research, and limitations are provided.

Methyl supplementation attenuates cocaine-seeking behaviors and cocaine-induced c-Fos activation in a DNA methylation-dependent manner.

Epigenetic mechanisms, such as histone modifications, regulate responsiveness to drugs of abuse, such as cocaine, but relatively little is known about the regulation of addictive-like behaviors by DNA methylation. To investigate the influence of DNA methylation on the locomotor-activating effects of cocaine and on drug-seeking behavior, rats receiving methyl supplementation via chronic l-methionine (MET) underwent either a sensitization regimen of intermittent cocaine injections or intravenous self-administration of cocaine, followed by cue-induced and drug-primed reinstatement. MET blocked sensitization to the locomotor-activating effects of cocaine and attenuated drug-primed reinstatement, with no effect on cue-induced reinstatement or sucrose self-administration and reinstatement. Furthermore, upregulation of DNA methyltransferase 3a and 3b and global DNA hypomethylation were observed in the nucleus accumbens core (NAc), but not in the medial prefrontal cortex (mPFC), of cocaine-pretreated rats. Glutamatergic projections from the mPFC to the NAc are critically involved in the regulation of cocaine-primed reinstatement, and activation of both brain regions is seen in human addicts when reexposed to the drug. When compared with vehicle-pretreated rats, the immediate early gene c-Fos (a marker of neuronal activation) was upregulated in the NAc and mPFC of cocaine-pretreated rats after cocaine-primed reinstatement, and chronic MET treatment blocked its induction in both regions. Cocaine-induced c-Fos expression in the NAc was associated with reduced methylation at CpG dinucleotides in the c-Fos gene promoter, effects reversed by MET treatment. Overall, these data suggest that drug-seeking behaviors are, in part, attributable to a DNA methylation-dependent process, likely occurring at specific gene loci (e.g., c-Fos) in the reward pathway.

A variant on the kappa opioid receptor gene (OPRK1) is associated with stress response and related drug craving, limbic brain activation and cocaine relapse risk.

Stress increases drug craving and relapse risk. The kappa opioid receptor gene (OPRK1) mediates stress responses. Here, we examined whether the OPRK1 rs6989250 C>G affects stress-induced cocaine craving and cortisol responses, subsequent cocaine relapse risk and the neural response to stress using functional magnetic resonance imaging (fMRI) in cocaine dependence. Sixty-seven treatment-engaged, abstinent cocaine-dependent African-Americans were genotyped (CG: N=10; CC: N=57) and participated in a 3-day experiment in which they were exposed to personalized script-driven imagery of stress, drug cues and neutral scenarios, one condition per day, randomly assigned and counterbalanced across subjects. Repeated measures of craving and cortisol were obtained. The subjects were followed prospectively for 90 days to assess relapse risk. A follow-up preliminary fMRI experiment assessed neural responses to stress, drug cue and neutral conditions in matched CG (N=5) and CC (N=8) subgroups. We found greater stress-induced craving (P=0.019), higher cortisol during stress and cue relative to the neutral condition (P's<0.003), and increased cocaine relapse risk (P=0.0075) in the CG compared with the CC group. The CG relative to the CC group also showed greater activation of limbic and midbrain regions during stress and cues relative to the neutral condition with additional stress-induced activation in the right amygdala/hippocampus (P<0.05, whole-brain corrected). These results suggest that OPRK1 is associated with stress-induced craving and cortisol, hyperactive hypothalamus/thalamus-midbrain-cerebellum responses, and also associated with greater subsequent cocaine relapse risk. Future studies to replicate these findings in a larger sample size are warranted.

Delayed developmental changes in neonatal vocalizations correlates with variations in ventral medial hypothalamus and central amygdala development in the rodent infant: effects of prenatal cocaine.

While variations in neonatal distress vocalizations have long been shown to reflect the integrity of nervous system development following a wide range of prenatal and perinatal insults, a paucity of research has explored the neurobiological basis of these variations. To address this, virgin Sprague-Dawley rats were bred and divided into three groups: [1] untreated, [2] chronic-cocaine treated (30 mg/kg/day, gestation days (GDs) 1-20); or [3] chronic saline treated (2 mg/kg/day, GDs 1-20). Pregnant dams were injected with Bromodeoxyuridine (10 mg/kg) on GDs 13-15 to label proliferating cells in limbic regions of interest. Ultrasonic vocalizations (USVs) were recorded on postnatal days (PNDs) 1, 14, and 21, from one male and female pup per litter. Variations in acoustic properties of USVs following cocaine-exposure were age and sex-dependent including measures of total number, total duration and amplitude of USVs, and percent of USVs with at least one harmonic. Following USV testing brains were stained with standard fluorescent immunohistochemistry protocols and examined for variations in neuronal development and if variations were associated with acoustic characteristics. Limbic region developmental differences following cocaine-exposure were sex- and age-dependent with variations in the ventral medial hypothalamus and central amygdala correlating with variations in vocalizations on PND 14 and 21. Results suggest maturation of the ventral medial hypothalamus and central amygdala may provide the basis for variations in the sound and production of USVs. As vocalizations may serve as a neurobehavioral marker for nervous system integrity, understanding the neurobiological basis of neonatal vocalizations may provide the basis for early intervention strategies in high-risk infant populations.

Agitated delirium associated with therapeutic doses of sustained-release bupropion.

CASE DESCRIPTION: We report a case of a patient initiated on therapeutic doses of sustained-release bupropion for the management of major depressive disorder who subsequently developed acute agitated delirium that required ICU level care. This patient's history was significant for alcohol and cannabis abuse but he was currently detoxified and beyond the withdrawal period. Throughout the course of treatment, all maintenance medications, including bupropion, were discontinued and the patient required escalating doses of benzodiazepines and typical antipsychotics to resolve symptoms. The patient's delirium subsided after approximately 5 days. CONCLUSION: Dopamine is thought to play a role in the pathophysiology of delirium and given the mechanism of action of this drug and the presence of delirium risk factors in our patient, we are faced with a likely causative factor of this acute delirious episode.

Double-blind, placebo-controlled evaluation of extended-release bupropion in elderly patients with major depressive disorder.

Major depressive disorder in the elderly is associated with increased morbidity and reduced quality of life. This 10 week, placebo-controlled study investigated the efficacy and tolerability of extended-release bupropion (150-300 mg once daily) in depressed patients aged 65 years or older. The statistical assumptions necessary for the validity of the protocol-specified analysis of covariance were not met for the analysis of the primary outcome variable (Montgomery-Asberg Depression Rating Scale total score at Week 10, last observation carried forward). Alternative statistical methods used for the analysis of this variable demonstrated statistical significance. Statistically significant improvements were observed on the majority of secondary end points when compared with placebo, including the health outcome measures for motivation and energy, and life satisfaction and contentment. Adverse events were generally mild to moderate and similar between treatment groups. This study demonstrated that the extended-release bupropion is an effective, well-tolerated treatment for major depression in the elderly.

Are nicotine replacement therapy, varenicline or bupropion options for pregnant mothers to quit smoking? Effects on the respiratory system of the offspring.

Nicotine occurs in tobacco smoke. It is a habit-forming substance and is prescribed by health professionals to assist smokers to quit smoking. It is rapidly absorbed from the lungs of smokers. It crosses the placenta and accumulates in the developing fetus. Nicotine induces formation of oxygen radicals and at the same time also reduces the antioxidant capacity of the lungs. Nicotine and the oxidants cause point mutations in the DNA molecule thereby changing the program that controls lung growth and maintenance of lung structure. The data available indicate that maternal nicotine exposure induces a persistent inhibition of glycolysis and a drastically increased AMP level. These metabolic changes are thought to contribute to the faster aging of the lungs of the offspring of mothers that are exposed to nicotine via the placenta and mother's milk. The lungs of these animals are more susceptible to damage as shown by the gradual deterioration of the lung parenchyma. The rapid metabolic and structural aging of the lungs of the animals exposed to nicotine via the placenta and mother's milk, and thus during phases of lung development characterized by rapid cell division, is likely due to 'programming' induced by nicotine. Since varenicline, a partial nicotine agonist, has basically the same structure as nicotine, and also binds to acetylcholine receptors in competition with nicotine (but with largely the same effect), it is not advisable to use nicotine or varenicline during gestation and lactation. Furthermore, the use of individual vitamin supplements is also not advisable because of the negative impact on the program that controls maintenance of lung structural and functional integrity and aging. A more appropriate smoking cessation program will also include a mixture of antioxidant nutrients such as in tomato juice.

Plasticity of L-type Ca2+ channels after cocaine withdrawal.

Increased reactivity of certain frontal cortical brain regions to cocaine re-exposure or drug-associated cues in cocaine-abstinent human addicts is linked to drug craving. Similarly, in rats tested after withdrawal from repeated cocaine exposure, cocaine or other strong excitatory stimuli produce greater activation of pyramidal neurons in the medial prefrontal cortex (mPFC). Our recent findings indicate that the increased mPFC neuronal activation depends primarily upon enhanced voltage-sensitive Ca(2+) influx, most likely through high-voltage activated (HVA) L-type Ca(2+) channels, but the mechanism underlying the enhanced Ca(2+) currents is unknown. In this study, we used a protein crosslinking assay to show that repeated cocaine injections, resulting in behavioral sensitization, increased total protein levels and cell surface expression of HVA-Ca(v)1.2 L-type channels in pyramidal neurons in deep layers of the mPFC. These changes in Ca(v)1.2 L-channels were time dependent and subtype specific (i.e., differed from those observed for Ca(v)1.3 L-channels). Furthermore, we found enhanced PKA activity in the mPFC of cocaine-sensitized rats that persisted for 21 days after withdrawal. PKA phosphorylation of L-channels increases their activity, so Ca(2+) currents after cocaine withdrawal could be enhanced as a result of both increased activity and number of HVA-Ca(v)1.2 L-channels on the cell surface. By increasing the suprafiring threshold excitability of mPFC pyramidal neurons, excessive upregulation of HVA L-channel activity and number may contribute to the cortical hyper-responsiveness that enhances vulnerability to cocaine craving and relapse. More generally, our results are the first to demonstrate that repeated cocaine exposure alters the membrane trafficking of a voltage-sensitive ion channel.

Daily cocaine self-administration under long-access conditions augments restraint-induced increases in plasma corticosterone and impairs glucocorticoid receptor-mediated negative feedback in rats.

Cocaine addiction appears to be associated with a drug-induced dysregulation of stressor responsiveness that may contribute to further cocaine use. The present study examined alterations in stressor-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis in rats provided daily access to cocaine for self-administration (SA) under long-access conditions (1.0 mg/kg/infusion; 6 hx14 days). Cocaine self-administering rats displayed reduced basal plasma corticosterone (CORT) levels but showed an augmented restraint-induced percent increase response from baseline compared to saline self-administering controls when measured 24 days after SA testing. This augmented CORT response may have been attributable to impaired glucocorticoid receptor (GR)-mediated feedback regulation of HPA function, since cocaine self-administering rats were also less susceptible to dexamethasone (0.01 mg/kg, i.p.) suppression of plasma CORT levels. GR protein expression measured using Western blot analysis was significantly reduced in the dorsomedial hypothalamus (including the paraventricular nucleus [PVN]) but not in the pituitary gland, ventromedial hypothalamus, dorsal hippocampus, ventral subiculum, medial prefrontal cortex or amygdala in cocaine self-administering rats. Surprisingly, basal corticotropin-releasing hormone (CRH) mRNA or post-restraint increases in CRH mRNA measured at a single (90 min) time-point in the PVN using in situ hybridization did not differ between groups. The findings suggest that cocaine use produces persistent changes in individual responsiveness to stressors that may contribute to the addiction process.

Restraint-induced corticosterone secretion and hypothalamic CRH mRNA expression are augmented during acute withdrawal from chronic cocaine administration.

Stress responses during cocaine withdrawal likely contribute to drug relapse and may be intensified as a consequence of prior cocaine use. The present study examined changes in stressor-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis during acute withdrawal from chronic cocaine administration. Adult male Sprague-Dawley rats received daily administration of cocaine (30 mg/kg, i.p.) or saline for 14 days. Twenty-four hours after the last injection, rats in each group were sacrificed under stress-free conditions or following 30 min of immobilization. Plasma corticosterone (CORT) was measured in trunk-blood using radioimmunoassay, corticotropin-releasing hormone (CRH) mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus were measured using in situ hybridization and glucocorticoid receptor (GR) protein expression in the pituitary gland and dissected brain regions was measured using Western blot analysis. Basal CRH mRNA in the PVN was unaltered as a result of prior cocaine administration. However, a significant increase in CRH mRNA was observed 90 min following the termination of restraint in cocaine withdrawn, but not saline-treated, rats. Basal CORT was also unaffected by prior cocaine administration, but the CORT response measured immediately after restraint was significantly augmented in cocaine-withdrawn rats. Differences in GR protein expression in number of regions implicated in negative feedback regulation of HPA function, including the hypothalamus, were not observed. These findings indicate that the HPA response to stressors is intensified during early withdrawal from cocaine administration and may be independent of changes in GR-mediated negative feedback.

Cortical inhibition and excitation in abstinent cocaine-dependent patients: a transcranial magnetic stimulation study.

Prior transcranial magnetic stimulation studies showed that resting motor threshold is elevated in abstinent cocaine-dependent patients, suggesting a decrease in axonal excitability. In contrast, the increased incidence of seizures and psychosis in this group suggests increased excitability or decreased inhibition. Here, we studied long-interval intracortical facilitation and long-interval intracortical inhibition, paired-pulse transcranial magnetic stimulation measures that are more directly linked to glutamatergic cortical facilitation and GABAergic inhibition, respectively. Ten cocaine-dependent and 10 healthy controls were examined. Resting motor threshold, long-interval intracortical facilitation and long-interval intracortical inhibition were tested from the left motor cortex. The cocaine group showed an elevated resting motor threshold and an increased long-interval intracortical facilitation, whereas long-interval intracortical inhibition was normal. Although the increase in long-interval intracortical facilitation suggests exaggerated cortical glutamatergic excitability, the increase in resting motor threshold may signify a protective mechanism against seizures and psychosis.

Context-dependent prefrontal cortex regulation of cocaine self-administration and reinstatement behaviors in rats.

Evidence of stimulus attribute-specificity within the prefrontal cortex (PFC) suggests that different prefrontal subregions may contribute to cocaine addiction in functionally distinct ways. Thus, the present study examined the effects of lidocaine-induced inactivation of two distinct PFC subregions, the prelimbic (PL) or dorsal agranular insular (AId) cortices, on drug-seeking and drug-taking behaviors under cocaine maintenance and reinstatement testing conditions in rats trained to self-administer 1 mg/kg cocaine under a second-order schedule of drug delivery. Throughout maintenance and reinstatement phases, rats were exposed to conditioned light cues and contextual odor or sound cues. Results showed that PL inactivation during maintenance test sessions significantly reduced drug-seeking and drug-taking behaviors, and disrupted patterns of responding in rats exposed to light-sound, but not light-odor, cues. Moreover, lidocaine-induced inactivation of the PL significantly attenuated drug-seeking behavior during cue-induced and cocaine prime-induced reinstatement in rats exposed to light-sound cues only. In contrast, AId inactivation significantly attenuated cue-induced reinstatement of drug-seeking behavior in rats exposed to light-odor cues only. Drug-seeking and drug-taking behaviors in these rats were not disrupted during maintenance and cocaine prime-induced reinstatement testing regardless of the type of contextual cues used. Together, these data suggest that PL and AId subregions play separate yet overlapping roles in regulating cocaine addiction in rats in ways that are dependent on the presence or absence of cocaine and on the types of contextual cues present in the cocaine self-administration environment.

Cocaine alters catalase activity in prefrontal cortex and striatum of mice.

Catalase is one of the enzymes that convert hydrogen peroxide (H2O2) to H2O presenting a protective role against free radicals. In this study, catalase activity was determined in homogenates of striatum (ST) and prefrontal cortex (PFC) in order to examine the participation of oxidative stress (OS) on cocaine actions in mice brain. Male Swiss mice were injected (i.p.) with cocaine at low (10 and 30 mg/kg) and high doses (90 mg/kg), and observed for 1 h. After cocaine overdose (90 mg/kg) some animals presented only status epilepticus (SE) while others died after seizures. These animals were dissected and divided in two groups, SE and death. Catalase activity was also determined after pretreatment with the anticonvulsant drug, diazepam, alone or injected before cocaine 90 mg/kg, and after seizures induced by a high dose of bupropion, a known inhibitor of NE and DA reuptake used for comparison. Results showed a decrease in catalase activity of the PFC and ST after SE and death induced by cocaine and bupropion overdoses. Cocaine at low doses decreased the enzyme activity only in ST. Diazepam treatment alone and before cocaine overdose did not interfere with catalase activity. This reduction in catalase activity may reflect an increase in H2O2 content in PFC and ST. Previous data reports that H2O2 inhibits dopamine transporter activity, suggesting that the decrease in catalase activity may potentiate the toxic mechanism of drugs that inhibit monoamines reuptake. As far as we know, this is the first report showing an involvement of OS in the cocaine's central mechanism of action.

Initial uptake and evidence of safe prescribing practice with Buproprion (Zyban).

PURPOSE: To study the effect of safety concerns and the introduction of freely available nicotine replacement therapy (NRT) on the prescribing of Buproprion within the General Medical Services (GMS) scheme in Ireland. METHODS: Using the state-supported GMS prescription database in Ireland, we identified 8166 patients who were prescribed Buproprion and 18,450 patients who were prescribed NRT over a 12-month-period. RESULTS: A decline in the prescribing of Buproprion was noted which coincided with concerns regarding the safety of the drug but which preceded the introduction of NRT to the GMS. Furthermore, patients who were prescribed Buproprion were less likely to be co-prescribed potentially interacting drugs (odds ratio (OR): 0.48, 95% confidence intervals (CI): 0.42, 0.54) or drugs known to reduce seizure threshold (OR: 0.63, 95% CI: 0.6, 0.67) indicating good prescribing practice. Patients aged 65 years or more were less likely to be prescribed any form of smoking cessation therapy compared with those aged <65 years (OR: 0.23, 95% CI: 0.22-0.24) indicating that such therapy was targeted at those most likely to benefit. CONCLUSIONS: We provide evidence that prescribers exercised caution in the prescription of Buproprion and were likely to have been influenced both by the safety concerns and the introduction of freely available NRT to the GMS population.

St John's wort for depression: what's the evidence?

There is a moderate amount of evidence to suggest that St John's wort is better than placebo in the short-term management of mild to moderate depressive illness, but there is increasing concern over reports of drug interactions. This article examines the scientific evidence and discusses relevant clinical issues.

Acute withdrawal from repeated cocaine treatment enhances latent inhibition of a conditioned fear response.

Psychostimulant-induced locomotor sensitization and disrupted latent inhibition (LI) of a classically conditioned association are two paradigms that have been widely studied as animal behavioural models of psychosis. In this study we assessed the effects of withdrawal from the repeated intermittent administration of cocaine on LI of a conditioned fear response. Animals which were either preexposed (PE) to a tone conditioned stimulus (CS) or naive to the tone (i.e. non-preexposed: NPE) subsequently experienced 10 pairings of the tone CS with footshock. Afterwards, both groups received five daily injections of cocaine (20 mg/kg, i.p.) or saline. After 3 days of withdrawal from drug treatment, animals were tested for conditioned freezing to the context of the footshock chamber, and 1 day later, for conditioned freezing to the tone CS. Cocaine-sensitized animals exhibited markedly enhanced LI compared to saline-treated animals, due to the fact that NPE-cocaine animals spent more time freezing during the tone CS than NPE-saline animals, whereas PE-cocaine animals showed a tendency toward reduced freezing compared to the saline groups. While these results suggest the presence of increased anxiety in cocaine-withdrawn NPE animals, the absence of this effect in cocaine-withdrawn PE rats indicates that cocaine withdrawal also influences the retrieval of previously learned information.

Neurochemical adaptation to cocaine abuse: reduction of N-acetyl aspartate in thalamus of human cocaine abusers.

BACKGROUND: The aim of this study was to determine the existence of, and possible mechanisms for, chronic cocaine use-induced neurotoxicity in the human brain. Because in vivo magnetic resonance spectroscopy (MRS) provides a noninvasive way to detect biochemical and physiological changes in the brain, we sought to specifically determine the neurochemical adaptations in chronic cocaine-dependent subjects. METHODS: Twenty-one cocaine users and 13 non-drug-using, age-matched normal volunteers were recruited for an in vivo proton MRS study. Following screening that included physical examination, histories, and blood testing, cocaine group subjects received a spectral scan on a 1.5-T GE Signa scanner. Spectra were obtained from the left basal ganglia and/or the left thalamus from subjects in both groups using an rf bird-cage type head coil with single-voxel localization. RESULTS: The level of N-acetyl aspartate in the region of left thalamus was lower (17%) in the chronic cocaine user group but not in the region of left basal ganglia, compared with the control group. CONCLUSIONS: These results suggest that chronic cocaine use may induce abnormal neurochemical activity and a state of neuronal dysregulation and/or neurotoxicity. It will now be important to determine if these alterations are reversible during withdrawal and what the functional implications of this observation are with respect to cognitive function and drug relapse.