The subjective effects of MDMA and mCPP in moderate MDMA users.

The present study is part of a research program designed to better understand the neurochemical mechanisms underlying the abuse liability of 3,4-methylenedioxymethamphetamine (MDMA) in humans. In these studies, MDMA will be compared to prototypical dopamine (D-amphetamine) and serotonin (meta-chlorophenylpiperazine, mCPP) releasing agents on a variety of measures related to dependence. In order to determine an acceptable dose range (safe but active) of MDMA and mCPP for these studies, moderate MDMA users were administered escalating doses of MDMA (75, 110 and 145 mg/70 kg) and mCPP (17.5, 35 and 52.5 mg/70 kg). Each participant received a single dose under controlled laboratory conditions, i.e. this was a six-group design with a separate group for each dose. There were five participants tested in each group. MDMA increased blood pressure and heart rate whereas mCPP had no effect on these physiological measures. MDMA produced increases in subjective effects indicative of both stimulant (increases in POMS Elation, ARCI Amphetamine, VAS High and Stimulated scale scores) and hallucinogenic effects (increases on five of the six scales of the Hallucinogenic Rating Scale). mCPP produced similar stimulant effects (e.g. increases on POMS Elation, VAS High and Stimulated), as well as hallucinogenic effects (four of the six scales of the Hallucinogenic Rating Scale), which has not been observed in previous studies.     

Social, circadian, nutritional, and subjective correlates of the spontaneous pattern of moderate alcohol intake of normal humans

The relationship of moderate alcohol intake to the subjective states of hunger, thirst, depression, and anxiety, to social facilitation, circadian rhythms, and the ingestion of other nutrients by humans spontaneously behaving in their natural environment was investigated. Ninety-six adults were paid to maintain 7-day diaries of everything they ingested, when and where they ingested it, the number of other people present, and their subjective states at the beginning and end of the meal. The data from the 64 subjects who reported alcohol intake were analyzed individually with univariate and multivariate regression techniques. Subjective states were not found to be associated with subsequent alcohol ingestion, but alcohol was found to be associated with a reduction in subsequent thirst and anxiety. The amount of alcohol ingested was found to be positively related to the amount of nonalcohol calories ingested, particularly carbohydrates, the hour of the day, and the number of other people present. These results suggest that moderate alcohol intake by normal humans in their natural environment is affected by a variety of influences, but is primarily related to the time of day and socio-cultural factors.     

Marital status, alcohol dependence, and GABRA2: evidence for gene-environment correlation and interaction

OBJECTIVE: The gene GABRA2 has been associated with the risk for alcohol dependence in independent samples. This article explores how this genetic risk factor interacts with marital status, another factor previously shown to be associated with the risk for alcohol dependence. METHOD: Data from more than 1,900 male and female subjects from the Collaborative Study of the Genetics of Alcoholism (COGA) sample were analyzed. Subjects were recruited based on membership in a family with multiple individuals with alcoholism. A series of analyses was performed to evaluate the relationship between the following: (1) GABRA2 and alcohol dependence, (2) marital status and alcohol dependence, (3) GABRA2 and marital status, and (4) interactions between GABRA2 and marital status on the development of alcohol dependence in the high-risk COGA sample. Additional analyses were carried out in a sample of approximately 900 individuals from control families to test the generalizability of results. RESULTS: Both GABRA2 and marital status contributed independently to the development of alcohol dependence in the COGA sample. The high-risk genotype at GABRA2 was also related to a decreased likelihood of marrying and an increased likelihood of divorce, which appeared to be mediated in part by personality characteristics. There was also differential risk associated with the GABRA2 genotype according to marital status. CONCLUSIONS: These analyses provide evidence of both gene-environment correlation and gene-environment interaction associated with GABRA2, marital status, and alcohol dependence. They illustrate the complex pathways by which genotype and environmental risk factors act and interact to influence alcohol dependence and challenge traditional conceptualizations of environmental risk factors.     

Markers in the 5'-region of GABRG1 associate to alcohol dependence and are in linkage disequilibrium with markers in the adjacent GABRA2 gene.

Following an initial report, there have been multiple replications of an association of alcohol dependence (AD) to markers within a haplotype block that includes the 3'-half of the gene encoding the GABA(A) alpha-2 subunit (GABRA2), on chromosome 4p. We examined the intergenic extent of this haplotype block and the association to AD of markers in the adjacent 5' haplotype block in GABRG1, which encodes the GABA(A) receptor gamma-1 subunit. We genotyped 15 single nucleotide polymorphisms in the GABRG1-GABRA2 interval as well as at 34 ancestry informative markers in three samples: 435 AD and 635 screened control subjects from Connecticut and 812 participants from a multicenter AD treatment trial. We observed two large haplotype blocks in the GABRG1-GABRA2 intergenic interval with a region of increased recombination midway between the two genes. Markers in the two haplotype blocks were in moderate linkage disequilibrium. Compared with markers in the GABRA2 haplotype block, markers in the 5' GABRG1 haplotype showed greater allelic, genotypic and haplotypic association with AD in European Americans from both AD samples. Logistic regression analysis indicated that genetic elements in the GABRG1 haplotype block likely contribute to AD risk in an additive manner, whereas those in the GABRA2 haplotype block may act in a dominant manner in relation to risk of AD.     

The vasorelaxant effects of milrinone and other vasodilators are attenuated by ouabain

The purpose of this study was to investigate the effect of ouabain pretreatment (1 microM) on relaxation induced by milrinone and other reference vasorelaxants in guinea pig aorta. Pretreatment with ouabain for 1 h significantly reduced the threshold concentration and increased the vasoconstrictor potency of phenylephrine. Relaxation by milrinone of aortic rings contracted by phenylephrine or by an equieffective concentration of phenylephrine in the presence of ouabain was significantly attenuated in the presence of ouabain. The effect of all other vasorelaxants tested, which included isosorbide dinitrate, hydralazine, sodium nitroprusside, forskolin, HA 1004, isoproterenol and verapamil, were also significantly reduced in the presence of ouabain. The vasorelaxant effects of milrinone and verapamil were also evaluated in K+-contracted guinea pig aorta. In contrast to results obtained with phenylephrine-contracted vessels, milrinone and verapamil were equipotent as vasorelaxants in K+-contracted vessels in the presence or absence of ouabain. The results show that ouabain not only potentiates the effect of the vasoconstrictor phenylephrine, but also reduces the potency of drugs that cause vasorelaxation in phenylephrine-contracted tissues, regardless of the mechanism of action of the vasorelaxant. These data may have clinical relevance to the concomitant use of vasodilators and digitalis in the treatment of congestive heart failure.     

The renal effects of atrial natriuretic peptide in man are not attenuated by (+)-sulpiride.

1. Human alpha atrial natriuretic peptide (ANP) was infused intravenously for 1 h in eight healthy salt-replete men on two occasions, with and without pretreatment with (+)-sulpiride. 2. ANP increased sodium excretion and urine flow rate but did not alter blood pressure or plasma renin activity. 3. (+)-sulpiride had no significant effect on baseline creatinine clearance, sodium excretion or urine flow rate and did not alter the increases in these parameters with ANP. 4. It is unlikely that the renal effects of ANP are mediated by dopamine DA1-receptors in man.     

Acute psychological effects of 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy") are attenuated by the serotonin uptake inhibitor citalopram.

3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy") is a recreational drug that has been shown to release serotonin (5-HT) and dopamine (DA) in animals. The effect of MDMA on 5-HT release can be blocked by 5-HT uptake inhibitors such as citalopram, suggesting that MDMA interacts with the 5-HT uptake site. It is unknown whether this mechanism is also responsible for the psychological effects of MDMA in humans. We investigated the effect of citalopram pretreatment (40 mg iv) on the psychological effects of MDMA (1.5 mg/kg po) in a double-blind placebo-controlled psychometric study in 16 healthy human volunteers. MDMA produced an emotional state with heightened mood, increased self-confidence and extroversion, moderate derealization, and an intensification of sensory perception. Most of these effects were markedly reduced by citalopram. This finding suggests that the psychological effects of MDMA are mediated via action at the 5-HT uptake site to increase 5-HT release through the carrier, as expected from animal studies.     

The cardiovascular effects of thyrotropin-releasing hormone (TRH) are attenuated by cimetidine in rats.

The modulation of cardioventilator effects of thyrotropin-releasing hormone (TRH) by histaminergic mechanisms was studied in anaesthetized rats pretreated with histamine receptor antagonists. TRH (1-100 nmol/kg) into the lateral cerebral ventricle dose-dependently elevated mean arterial pressure, heart rate and stimulated respiration. The respiratory stimulating effect of TRH remained unchanged after pretreatments with histamine H1-receptor antagonist diphenhydramine or H2-receptor antagonists cimetidine and ranitidine, while the TRH-induced hypertension and tachycardia were attenuated by cimetidine. This antagonism was not due to an interaction between TRH and cimetidine at their central binding sites, since there was no displacement of [3H]MeTRH binding in the presence of cimetidine nor did TRH displace [3H]cimetidine in rat brain homogenates. Inability of diphenhydramine to modify the cardiovascular effects of TRH indicates that these effects are not due to histamine liberation, as cardiovascular stimulation after central administration of histamine is mainly mediated via H1-receptors. The antagonism of the cardiovascular responses to TRH by cimetidine was not due to blockade of H2-receptors, since another potent H2-receptor antagonist ranitidine was unable to affect the cardiovascular effects of TRH. Therefore, we suggest that cimetidine exerted antagonism of TRH by some non-specific action.     

The Addiction Research Center Inventory: Standardization of scales which evaluate subjective effects of morphine,amphetamine, pentobarbital,alcohol, LSD-25, pyrahexyl and chlorpromazine

Summary The ARCI, a 550-item inventory for assessing subjective drug effects and personality characteristics, was standardized using former addict subjects on a number of drug conditions. The inventory was administered under “no-drug” and placebo, and various doses of morphine, pentobarbital, chlorpromazine, LSD-25, amphetamine, pyrahexyl, and alcohol. By means of item analysis, cross-validity and other initial comparisons, items were chosen to comprise each drug scale that discriminated the particular drug from placebo; the (no-drug)-placebo comparison also produced a tentative placebo scale. Since non-significant differences were found when scoring each of the drug scales separately on the nodrug and placebo conditions, these data were combined for standardizing all scales. Validity generalization, dose-effect, and retest studies showed that the drug scales possessed a high degree of validity and reliability. In contrast, the placebo scale lost discrimination entirely in the validity generalization group. Because of the very considerable number of item comprising the scales, only examples were presented. Subjective effects of the various drugs were discussed in terms of specific and general, non-specific actions and patterns of these alterations.     

The influence of alcohol pre-treatment on the discriminative stimulus, subjective, and relative reinforcing effects of nicotine

Alcohol intake may acutely alter the discriminative stimulus and subjective effects of nicotine, perhaps explaining why alcohol increases tobacco smoking. In this study, cigarette smokers were initially trained to discriminate 20 microg/kg nicotine by nasal spray from placebo. Three sessions then followed, in which the generalization of nicotine discrimination was tested across a range of doses (0--20 microg/kg) following pre-treatment with 0, 0.4, and 0.8 g/kg alcohol p.o. Intermittent 'topping' doses of alcohol maintained a steady breath alcohol level (BAL) throughout testing. Generalization testing involved both two- and three-choice ('novel' option) procedures. A visual discrimination task was also conducted to determine the specificity of effects of alcohol. Subjective and cardiovascular measures were obtained concurrent with discrimination responding. The relative reinforcing effects of nicotine were assessed after the end of generalization testing using a choice procedure. Alcohol pre-treatment had no significant effects on nicotine discrimination or self-administration behavior. Alcohol and nicotine each influenced selected subjective responses and heart rate, but virtually no interactions between the drugs were observed. Within the limitations of this study, these results do not support the notion that alcohol acutely alters nicotine's discriminative stimulus, subjective, or relative reinforcing effects at these low nicotine doses. Acute effects of alcohol on smoking behavior may be due to alterations in other effects of nicotine intake or in non-nicotine effects of tobacco smoking.     

Disruption of sensory gating by moderate alcohol doses

Rationale

Evidence from a growing body of literature suggests that alcohol, even at moderate-dose levels, disrupts the ability to ignore distractors. However, little work has been done to elucidate the neural processes underlying this deficit.

Objective

The present study was conducted to determine if low-to-moderate alcohol doses affect sensory gating, an electrophysiological phenomenon believed to reflect the pre-attentive filtering of irrelevant sensory information.

Methods

Sixty social drinkers were administered one of three doses intended to produce breath alcohol concentrations of 0.0 % (placebo), 0.04 % (i.e., low dose), and 0.065 % (i.e., moderate dose). A paired-click paradigm consisting of 100 pairs of identical tones (S1 and S2) was used to assess sensory gating. Amplitudes of P50, N100, and P200 auditory evoked potentials (AEPs) were used to calculate gating difference (S1–S2) and ratio (S2/S1) scores.

Results

The moderate alcohol dose significantly decreased P50 and N100 gating relative to placebo. Comparisons between the difference and ratio scores helped characterize the gating mechanisms affected at these stages of information processing. Alcohol did not alter P200 sensory gating.

Conclusions

These data suggest that alcohol disrupts pre-attentional sensory-filtering processes at breath alcohol concentrations (BrACs) below the current 0.08 % legal limit. Future studies should perform a combined assessment of sensory gating and selective attention to better understand the relationship between these two alcohol-induced deficits.     

Choice of nitrous oxide and its subjective effects in light and moderate drinkers

BACKGROUND: Alcohol-drinking status has been shown to modulate the reinforcing and subjective effects of a number of drugs. We have previously published two studies on the modulating effects of alcohol-drinking status on choice for, and subjective effects of, nitrous oxide, but the results were equivocal. Using a methodology different from our previous studies, we sought to determine in a more definitive fashion the degree to which the choice of nitrous oxide and its subjective effects were modulated by drinking status. METHODS: Four concentrations of nitrous oxide (0, 20, 30, and 40%) were administered to 16 moderate drinkers (MDs) and 16 light drinkers (LDs) across four 3.5-h sessions. During experimental sessions, subjects first completed two 10-min sampling trials in which one of the nitrous oxide concentrations and placebo (100% oxygen) were inhaled. Subjective and psychomotor tests were given 5min into each sampling trial. During the subsequent choice period, subjects were allowed to choose what they wanted to inhale (drug, placebo, or "drug-free air") on nine contiguous 5-min choice trials. RESULTS: Choice of nitrous oxide was modulated by drinking status: MDs but not LDs chose nitrous oxide significantly more times than placebo, and MDs also chose nitrous oxide significantly more times than did LDs. At each active nitrous oxide concentration, MDs reported more abuse liability-related subjective effects, especially at the 20% and 30% concentrations. CONCLUSIONS: The results of the present study provide more conclusive evidence that choice as well as subjective effects of nitrous oxide is modulated by alcohol-drinking status.     

Hyperventilation, anxiety sensitivity, and the expectations for alcohol use: subjective and physiological reactivity to alcohol cues.

The present study examined the relation between alcohol-related expectancies, body sensation fear and reactions to cues for alcohol following a hyperventilation task. Forty-two undergraduate students participated for course credit. Each student hyperventilated for 5 min, paced at a rate of 30 breaths per minute. Following hyperventilation, each student was exposed to containers with alcohol (beer and wine coolers), with subjective urge to consume and heart rate measures taken. Path analysis supported models associated with tension reduction and self-focused attention expectancies as significant contributors to increased urge to consume alcohol and lowered heart rate following hyperventilation. However, social-anxiety-related expectancies failed to demonstrate a relationship. These results suggest that additional work on the tension reduction model of alcohol use should examine physiological stressors in association with subject characteristics such as proneness to experience panic symptoms.     

The effects of alcohol and alcohol expectancies on subjective reports and physiological reactivity: a meta-analysis

The balanced placebo design (BPD) has been used to understand the etiology and maintenance of alcohol consumption. The utility of this design lies in its ability to examine both actual alcohol consumption and the expectation of alcohol consumption. A meta-analysis of the BPD literature was conducted in the context of cue-reactivity, which may be characterized as an experimental phenomenon observed in studies utilizing alcohol. Sixty-four studies were obtained in literature searches and coded for type of experimental setting and cues present during the actual beverage consumption. Lab setting was a moderator for both pharmacological (alcohol) and expectancy effects with the largest effects (in the same direction) noted in natural environment labs (i.e., an easy chair and casual environment). Contrary to predictions, the bar lab produced the smallest effects. Cues present during alcohol consumption served as a moderator of pharmacological effect, with the largest effect observed when alcohol was placed on the rim of the glass. Implications of these findings for cue-reactivity studies and the treatment of alcohol abuse are discussed.     

Acute effects of memantine in combination with alcohol in moderate drinkers

Rationale Alcohol effects in humans involve N-methyl-d-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission. It has been proposed that NMDA receptor antagonists may be effective in the treatment of alcohol dependence.Objective This study evaluated the acute effects of memantine, an NMDA receptor antagonist, on the subjective, physiological, and performance effects of alcohol in moderate (10–30 drinks per week) alcohol drinkers.Methods Eighteen volunteers without alcohol dependence were tested using a double-blind design with three 3-day long inpatient phases separated by at least a 2-week wash-out period. Memantine (0, 15, and 30 mg) was administered 4 h before alcohol (1.5 g/l body water), which was given in four divided doses every 20 min.Results Pretreatment with memantine attenuated the craving for alcohol before alcohol administration, but not after alcohol was given. Memantine increased the dissociative effects of alcohol, without altering its sedative, stimulant, and overall intoxicating effects. Memantine also did not affect alcohol-induced impairment in performance, physiological changes, or pharmacokinetics. Memantine increased subjective reports of dissociation, confusion, and stimulation, and impaired motor coordination on the balance task.Conclusions Memantine was well tolerated in combination with alcohol. The findings suggest that NMDA receptor neurotransmission may be involved in alcohol craving and alcohol-induced subjective dissociative effects.     

Choice of sevoflurane and its subjective and psychomotor effects in light and moderate drinkers

BACKGROUND: Sevoflurane, an inhalant of the volatile anesthetic class, has neurobiological and behavioral effects in common with abused inhalants and ethanol. We sought to determine if choice for subanesthetic doses of sevoflurane, and its subjective and psychomotor effects, would differ as a function of alcohol-drinking status in healthy volunteers. METHODS: The effects of four concentrations of sevoflurane (0, 0.2, 0.4, 0.8% sevoflurane in oxygen) were studied in 16 light drinkers and 16 moderate drinkers. During each of four sessions, subjects sampled a concentration of sevoflurane and 100% O(2) (placebo) for 10 min each. Subjective and psychomotor testing commenced 5 min into each sampling trial. Later, within the session, subjects chose nine times, once every 5 min, among sevoflurane (e.g., "Agent A"), placebo (e.g., "Agent B," 100% O(2)), or neither (and were administered 100% O(2), identified as "drug-free air"). RESULTS: Choice for sevoflurane at the 0.4% concentration was significantly higher in the moderate drinkers than in the light drinkers. A number of subjective effects reported during inhalation of sevoflurane were markedly lower in the moderate-drinking group than in the light-drinking group. However, psychomotor impairment induced by sevoflurane was similar in magnitude in both groups. CONCLUSIONS: Alcohol-drinking status affected sevoflurane choice. The results are consistent with several studies comparing light and heavier drinkers, using other drugs. Although both drinking groups were similarly impaired by sevoflurane, the moderate drinkers reported less of a subjective response than light drinkers, suggestive of cross-tolerance.     

Associations of anxiety sensitivity and emotional symptoms with the subjective effects of alcohol,cigarettes, and cannabis in adolescents

Maladaptive emotional traits (anxiety sensitivity [AS], fear of anxiety-related sensations and consequences) and symptoms (major depressive disorder [MDD] and generalized anxiety disorder [GAD] symptoms) could play a role in altering sensitivity to the subjective effects of drugs of abuse in adolescents. Data were drawn from a longitudinal study of high school students in Los Angeles, CA, USA who completed surveys and reported past six-month use of alcohol (n = 1054), cigarettes (n = 297), or cannabis (n = 706). At each of the four semi-annual waves during mid-adolescence (14–16 years old), students reported positive and negative subjective drug effects experienced in the prior six-months. Controlling for covariates and the simultaneous covariance across the three domains of emotional dysfunction, AS was associated with more positive and negative cannabis effects (βs = 0.09–0.16, ps < 0.05), and MDD symptoms were associated with fewer negative cigarette effects (β = − 0.13, p = 0.04) and more negative cannabis effects (β = 0.10, p = 0.004). The acceleration of positive alcohol and cannabis effects over time was slower among adolescents with higher baseline MDD (MDD × time: β = − 0.04, p = 0.044) and GAD (GAD × time: β = − 0.05, p = 0.03) symptoms, respectively. These findings suggest that emotional dysfunction factors show differential and overlapping effects on subjective drug effects, which may vary across time. Future research should investigate emotional dysfunctions and subjective drug effects in relation to substance use across adolescence and emerging adulthood.     

Hemodynamic effects of a single moderate dose of alcohol in elderly subjects

The effects of 0.5 g ethanol/kg body weight and of an iso-volumic control drink were compared in eight normotensive subjects aged 70-96 years. Blood alcohol concentration reached a mean (+/- SEM) maximum of 44.4 +/- 5.0 mg/dl at 50 minutes after the start of drinking. Compared to control, alcohol increased mean sitting and standing heart rates by 3.4 +/- 1.3 (p = .08) and 5.4 +/- 1.9 (p less than .05) beats/minute, respectively; mean venous haematocrit rose by 3.9 +/- 1.3% (p less than .05). There were no significant changes in sitting or standing systolic or diastolic blood pressures after alcohol compared to the control drink. A single moderate dose of alcohol has only minor haemodynamic effects in normotensive elderly subjects. The rise in heart rate after alcohol may be a reflex response that helps to maintain blood pressure in the face of reduced circulating plasma volume due to alcohol-induced diuresis.     

Gender and alcohol moderate prenatal cocaine effects on teacher-report of child behavior

Prenatal cocaine exposure has been associated with behavior problems at school age. However, the correspondence between use of cocaine and alcohol during pregnancy is often high, making appropriate allocation of variance and control for other exposures and their interactions difficult. Additionally, gender-specific effects are not typically reported. The purpose of the current study was to determine the degree to which gender-specific effects of prenatal cocaine exposure on teacher-reported child externalizing behavior problems were evident when evaluated in relation to prenatal alcohol exposure. Subjects were singleton infants of mothers who were prospectively evaluated during pregnancy. At age seven, 499 children (214 exposed prenatally to cocaine) were evaluated in our laboratory and teacher reports were solicited. Analyses stratified by gender and prenatal alcohol exposure status, and controlled for significant pre- and postnatal confounders, revealed that among boys with prenatal alcohol exposure, those with persistent cocaine exposure throughout pregnancy had significantly higher levels of Delinquent Behavior compared to boys with no cocaine exposure. Boys with any prenatal cocaine exposure were twice as likely as unexposed boys to have clinically significant Externalizing Behavior scores. However, no association was found between prenatal cocaine exposure and scores on Externalizing Behavior and specific syndromes for boys with no prenatal alcohol exposure. Among girls with no prenatal alcohol exposure, those with persistent cocaine exposure had significantly higher levels of Externalizing Behaviors and Aggressive Behaviors compared to girls with no prenatal cocaine exposure after control for confounding, and were almost five times as likely to have clinically significant Externalizing Behavior scores. However, for girls with prenatal alcohol exposure, no association between prenatal cocaine exposure and scores on Externalizing Behavior and specific syndromes was found after control for confounding. The current findings support gender- and alcohol-moderated effects of prenatal cocaine exposure on school-age teacher-reported child behavior problems. These findings are similar to what we have reported for independent parent-reported behavioral evaluation.     

A human laboratory study of the effects of quetiapine on subjective intoxication and alcohol craving

Rationale  

The available treatments for alcoholism are only modestly effective, and patients vary widely in their treatment response. Quetiapine, an atypical antipsychotic medication with antagonist activity at D1 and D2, 5-HT_1A and 5-HT_2A, H₁, and α1 and α2 receptors was shown to promote abstinence, reduce drinking days, and reduce heavy drinking days in a 12-week double-blind placebo-controlled trial.