The subjective,behavioral and cognitive effects of subanesthetic concentrations of isoflurane and nitrous oxide in healthy volunteers

A prospective, crossover, double-blind trial was conducted in nine healthy volunteers in which the subjective, psychomotor and memory effects of isoflurane (0.0, 0.3 and 0.6%) and nitrous oxide (N₂O) (0, 20 and 40%) were examined. Dependent measures included visual analog scales and a standardized drug effects inventory (subjective effects), reaction time and eye-hand coordination (e.g., psychomotor performance), and immediate and delayed free recall (memory). There were some similarities in subjective effects between the two inhaled drugs (e.g., increased ratings of drunk and spaced out), but isoflurane had effects which N₂O did not have. Isoflurane but not N₂O increased visual analog scale ratings of confused, sedated, and carefree, and decreased ratings of in control of thoughts and in control of body. An odor was detected with isoflurane and it was disliked. Psychomotor performance was more grossly impaired during isoflurane inhalation than during N₂O inhalation. Psychomotor recovery from both agents was rapid and complete so that 5 min after the inhalation period had ceased, performance had returned to baseline levels. Both isoflurane and nitrous oxide impaired immediate and delayed free recall. The feasibility of using isoflurane in conscious sedation procedures is discussed.     

Characterizing the subjective and psychomotor effects of carisoprodol in healthy volunteers

Carisoprodol is a centrally acting drug used to relieve skeletal muscle spasms and associated pain in acute musculoskeletal conditions. There is evidence from different sources that this oral muscle relaxant is abused and that it is associated with impairment leading to arrests for “driving under the influence” as well as increased risk of automobile accidents. Its subjective and psychomotor effects in healthy volunteers at therapeutic and supratherapeutic doses have not been well-characterized, and form the basis of this report. Fifteen healthy volunteers (8 males, 7 females) were administered 0, 350, and 700 mg of carisoprodol in separate sessions and for 6 h afterwards they completed a battery of tests at fixed time intervals so as to assess the subjective and psychomotor effects of the drug. The supratherapeutic dose, 700 mg, increased visual analog scale ratings of terms that were more reflective of sedation (e.g., “sleepy,” “heavy, sluggish feeling”) than those of abuse liability, and produced impaired performance on several psychomotor tests. The therapeutic dose, 350 mg, while producing few and mild subjective effects, still produced psychomotor impairment. The fact that the therapeutic dose of carisoprodol produced minimal subjective effects while adversely affecting performance is of concern in that patients prescribed this drug may feel relatively normal and engage in tasks (driving) that could put themselves and others at risk.     

Sex differences in the subjective and reinforcing effects of cigarette nicotine dose

RATIONALE: Some research with novel nicotine delivery methods suggests that nicotine itself may be less reinforcing in women than in men. However, sex differences in the reinforcing effects of nicotine dose via cigarette smoking have received little attention. OBJECTIVES: Sex differences in the subjective and reinforcing effects of smoking were examined as a function of two cigarette nicotine "dose" levels (moderate - subjects' preferred brand, > or = 0.7 mg yield; low - Carlton "ultra-light", 0.1 mg yield). METHODS: Male and female smokers ( n = 30) participated in three sessions, the first two involving independent assessment (only one brand available), and the third involving concurrent assessment (both brands available), of subjective ratings (e.g. "liking") and reinforcement for the two cigarette brands. Subjects were blind to the brand of each cigarette, and subjects abstained overnight prior to each session. Reinforcement was determined by responses on a computer task to earn single puffs on the designated cigarette. RESULTS: Subjective ratings differed between the low versus moderate cigarette nicotine dose under both independent and concurrent assessment conditions, as expected. Notably, this dose difference was smaller in women than in men (i.e. significant sex by dose interactions). The dose effect on smoke reinforcement also was smaller in women than men, but only under the independent and not concurrent assessment condition. CONCLUSIONS: These results indicate that cigarette nicotine dose is a less important influence on the subjective and, under some conditions, reinforcing effects of smoking in women than in men.     

Sex differences in plasma cocaine levels and subjective effects after acute cocaine administration in human volunteers

Gender differences after acute cocaine administration have received little attention in spite of the fact that males and females respond differently to many drugs. Seven male and seven female occasional cocaine users received both an intranasal dose of cocaine hydrochloride (0.9 mg/kg) and placebo powder in a randomized order and reported subjective effects via an instrumental joystick device and various questionnaires. Blood samples were withdrawn at 5-min intervals to assess pharmacokinetic differences. Male subjects achieved the highest peak plasma cocaine levels (144.4 ± 17.5 ng/ml), detected cocaine effects significantly faster than females and also experienced a greater number of episodes of intense good and bad effects. Women studied during the follicular phase of their menstrual cycle had peak plasma cocaine levels of 73.2 ± 9.9 ng/ml, which was significantly higher than when they were studied during their luteal phase (54.7 ± 8.7 ng/ml), but there were no differences in their subjective reports of cocaine effects. In spite of the different cocaine blood levels and subjective effects, peak heart rate increases did not differ between males and females suggesting that women may be more sensitive than males to the cardiovascular effects of cocaine. These data suggest that there are significant gender and menstrual cycle differences in the response to acute intranasal cocaine administration and these differences may have implications for the differential abuse of this drug.This paper is dedicated to Xavier Lamas, MD, PhD, who lost his life while ascending Mt. Everest, August 1995     

Subjective, psychomotor, and physiological effects of pregabalin alone and in combination with oxycodone in healthy volunteers

Pregabalin is an anticonvulsant drug indicated for neuropathic disorders and fibromyalgia. Some chronic pain patients suffering from these disorders take both this drug and an opioid for pain relief. Pregabalin is a scheduled drug under the Controlled Substances Act. The subjective effects of this drug have not been well-characterized, and the extent to which it alters the subjective effects of opioids has not been studied to the best of our knowledge. Using a double-blind, randomized, crossover design, 16 healthy volunteers were administered (in separate sessions) capsules containing placebo, 75 mg pregabalin, 150 mg pregabalin, 10 mg oxycodone, and 75 mg pregabalin combined with 10 mg oxycodone. Subjective, psychomotor, and physiological measures were assessed during each of the five sessions. Pregabalin produced dose-related increases in some subjective effects and decreased respiration rate, but did not impact on psychomotor performance. Abuse liability-related subjective effects such as drug liking and desire to take the drug again were not increased by either pregabalin dose. Oxycodone produced increases in several subjective effects, including ratings of drug liking. When 75 mg pregabalin was combined with oxycodone some subjective effects were altered relative to placebo, in contrast to when each drug was tested alone. Liking of oxycodone was not increased by 75 mg pregabalin. However, recent studies have suggested that this drug is abused, and we would recommend that further psychopharmacological studies with pregabalin are warranted, including a study assessing its abuse liability across a range of doses in sedative abusers.     

性别因素对替利定及其代谢物去甲替利定在中国健康志愿者中药代动力学的影响(英文)

比较替利定和它的代谢物去甲替利定在不同性别中国健康志愿者中的药代动力学特征。9例（4例男性,5例女性）健康志愿者单次口服50 mg盐酸替利定口服液,在规定时间内采血,采用GC-NPD测定血药浓度,用非房室模型计算药代动力学参数。替利定和代谢物去甲替利定的主要动力学参数分别为:C_max（63.39±28.99）和（122.53±23.23）ng/mL;T_max（0.37±0.07）和（0.64±0.30）h;t_1/2（2.83±1.35）和（5.72±1.37）h;AUC_0-∞（101.59±41.85）和（577.13±189.77）ng·h/mL。替利定的男性和女性药动学参数分别为:C_max（73.88±40.88）和（55.01±15.16）ng/mL,T_max（0.37±0.08）和（0.36±0.08）h,t_1/2（4.05±1.07）和（1.86±0.41）h,AUC_0-∞（119.00±55.11）和（87.66±26.08）ng·h/mL。代谢物去甲替利定的男性和女性药动学参数分别为:C_max（108.82±27.88）和（133.49±12.56）ng/mL,T_max（0.94±0.13）和（0.40±0.09）h,t_1/2（4.66±1.18）和（6.57±0.84）h,AUC_0-∞（601.59±281.07）和（557.57±108.16）ng·h/mL。替利定的t_1/2男性比女性长,代谢物去甲替利定的T_max男性比女性慢,其它主要药代参数男性和女性之间没有统计学差异。受试者无严重不良事件发生,男性和女性的不良事件发生率有显著性差异。药代动力学研究显示,替利定口服液在应用于中国人时无需改变用药剂量,且性别因素影响不大。     

Factors influencing the reinforcing and subjective effects of ephedrine in humans

There has been little study of the abuse liability of ephedrine, a naturally occurring drug used in medicine for thousands of years and currently sold as a legal stimulant. The present study measured the reinforcing and subjective effects of ephedrine in a group of 27 adults (18 females and 9 males) with no history of drug dependence. A discrete-trial choice procedure was used to assess the reinforcing effects of a single oral dose of ephedrine selected to produce a moderate subjective response in each subject (range: 37.5-75 mg). A number of variables (gender, current and past drug use, personality, and baseline mood and arousal) were examined in an attempt to identify sources of variability in response to ephedrine. Of the 27 subjects, 5 chose ephedrine on either 2 or 3 out of a possible 3 occasions; overall, ephedrine was chosen on 17% of occasions. In the group as a whole, ephedrine had no effect on ratings of drug liking, but did increase ratings of high and scores on the MBG (euphoria) scale of the Addiction Research Center Inventory. Ephedrine also increased scores on a number of mood scales reflecting CNS stimulation and anxiety. Ephedrine choice was positively associated with current use of marijuana and lower levels of baseline anxiety and hunger, as well as with lower scores on two scales measuring dimensions of the personality trait of harm avoidance. Males and females differed in their response to ephedrine — males chose ephedrine more frequently than females and showed a more positive mood response to the drug. When compared to the results of a prior study of the same design withd-amphetamine, these results demonstrate that ephedrine produces a different profile of subjective effects and is a less efficacious reinforcer than amphetamine, suggesting that ephedrine has a lower liability for abuse.     

The effects of nitrous oxide on the human auditory evoked response

Summary The effects of inhaling 12.5 per cent and 25 per cent nitrous oxide in oxygen were compared with those of pure oxygen in 12 normal subjects. The vertex (non-specific) electroencephalographic evoked responses to clicks were measured using a special-purpose averaging computer during each of the drug conditions. Palmar sweat-gland activity (skin conductance) and subjective ratings were also recorded. Nitrous oxide produced regular diminutions in certain of the components of the evoked response and rectilinear dose-effect curves with relatively narrow confidence limits could be constructed. Sweat-gland activity was not affected by the drug but subjective feelings of relaxation and drowsiness were noted.     

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide in healthy volunteers

Within- and between-subject variability in the reinforcing and subjective effects of nitrous oxide (N(2)O) was studied across five sessions. Twelve volunteers with no history of drug dependence sampled 30% N(2)O and 100% oxygen for 10 min each, then chose nine times, once every 5 min, among N(2)O (e.g. "Agent A"), oxygen (e.g. "Agent B"), or "drug-free air." Choice varied across subjects but was stable within subjects. Quantitative differences in subjective effects occurred within and across subjects. Some subjective effects were correlated with choice and/or differed between subjects who were consistent choosers of N(2)O versus those who were not. However, drug liking and euphoria, two face-valid measures of abuse liability, were unrelated to choice. Thus, the present study found individual differences (i.e. between-subject variability) in subjective and reinforcing effects of N(2)O and, in terms of within-subject variability, suggested that subjective effects fluctuate across sessions to a relatively greater extent than do reinforcing effects. The varying degrees of correlation between N(2)O choice and its subjective effects emphasize the need for obtaining multiple measures when characterizing abuse liability of this drug.     

Paradoxical effects of nitrous oxide on human memory

Using the method of adjusted learning, subjects learned number-noun pairs while breathing either placebo or 30% nitrous oxide. Subjects breathing nitrous oxide required more acquisition trials to attain a learning criterion than did subjects breathing placebo. Two weeks later, half of the subjects from each group were administered either placebo or nitrous oxide and were asked to recall the noun that had accompanied each number cue. Results showed that: 1) nitrous oxide inhalation can decrease the accessibility of to-be-recalled material and 2) nitrous oxide administered during the acquisition of material can paradoxically improve the recall of that material 2 weeks later. The additional number of acquisition trials subjects received during nitrous oxide inhalation could potentially account for this paradoxical enhancement of delayed recall; however, correlational analyses suggest this was not the case. No evidence for any state-dependent effects of nitrous oxide on cued recall were found.This investigation was supported by NIH grants DE 00161, DE 07150, and RR 05346 with additional support from the Alcohol and Drug Abuse Institute of the University of Washington.     

Reinforcing and subjective effects of caffeine in normal human volunteers

The reinforcing and subjective effects of caffeine (100 and 300 mg, PO) were determined in a group of 18 normal, healthy adults. Subjects (eight females, ten males) were light to moderate users of caffeine, and had no history of drug abuse. A discrete-trial choice procedure was used in which subjects were allowed to choose between the self-administration of color-coded capsules containing either placebo or caffeine. The number of times caffeine was chosen over placebo was used as the primary index of reinforcing efficacy. Subjective effects were measured before and several times after capsule ingestion. The low dose of caffeine was chosen on 42.6% of occasions, not significantly different from chance (50%). The high dose of caffeine was chosen on 38.9% of occasions, significantly less than expected by chance, indicating that this dose served as a punisher. Both doses of caffeine produced stimulant-like subjective effects, with aversive effects such as increased anxiety predominating after the high dose. When subjects were divided into groups of caffeine-sensitive choosers and nonchoosers, a consistent relationship emerged between caffeine choice and subjective effects; nonchoosers reported primarily aversive effects after caffeine (increased anxiety and dysphoria), whereas choosers reported stimulant and positive mood effects. When compared with previous findings, these results demonstrate that caffeine is less reinforcing than amphetamine and related psychomotor stimulants.     

The reinforcing effects of brief exposures to nitrous oxide in healthy volunteers

The reinforcing and subjective effects of brief (about 1.5 min) exposures to nitrous oxide, ranging from inspired concentrations of 20–80% in oxygen, were examined in 11 healthy volunteers. A choice procedure was used in which during each of four sessions, subjects first sampled a given concentration of nitrous oxide and placebo oxygen, and then chose between the two. 20, 40, 60 and 80% nitrous oxide were chosen by five, four, three, and three subjects, respectively—these choice levels did not exceed that of chance. All concentrations had psychoactive effects, and in general, concentration-related subjective effects were found. We conclude that in a medical setting, nitrous oxide inhaled in a manner similar to that when used recreationally in a naturalistic setting, does not function as a reinforcer across a wide range of concentrations, in subjects with a modest lifetime history of psychoactive drug use.     

Subjective and psychomotor effects of nitrous oxide in healthy volunteers

The effects of nitrous oxide at subanesthetic doses (0%, 10%, 20%, and 40% in oxygen) on mood and psychomotor performance were determined in a group of 12 healthy volunteers (six males and six females). A randomized, placebo-controlled, double-blinded, crossover trial of five experimental sessions was used. Effects were measured before, during and after a 30-min inhalation period of the agent, using three subjective effects questionnaires (the Profile of Mood States, the Addiction Research Center Inventory, and the Visual Analogue Scale); and two psychomotor tests (auditory reaction time and Digit Symbol Substitution Test). In addition, an End-of-Session questionnaire, administered 60min after cessation of inhaling the agent, was used, which measured the subjects' reactions to the agent inhaled that day (i.e. peak concentration effect and concentration liking). The primary effects observed from nitrous oxide were confined to the inhalation of 20% and 40% concentrations. Subjects became more confused, sedated, high, dysphoric, and stimulated during inhalation of 40% nitrous oxide; fatigue, depression and anxiety increased after inhalation of 40% nitrous oxide had ceased. Significant or near-significant differences on several measures of subjective effects emerged between sexes. On the End-of-Session questionnaire, subjects' ratings of the peak effect of nitrous oxide were dose-related. There was individual variation in the degree to which subjects liked nitrous oxide: eight of the 12 subjects reported liking the 40% concentration, one was neutral, and three did not like it. Subjects' performance on the DSST was significantly impaired during inhalation of 40% nitrous oxide, but recovered soon after inhalation stopped. In summary, nitrous oxide had robust effects on mood, there appeared to be sex differences in the magnitude of subjective effects of nitrous oxide, and there was some variability in the extent to which subjects liked the anesthetic agent.     

Effects of information on the reinforcing,subjective, and psychomotor effects of nitrous oxide in healthy volunteers

The purpose of this study was to characterize the reinforcing, subjective, and psychomotor effects of nitrous oxide (N₂O) in healthy volunteers who were given different amounts of information regarding the drugs they were being administered in the experiment. A choice procedure was used in which subjects first sampled a placebo and a given concentration of N₂O, and then chose between the two. N₂O concentration varied across the four-session experiment from 10–40%. Besides choice, subjective and psychomotor effects served as dependent measures. In the INFORMED group (n = 11), subjects were told at the beginning of each sampling trial what concentration of N₂O they were inhaling or whether they were inhaling 100% oxygen (placebo). They were also informed about the prototypic effects of N₂O (e.g. tingling or numbing, euphoria, dysphoria) and oxygen (e.g. no discernible effects). In the NON-INFORMED group (n = 11), subjects were only told at the beginning of each sampling trial that the drugs they would be inhaling came from one of six classes of drugs. Thirty percent N₂O was chosen by a significantly higher proportion of subjects than expected by chance in the INFORMED group, but not in the NON-INFORMED group. Further, the probability of choosing 20–40% N₂O was higher in the INFORMED group than in the NON-INFORMED group. Subjective effects of N₂O were not affected by the information manipulation. Psychomotor performance at the highest N₂O concentration tested (40%) was impaired to a greater extent in the NON-INFORMED than in the INFORMED group. We conclude that the reinforcing effects of N₂O, and perhaps the impairing effects, can be modulated by telling subjects beforehand that they are inhaling N₂O and what effects they might be expected to experience from the drug.     

Examining the subjective, psychomotor and reinforcing effects of nitrous oxide in healthy volunteers: a dose-response analysis

The present study examined the subjective, psychomotor and reinforcing effects of 10%, 20%, 30% and 40% nitrous oxide in oxygen in 16 healthy volunteers using a choice procedure in which sampling (e.g. 20% nitrous oxide and oxygen-placebo) and choice trials (e.g. 20% nitrous oxide vs. oxygen placebo) were within the same session. Across the four-session study, nitrous oxide dose was varied. Nitrous oxide in a dose-related manner altered subjective effects (e.g. increased visual analog scale ratings of "high", "stimulated" and "tingling") and decreased performance on the Digit Symbol Substitution Test. 10%, 20%, 30% and 40% nitrous oxide were chosen over oxygen by 6, 7, 7 and 8 subjects, respectively. We conclude that nitrous oxide across a range of subanesthetic doses did not function as reinforcer in the majority of subjects tested.     

Effects of a subanaesthetic concentration of nitrous oxide on memory and subjective experience: Influence of assessment procedures and types of stimuli

Subjects (16 men and 16 women) breathing 30 per cent nitrous oxide in oxygen, or 100 per cent oxygen, were tested to see if the effects of nitrous oxide on memory varied with different types of auditory stimuli and memory-testing procedures. The drug produced substantial memory impairments. These impairments were milder in forced-choice recognition than in yes/no recognition and for certain stimuli (first names of each subject's close relatives), but were not influenced by several other variations in test procedures and stimuli. Additional assessments indicated that nitrous oxide produced numerous subjective effects including some that are characteristic of psychedelic drugs. Subjective rating scales of the kind frequently used in drug studies revealed sedation but not the other mood effects.     

甲磺酸加替沙星片健康人单剂口服药代动力学

目的研究健康人口服单剂甲磺酸加替沙星片后药代动力学特征,为该药II期临床试验提供依据。方法采用3剂量3周期拉丁方实验设计。9名健康受试者单剂口服甲磺酸加替沙星片100、200、300mg,HPLC法测其血清、尿药物浓度。结果受试者口服甲磺酸加替沙星片后,人体耐受良好,体内过程符合二室开放模型。主要药代动力学参数与给药剂量呈线性关系,tmax为0.5～0.7h,Cmax分别为1.42、2.42、3.25μg/ml,AUC0-∞分别为11.33、21.85、32.32μg·h/ml,V/Fc值为50～80L,t1/2β为8～9h,72h尿药累积回收率约为63.5%。结论甲磺酸加替沙星片口服吸收良好,血峰浓度高,组织分布广,消除半衰期长。200mg每日一次口服用于治疗敏感菌感染。     

Comparison of nitrous oxide,morphine and diazepam effects in the mouse staircase test

Mice were exposed for 10–20 min to room air, 100% oxygen (O₂) or increasing concentrations of nitrous oxide (N₂O) in O₂, then tested for 3 min in a staircase inside a glovebag. N₂O produced a concentration-dependent increase in the number of steps ascended (NSA) but no change in the number of rears (NR). Pretreatment with naloxone reversed the increase in NSA and also unmasked N₂O reduction in NR. By comparison, increasing doses of the narcotic standard morphine reduced NSA and NR; these changes in NSA and NR were sensitive to antagonism by naloxone. The benzodiazepine standard diazepam produced a dose-related reduction in NR while reducing NSA only at higher doses. These data indicate that N₂O influences on NSA and NR resemble neither morphine nor diazepam. In addition, it appears that the opioid activity of N₂O might mask its antianxiety activity in this particular paradigm.     

Evaluation of potential sex differences in the subjective and analgesic effects of morphine in normal, healthy volunteers

Rationale

Sex differences in the analgesic effects of mu-opioid agonists have been documented extensively in rodents and, to a lesser extent, in non-human primates. To date, there have been few experimental studies investigating this effect in humans, and the conclusions have been equivocal.

Objectives

The aims of the present study were to examine potential sex differences in the analgesic, subjective, performance, and physiological effects of morphine in human research volunteers.

Methods

Using a double-blind outpatient procedure, the present study investigated the effects of intramuscular morphine (0, 5, and 10 mg/70 kg, i.m.) in men (N?=?8) and women (N?=?10). The primary dependent measure was analgesia, as assessed by the cold pressor and mechanical pressure tests. Secondary dependent measures included subjective, performance, and physiological effects of morphine, as well as plasma levels of morphine.

Results

No differences in the analgesic and performance effects of morphine were observed between men and women, but significant differences in morphine’s subjective effects were found. Specifically, men reported greater positive effects, whereas women reported greater negative effects after morphine administration.

Conclusions

These data suggest that, in humans, there are sex differences in the subjective mood-altering effects of morphine but, based on this limited sample, there is little evidence for sex differences in its analgesic effects.