Nitrous oxide and human state-dependent memory.

State-dependent effects of nitrous oxide on human memory were examined by administering serial and paired-associate learning tasks to subjects receiving 20 and 30% nitrous oxide or placebo. Nitrous oxide in 30% concentration impaired learning of both tasks. In addition, it produced an atypical form of asymmetric state-dependent memory; subjects who learned while receiving placebo and recalled while receiving nitrous oxide displayed the worst recall.

Comparison of two benzodiazepines with differing accumulation: behavioral changes during and after 3 weeks of dosing.

The effects of diazepam (0.2 mg/kg for 15 days followed by 0.3 mg/kg for 7 days), oxazepam (0.8 mg/kg for 15 days followed by 1.2 mg/kg for 7 days), and placebo were studied in healthy subjects after the first dose, once a week during chronic dosing, and at 48 and 96 hours after withdrawal through a battery of psychologic tests. Diazepam produced quick effects followed by relatively rapid recovery, whereas the effects of oxazepam appeared slowly and lasted longer. Tolerance developed to the effects of both active drugs, so that when the dosages were increased, effects did not. There were no symptoms or signs indicative of withdrawal reactions. There were also no differences between the effects of the two active drugs after repeated dosing, although diazepam is an accumulating drug with active metabolites and oxazepam is a slightly accumulating one with inactive metabolites.

The behavioral actions of diazepam and oxazepam are similar.

In a double-blind and randomized study, we assessed the comparative pharmacodynamic profiles and behavioral effects of diazepam and oxazepam administered to young healthy volunteers. Diazepam 0.3 mg/kg or oxazepam 1.2 mg/kg or placebo were each administered orally to 13 subjects who were tested with tasks which measured learning and memory, cognition, psychomotor performance and mood before and for 9 h after treatment. The two drugs had similar actions, although subjective effects were milder after oxazepam, which also had a slower onset of action. There was no evidence of rebound behavioral impairment.

Ketamine: behavioral effects of subanesthetic doses.

Effects of subanesthetic doses of ketamine (0.25 and 0.5 mg/kg) on memory, cognition, psychomotor function, subjective moods, and incidence of adverse reactions were investigated in 34 healthy young volunteers. The drug caused impairment of immediate and delayed recall. Most of the impairment was due to interference with retrieval processes. Recovery was virtually complete 60 minutes after administration. The incidence of adverse reactions was high. Benzodiazepines need to be administered even when ketamine is used in subanesthetic doses.

Behavioral effects of oral versus intravenous administration of diazepam.

The behavioral effects of oral versus intravenous administration of diazepam were studied in 50 volunteers using a battery of memory, cognitive, mood and psychomotor tests repeated over a 4.5 hr period. Subjects received diazepam 0.2 mg/kg or placebo as capsules, commercial tablets or intravenous solution in a randomized double blind manner. While a quick onset of effects occurred with intravenous administration followed by the capsule and tablet oral administrations in that order, the recovery rate was similar for the 3 methods of administration. Contrary to many claims in the literature the effects of oral administration were substantial. Behavioral impairment was directly related to the magnitude of the memory component of the task. On many of the tasks the pattern of diazepam impairment was one of delayed improvement of performance, a pattern which would only be apparent with repeated testing. Subjects who received diazepam showed a paradoxical enhancement of recall for material learned before the drug.

Dose-response analysis of the behavioral effects of diazepam: I. Learning and memory.

A total of 120 healthy volunteers were randomly assigned to four treatments (placebo, 0.1, 0.2, and 0.3 mg/kg) and three testing times (7 AM, 1 PM and 7 PM). Immediate and delayed free recall of word lists revealed consistent decreases in performance as oral diazepam dose increased from 0.1, 0.2, to 0.3 mg/kg. Paradoxically, as the dose increased, the number of predrug list words recalled also increased. A serial number-learning task displayed a pattern of delayed improvement of acquisition as the dose increased. Response times in a semantic-categories task were prolonged as the dose increased. Parallel recovery functions were observed for all doses and tasks. Full recovery after a single administration of 0.1, 0.2, and 0.3 mg/kg doses was estimated to occur after 3.5, 4.5, and 5.5 h, respectively. Several analyses were consistent with the view that acquisition and not retrieval was impaired by diazepam. There were no circadian interactions with the effects of the drug.

Dose-response analysis of the behavioral effects of diazepam: II. Psychomotor performance, cognition and mood.

The psychomotor, cognitive, and mood effects of orally administered diazepam and placebo were measured over approximately equal to 3.5 h. A total of 120 volunteers were assigned to 12 groups of 10 each, representing the combination of four treatments (placebo, 0.1, 0.2, and 0.3 mg/kg diazepam) and three testing sessions (7 AM, 1 PM, and 7 PM). A variety of cognitive tasks, tapping and postural stability tests, and a mood evaluation scale were used. Psychomotor and cognitive functions showed consistent dose-response effects, while for subjective evaluations, the only effect of dose level was in the duration of sedation. The pattern of impairment of cognitive functions suggests that the drug affects speed rather than accuracy, and it primarily blocks acquisition of new information or skills. Use of repeated testing may therefore be necessary to detect subtle drug effects. Subjects reported no tranquilization , which suggests that the anxiolytic action of the drug cannot be studied in healthy volunteers. There was no circadian influence on the actions of the drug.

Diazepam and memory: retrograde facilitation produced by interference reduction.

Although diazepam (Valium) reduces learning and memory of information presented after administration (anterograde amnesia), in some cases it improves retention of predrug information (retrograde facilitation). Three experiments examined the magnitude and the conditions for producing retrograde facilitation and tested three hypotheses about the cause of memory enhancement. Differential effort and enhanced consolidation explanations were rejected in favor of a reduced interference interpretation. Improvement in predrug memory occurs because poor postdrug learning reduces the amount of new information available to interfere with prior learning.

Diazepam and learning: assessment of acquisition deficits.

Subjects treated with diazepam (0.3 mg/kg) showed significant reductions in performance on multiple-trial free recall, paired-associate learning, and serial learning tasks compared to placebo control subjects. The free recall task showed the largest drug effect with diazepam subjects failing in six acquisition trials to attain the level of performance achieved by placebo subjects on the first trial. Serial position curves in the serial learning task were changed by the diazepam treatment from their usual skewed form to symmetrical functions. Results indicate that diazepam exerts its greatest memory influence on the acquisition of new information.

Diazepam effects and kinetics in Caucasians and Orientals.

Mental and psychomotor effects and diazepam kinetics were studied in Caucasian and Orientals. 12 Caucasian and 13 Oriental young adults received on one of two occasions, separated by 2 weeks, either 0.2-mg/kg diazepam or saline intravenously. Serum diazepam and desmethyldiazepam concentrations were measured by electron-capture gas-liquid chromatography in samples drawn up to 72 hr after injection. Serum protein binding was measured by equilibrium dialysis. Subjects were tested on a battery of psychological tests before and 0.5, 2, and 4 hr after treatment. While the free fraction of diazepam was identical in both races (0.02), volume of distribution at steady state (Vdss) was different when calculated as absolute volume (Vdss = 76.55 +/- 9.63 l in Caucasians and 54.96 +/- 4.55 l in Orientals, p = 0.04) and marginally significant when corrected for body weight (Vdssl/kg = 1.10 +/- 0.11 in Caucasian and 0.88 +/- 0.05 in Orientals, p = 0.07). total body clearance (Cl), but not elimination half-life (t 1/2), was higher in Caucasians than Orientals, p less than 0.01; t 1/2 = 37.70 +2- 5.53 hr in Caucasians and 41.77 +/- 3.80 in Orientals). Desmethyldiazepam levels were higher in Orientals than Caucasians. Mental and psychomotor effects were maximal at the first session (0.5 hr), followed by complete recovery by the 4-hr session. Effects were similar in both groups. If repeated dosing causes a higher rate of cumulated diazepam serum levels in Orientals, as expected, there might be deeper brain depression in that group.

Time course of mental and psychomotor effects of 30 per cent nitrous oxide during inhalation and recovery.

Two experiments were conducted testing the duration of action of nitrous oxide on human performance. In the first experiment, 11 subjects inhaled 30 per cent nitrous oxide for two periods of 40 min each, 45 min apart. Their mental and psychomotor skills were measured using free recall, tapping board, arithmetic and flicker fusion tests before and 2, 12, 22 and 32 min after establishing and end-tidal concentration of N2O of 30 per cent. Recovery was tested using the same tests 2, 12, 22 and 32 min after discontinuation of N2O. Eleven additional subjects inhaled oxygen only and served as a control group. In the second experiment, 8 subjects received both 30 per cent N2O and oxygen in cross-over fashion, and their flicker fusion threshold was measured. When compared to baseline or oxygen administration, N2O significantly impaired tapping rate, number of words recalled, and performance in arithmetic tests. The effects of N2O were maximal at 2 min and remained similar throughout the entire administration. In flicker fusion tests, the effects of N2O were similar to those of stimulant drugs; N2O improved the subjects' ability to discriminate the fusion of flickering light. Recovery was complete in 22 min. The effects of, and recovery from the second administration of N2O were similar to those of the first experiment. There was no evidence of development of tolerance to mental and psychomotor effects of the drug.

Memory and performance effects of single and 3-week administration of diazepam.

The effects of diazepam of several cognitive and performance tasks were investigated in 30 healthy volunteers randomly assigned to three groups: A chronic group received diazepam for 21 days; an acute group received placebo during the same period, except at session 4 when they received diazepam; and a third group received placebo only at the sessions. Diazepam was given orally in a dose of about 0.2 mg/kg. Behavioral sessions were conducted before treatment (practice), after one administration (session 2), after 19 days (session 3), after 20 days (session 4), and 7 days following withdrawal (session 5). A single administration of diazepam produced significant memory impairment in both immediate and delayed free recall. Reduced memory performance was the result of impaired acquisition rather than reduced retention. Comparison of the chronic and acute groups in sessions 3 and 4 and analysis of the performance of the chronic group over sessions indicated the development of some tolerance to the memory impairment with continued administration. No residual memory effects were apparent following withdrawal. No other cognitive or psychomotor functions differed among the three treatment groups.

The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory.

Seventy college age subjects learned and recalled a series of word lists prior to being injected with methamphetamine (0.2 mg/kg or 0.3 mg/kg), scopolamine (8 microgram/kg), or a placebo. Following the injection subjects were tested for their free recall and recognition of the words and they completed a short-term digit recall task. Subjects who had previously received scopolamine were next injected with either methamphetamine (0.2 mg/kg or 0.3 mg/kg), physostigmine (32 microgram/kg), or placebo, while other subjects received a placebo injection. The above memory procedure was then repeated with a second series of word lists. In addition, subjective feelings were measured with a questionnaire. Scopolamine and methamphetamine did not affect recall of information learned prior to injection. Scopolamine did, however, impair performance in both the digit recall task and in the second series of memory tests. Physostigmine and methamphetamine alleviated most of the memory deficits and sedation produced by scopolamine. Methamphetamine alone produced subjective arousal and a small improvement in recall of words learned after injection and a large increase in incorrect responding.

Studies on human memory: the interactions of diazepam, scopolamine, and physostigmine.

Seventy volunteers were injected with diazepam (0.3 mg/kg), scopolamine (8 mug/kg), or placebo, followed 70 min later by another injection of physostigmine, physostigmine and methscopolamine (in case of diazepam treatment), or placebo. Physostigmine was given in two doses, 16 and 32 mug/kg; methscopolamine, 8 and 16 mug/kg. Subjects (Ss) were tested in groups of 5 in a double blind procedure with treatments distributed according to a Latin square design. Prior to treatment, Ss heard a series of lists of words, followed by an immediate recall test. Following the first injection, delayed free recall and recognition tests were given. The second drug was then injected, followed by a presentation of another two sets of lists which were tested similarly. Subjective feelings were also evaluated with a rating questionnaire. Diazepam and scopolamine did not affect recall of information which had been learned prior to drug injection. However, both drugs impaired the learning or acquisition of new information. Physostigmine, especially in its high dose, antagonized most of the memory deficits produced by scopolamine while those of diazepam remained. This is a strong indication that scopolamine acts centrally through an anticholinergic mechanism while diazepam may act through a different system.

Effects of diazepam and scopolamine on storage, retrieval and organizational processes in memory.

The effects of intramuscular injections of diazepam (0.3 mg/kg) and scopolamine (8 mug/kg) on memory processes and subjective moods were studied in 36 volunteers. Subjects (Ss) were tested in groups of four in a double blind procedure with treatments distributed according to a Latin square design. Lists of words were presented to Ss who were then tested with an immediate free recall test prior to drug administration. Following injection delayed free recall and recognition tests were given. Subsequently two sets of lists were presented separately and tested in the same fashion. Two of the lists in the last set were composed of words falling into distinct categories. Memory was additionally analyzed by testing immediate recall of digit sequences and employing a visual recognition test. Subjective moods were evaluated with a rating questionnaire. Both diazepam and scopolamine impaired memory functions although the action of the latter drug was more pronounced and prolonged. The deficit appeared to be in the storage process leaving retrieval processes unaffected. Scopolamine in addition interfered with organizational processes. Subjectively, scopolamine also produced a larger sedative effect than diazepam.