An adjusting-dose procedure for assessing the reinforcing effects of nitrous oxide with humans.

Despite continued abuse, there is a paucity of empirical investigations on inhalants as reinforcers. The present study attempted to derive a method for studying the reinforcing effects of nitrous oxide (N2O) with human participants. An adjusting-dose procedure was employed to assess choice allocation for inhalation periods of varying doses of N2O. After experiencing the experimental parameters in forced-choice trials, participants made choices between a fixed dose of 0% N2O (i.e., 100% O2) and an adjusting dose of N2O (0-50% N2O in O2). The adjusting dose titrated as a function of the participant's choices. Conditions were run to stability and systematically replicated within-subject. Stable choice allocation served as both the chief dependent variable and an indication of the optimal reinforcing dose of N2O for that participant. Consistent with previous research on N2O, there was between-subject variability in the reinforcing effects of N2O; however, stable within-subject choice allocation was observed for 6 out of 8 participants. This method of assessing drug choice in humans allows for the testing of multiple doses within-subject, which is imperative, given that the reinforcing effects of drugs are known to vary across subjects and as a function of dose.

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.

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.

Within-subject comparison of the subjective and psychomotor effects of a gaseous anesthetic and two volatile anesthetics in healthy volunteers.

Inhalant abuse is a serious public health problem throughout the world. The present study compared the states of intoxication produced by three inhaled anesthetics that represent two of the three major classes of abused inhalants, as classified by [Balster, R.L., 1998. Neural basis of inhalant abuse. Drug Alcohol Depend 51, 207-214.]. Isoflurane and sevoflurane represent the class of volatile substances, and nitrous oxide (N2O) comprises a class of its own. Fourteen healthy volunteers inhaled the vehicle (100% O2) and two concentrations each of isoflurane (0.1 and 0.2%), sevoflurane (0.2 and 0.4%), and N2O (15 and 30%) for 40 min each, across seven separate sessions. Drug concentrations were chosen to produce similar ratings of drug effect strength and similar impairment on a psychomotor test, the digit-symbol substitution test (DSST). Ratings of drug effect strength and performance on the DSST were similar across drugs; however, the volatile anesthetics produced greater sedation and greater impairment on three other psychomotor tests than N2O, whereas N2O produced a greater magnitude of putatively pleasant and psychedelic-like subjective effects. These results are consistent with the drugs' putative receptor mechanisms of action and confirm Balster's classification of the volatile anesthetics into a class distinct from N2O.

Reinforcing and subjective effects of the volatile anesthetic, sevoflurane.

Sevoflurane is a volatile anesthetic that is chemically similar to volatile substances of abuse and can be safely administered to humans in laboratory research. In this study, the reinforcing and subjective effects of five concentrations of sevoflurane (0, 0.2, 0.4, 0.6, 0.8% sevoflurane in O2) were studied in 20 non-drug-abusers. During each of five sessions, subjects sampled a concentration of sevoflurane and 100% O2 (placebo) for 10 min each. Later, within the session, they chose nine times, once every 5 min, among sevoflurane (e.g. "Agent A"), placebo (e.g. "Agent B"), or neither (and were administered 100% O2, identified as "drug-free air"). Although "neither" was selected most frequently, mean preference ratios (sevoflurane choices/[sevoflurane choices+placebo choices]) and total sevoflurane choice peaked at the 0.4% concentration. Choice patterns varied across subjects, with some subjects never choosing sevoflurane and other subjects showing monotonic increasing or bitonic concentration-choice functions. Concentration-related increases in subjective effects were observed, including effects that are putatively associated with abuse liability. Ratings of drug liking and of wanting to inhale the drug again were positively correlated with sevoflurane choice. This study shows that sevoflurane can function as a reinforcer and produce abuse liability-related subjective effects in some healthy volunteers.

Assessing subjective and psychomotor effects of the herbal medication valerian in healthy volunteers.

Valerian is the common name given to the genus Valeriana, an odiferous, herbaceous perennial plant widely distributed in the temperate regions of Asia, Europe, and North America. It is among the most widely used herbal medicines in the world. Numerous clinical studies have demonstrated valerian's ability to improve sleep; however, to the best of our knowledge, no study has systematically assessed subjective and psychomotor/cognitive effects of valerian in young healthy adults across a range of doses. In the present study, we sought to determine whether valerian extract (Valeriana officinalis) altered mood and/or impaired psychomotor/cognitive performance in young healthy volunteers. We examined the effects of valerian extract (600, 1200, and 1800 mg) and 10 mg diazepam (positive control) compared to placebo in 10 young healthy volunteers. Dependent measures included subjective and psychomotor variables. The valerian extract had no significant effects on any of the dependent measures. Diazepam, though, produced subjective effects as measured by four different rating scales, and impaired psychomotor/cognitive performance. The data suggest that acute administration of valerian does not have mood-altering or psychomotor/cognitive effects in young healthy volunteers.

Bitonic dose-response functions for reinforcing and self-reported effects of nitrous oxide in humans.

The reinforcing and self-reported effects of nitrous oxide (10%, 30%, and 50% N(2)O in O(2)) were examined in 13 humans. During each of three sessions, subjects sampled one dose of N(2)O and 100% O(2) (placebo) for 10 min each, separated by 30-min recovery periods. The agents were identified by letter code, and later in the session, subjects chose nine times, once every 5 min, among N(2)O (e.g., "Agent A"), placebo (e.g., "Agent B"), or "neither" (also 100% O(2), identified as "drug-free air"). Self-reported and psychomotor effects were measured at various times. Dose-response functions varied across subjects and included bitonic, monotonic increasing, monotonic decreasing, U-shaped, and flat dose-response functions for reinforcing and/or self-reported effects. For subjects who showed bitonic reinforcing effects, the descending limb of the dose-response function could not be attributed to behavioral impairment. This study replicates previous studies showing dose-dependent effects of N(2)O, as well as between-subject variability in N(2)O effects. Bitonic dose-response functions for some subjects extend the generality of the phenomenon of bitonicity of drug effects to N(2)O effects in humans.

Analysis of the reinforcing and subjective effects of different doses of nitrous oxide using a free-choice procedure.

The reinforcing and subjective effects of five doses of nitrous oxide (0, 10, 20, 30, 40% N(2)O in O(2)) were studied in 20 non-drug-abusers using a free-choice procedure. During each of five sessions, subjects sampled a dose of N(2)O and 100% O(2) (placebo) for 10 min each. Later they chose nine times, once every 5 min, among N(2)O (e.g. 'Agent A'), placebo (e.g. 'Agent B'), or a no-drug option. Mean preference ratios (N(2)O choices/[N(2)O choices+placebo choices]) and total N(2)O choice increased with increasing N(2)O dose. Individual preference ratios suggested that at least one active dose of N(2)O functioned as a reinforcer in 80% of subjects, and the doses that functioned as reinforcers varied across subjects. N(2)O choice was positively correlated with end-of-session and post-session ratings of N(2)O liking and of wanting to inhale N(2)O again, but not with ratings of those effects during sampling. Placebo was chosen significantly less than the no-drug option, even though both were 100% O(2). More robust reinforcing effects of N(2)O were observed in this subject population than in previous studies. Choice data emphasize the importance of examining a range of doses, and of examining those effects within-subject, when assessing reinforcing effects of drugs. Inclusion of the no-drug option eliminated the 'forced' choice of placebo, making preference ratios easier to interpret than in previous, forced-choice procedures. Reinforcing effects were more correlated with subjective effects assessed after the session than with subjective effects obtained while subjects were under the influence of the drug.