Effects of food deprivation on subjective responses to d-amphetamine in humans

The effects of 24 hours of food deprivation on the subjective response to 10 mg oral d-amphetamine were studied in 12 healthy normal volunteers. A within-subjects design was used in which subjects ingested amphetamine and placebo capsules in both a fed and a fasting state. Each of the four experimental conditions-FED/DRUG, FED/PLACEBO, FAST/DRUG, FAST/PLACEBO--was enacted twice according to a randomized block design. Three subjective effects questionnaires, the Profile of Mood States, the Addiction Research Center Inventory, and the Visual Analogue Scale, were completed prior to and 1, 3 and 6 hr after the early morning capsule ingestion. Typical elevations in such subjective effects as elation and vigor were obtained after amphetamine ingestion in both feeding conditions, but fasting neither potentiated nor attenuated the drug response. Subjects at the end of the session, however, were more likely in the FAST/DRUG condition than in the FED/DRUG condition to label the capsule they had ingested at the beginning of the session as a stimulant.     

The effects of acute haloperidol or risperidone on subjective responses to methamphetamine in healthy volunteers

Despite extensive evidence that selective dopamine antagonists attenuate the reinforcing effects of stimulants in laboratory animals, there is little evidence that dopamine antagonists block the positive subjective effects of stimulants in humans. However, recent evidence suggests that the subjective effects of stimulants in humans may depend in part on serotonin. The goal of this study was to examine the effects of haloperidol, a drug that primarily blocks dopamine receptors, and risperidone, a drug that blocks both dopamine and serotonin receptors, on the physiological and subjective effects of methamphetamine in healthy volunteers. Two groups of subjects participated in a placebo-controlled, within-subject, 2 x 2 repeated measures design. One group was tested with haloperidol (3 mg; N = 18), the other with risperidone (0.75 mg; N = 18). Each subject participated in four sessions receiving all combinations of antagonist or placebo and methamphetamine (20 mg) or placebo. Dependent measures included vital signs and standardized questionnaires of subjective effects. At these doses, both haloperidol and risperidone produced mild sedative-like effects compared to placebo. However, neither drug consistently reduced the stimulant-like effects of methamphetamine. These results add to the growing body of literature suggesting that D(2) dopamine receptor antagonists do not block the euphorigenic subjective effects of stimulant drugs in humans, and also do not support the idea that serotonin contributes significantly to these effects.     

Effect of d-amphetamine on post-error slowing in healthy volunteers

Rationale  

Post-error slowing has long been considered a sign of healthy error detection and an important component of cognitive function. However, the neuropharmacological processes underlying post-error slowing are poorly understood.     

Personality factors moderate subjective and psychophysiological responses to d-amphetamine in humans

The aim of the present study was to examine the relationship between measures of novelty and sensation seeking and both psychophysiological and subjective measures of stimulation after a pharmacological challenge with an indirect dopamine agonist, d-amphetamine. Prepulse inhibition (PPI) of the startle reflex and subjective responses were assessed after the challenge. The results indicated that the Novelty Seeking scale of the Tridimensional Personality Questionnaire (TPQ; M. Zuckerman, 1994). TPQ was a significant predictor of lower PPI and greater subjective stimulation. The Disinhibition scale of the Sensation Seeking Scale (SSS; M. Zuckerman, S. B. G. Eysenck, & M. J. Eysenck, 1978) moderated the effects of amphetamine on stimulation and elation, whereas the Boredom Susceptibility and Experience Seeking subscales of the SSS moderated subjective stimulation. These findings indicate that higher scores on novelty and sensation seeking correspond to heightened sensitivity to the effects of a stimulant medication.     

Acute administration of d-amphetamine decreases impulsivity in healthy volunteers.

This study investigated the acute behavioral effects of d-amphetamine on several behavioral indices of impulsivity. Impulsivity has been defined, variously, as difficulty in inhibiting inappropriate behaviors, inability to wait, insensitivity to delayed consequences or an alteration in the perception of time; standardized procedures have been developed to measure these behavioral dimensions. However, it is not known how drugs affect these measures, and few studies have examined more than one measure in a single study. In this study, 36 healthy men and women participated in three sessions, in which they received placebo, 10 mg, or 20 mg d-amphetamine in randomized order. On each session they performed the following five tasks: the Stop Task, which measures behavioral inhibition, a delay discounting task, which measures the relative value of immediate vs. delayed rewards, a delay of gratification task, a Go/No-Go task, and a time estimation task. Subjects also completed mood questionnaires. Amphetamine produced its expected subjective, mood-altering effects, including increases in POMS Friendliness and Elation scales, and ARCI Euphoria and Stimulant scales. On the measures of impulsivity, amphetamine decreased impulsive responding on three of the tasks: on the Stop Task it decreased Stop reaction times without affecting Go reaction time, on the Go/No-Go task, it decreased the number of false alarms, and on the delay discounting measure, amphetamine (20 mg) decreased k values indicating less discounting of delayed reward. Other measures of impulsive behavior were unaffected. These results suggest that acute doses of amphetamine decrease several forms of impulsive behavior. These findings extend and confirm previous findings in humans and laboratory animals.     

Acute hydrocortisone administration does not affect subjective responses to d-amphetamine in humans

RATIONALE: Stress and glucocorticoids facilitate and reinstate psychostimulant self-administration in rodents. However, the effects of stress and glucocorticoids on the subjective and behavioral effects of psychostimulants have not been well studied in humans. OBJECTIVES: To examine the effects of acute hydrocortisone pretreatment on the subjective and behavioral effects of d-amphetamine. METHODS: Hydrocortisone (100 mg) and d-amphetamine (20 mg) were administered orally to 16 healthy male and female volunteers in a four-session, placebo-controlled, within-subject, crossover design. To prevent stomach irritation, subjects received rantidine hydrochloride before each experimental session. Dependent measures included self-reported mood and subjective effects (Addiction Research Center inventory, the profile of mood states, and a series of visual analogue scales), vital signs, salivary cortisol, and psychomotor performance. RESULTS: Hydrocortisone elevated salivary cortisol levels, produced modest dysphoria, and reduced subjects' reports of wanting more drug. However, hydrocortisone pretreatment did not affect any of the physiological, behavioral, or subjective effects of d-amphetamine. CONCLUSIONS: In contrast to the effects of glucocorticoids in rodent studies, these results indicate that an acute increase in cortisol does not enhance the psychostimulant effects of d-amphetamine in humans.     

Behavioral and subjective effects of d-amphetamine and modafinil in healthy adults

Modafinil is indicated for the management of excessive daytime sleepiness; however, recent studies have examined a broad range of potential uses. Given that clinical uses of modafinil may be expanding, this study compared modafinil and d-amphetamine effects on subjective and performance measures. Across 11 sessions, 11 healthy adults were tested after oral doses of placebo (5 sessions), modafinil (1.75 mg/kg, 3.50 mg/kg, or 7.00 mg/kg), and d-amphetamine (0.035 mg/kg, 0.070 mg/kg, 0.140 mg/kg) under double-blind, randomized conditions. Assessments of cognitive performance and subjective effects were completed before drug administration, 30 min after drug administration, and at hourly intervals after drug administration for 5 hr. Modafinil increased ratings on the Amphetamine and Morphine Benzedrine Group scales of the Addiction Research Center Inventory (ARCI) and increased ratings on the Vigor and Total Positive scales of the Profile of Mood States. d-Amphetamine increased visual analog ratings of feeling stimulated and liking the drug and increased ratings on the Morphine Benzedrine Group scale of the ARCI. Both medications significantly reduced visual analog scale ratings of feeling sleepy, and modafinil decreased ratings on the ARCI Pentobarbital-Chlorpromazine-Alcohol Group scale. Both medications sustained performance that deteriorated across time on the Sternberg Number Recognition Test. Modafinil also enhanced performance rate on the Digit-Symbol Substitution Task above baseline levels and increased response rate on the Repeated Acquisition of Response Sequences Task. These results suggest that modafinil engenders alerting effects and increases performance in healthy non-sleep-deprived individuals comparable with that of d-amphetamine.     

Effects of naltrexone on the subjective response to amphetamine in healthy volunteers

While dopaminergic mechanisms in amphetamine-taking behavior have been extensively studied, the contribution of the endogenous opioid system is less clear. We assessed the effects of an opioid antagonist, naltrexone (50 mg), on the subjective response to an oral dose of dexamphetamine (30 mg) in 12 healthy volunteers in a double-blind, placebo-controlled design. Volunteers received a total of 4 combinations of the study preparation (placebo-naltrexone, placebo-amphetamine) over 4 occasions with 1-week intervals. The primary objective of the study was to evaluate the effect of pretreatment with naltrexone on the subjective response to amphetamine. This was measured using a Visual Analog Scale, assessing the subjective effects over 7 hours. The secondary objective was to measure the effects of naltrexone on behavioral and physiologic responses to amphetamine. This was measured by blood pressure, heart rate, skin conductance, and speed of reading at the end of each session. Amphetamine produced significant effects on subjective arousal when compared to placebo after 1 hour (P < 0.001) and continued to be evident until 7 hours. Pretreatment with naltrexone significantly attenuated the subjective effects of amphetamine (P < 0.05), and this effect was time-dependent with a reduction from the 3-hour time point. Naltrexone did not influence the behavioral and physiologic effects of amphetamine in this sample. The results provide preliminary evidence that naltrexone may reduce the reinforcing effects of amphetamine via modulation of the opioid system. The potential of naltrexone as an adjunct pharmaceutical for the treatment of amphetamine dependence is promising and needs to be investigated further.     

Effects of d-amphetamine and haloperidol on latent inhibition in healthy male volunteers

Latent inhibition (LI) refers to a retardation of learning about the consequences of a stimulus when that stimulus has been passively presented a number of times without reinforcement. Acute positive-symptom schizophrenics, normal volunteers who score high on questionnaire measures of schizotypy and non-patients or animals treated with dopamine agonists show reduced LI. Neuroleptic drugs, such as haloperidol, administered at low doses, potentiate LI and effectively reverse disruption of LI induced by dopamine agonists in animals. However, a high dose of haloperidol, administered on its own, has been found to reduce LI. We examined the effects on LI of acute oral administration of an indirect dopamine-agonist, d-amphetamine (5 mg), and a nonselective dopamine receptor antagonist, haloperidol (5 mg), in normal male volunteers, using an associative learning task. Replicating previous reports, we found that d-amphetamine reduced LI; haloperidol also reduced LI, but only in subjects who scored low on the Psychoticism scale of the Eysenck Personality Questionnaire. In a subsequent study, no effect was found of 2 mg oral haloperidol administration on LI. The effect of 5 mg haloperidol on LI is interpreted as similar to that observed with a high dose of haloperidol in rats.     

Subjective and behavioral responses to intravenous fentanyl in healthy volunteers

Fentanyl is a mu opiate agonist which is occasionally abused by medical personnel who have ready access to the drug. We examined in healthy volunteers (N=13) the subjective and psychomotor-impairing effects of intravenous fentanyl (0–100 µg/70 kg). A randomized, placebo-controlled, crossover design was used in which subjects were injected with 0, 25 (N=6), 50 and 100 µg/70 kg fentanyl in a double-blind fashion. Subjects completed several questionnaires commonly used in abuse liability testing studies before drug injection and at periodic intervals for up to 3 h after drug injection. Subjects also completed several psychomotor tests at these times. Some aspects of psychomotor functioning (e.g., eye-hand coordination) were impaired by fentanyl. Fentanyl produced dose-related increases in ratings of high and sedated, but also tended to produce dysphoria and somatic symptomatology. Most subjects reported liking the effects of the two higher doses of fentanyl for at least a brief time after injection, but they varied widely in their liking ratings across the 3-h post-drug injection period. Despite the transient increases in liking ratings, fentanyl did not increase scores on a widely-used measure of drug-induced euphoria (morphine-benzedrine group scale of the Addiction Research Center Inventory). The present results suggest that some medical personnel who experiment with fentanyl may like it, and thus be at increased risk for abusing the drug in the future.     

Lack of sex differences to the subjective effects of nitrous oxide in healthy volunteers

Background

Although numerous studies have assessed subjective effects of nitrous oxide, few studies have analyzed for sex differences. Since sex differences have been reported in subjective effects of several drugs such as opioids, nicotine and alcohol, we sought to determine if sex modulates the subjective effects of the inhalant, nitrous oxide, in healthy volunteers.

Methods

Thirty-eight females and seventy-two males from nine studies that were conducted in our laboratory were included in this retrospective analysis. All experimental studies utilized randomized, placebo-controlled, repeated measures designs in which subjects inhaled 30% nitrous oxide in oxygen and 100% oxygen (placebo). Dependent measures in this analysis were subjective effects measured at baseline and 15 min into the inhalation period.

Results

Nitrous oxide produced a number of subjective effects, including those that could be considered abuse liability-related (“elated,” “having pleasant thoughts,” drug liking), but sex did not modulate these effects.

Conclusions

Females and males showed similar subjective responses to 30% nitrous oxide. Future prospective studies might assess other concentrations, other measures (choice, analgesic response), and other inhaled general anesthetics to more comprehensively characterize the role of sex in response to inhalants.     

Effects of fasting on responses to intravenous fentanyl in healthy volunteers

The effects of food deprivation on the subjective, psychomotor, and physiological responses to intravenous fentanyl (50 μg/70 kg) were studied in 6 healthy male volunteers. A randomized, placebo-controlled, crossover design was used in which subjects were injected with fentanyl or saline after either 2, 12, or 24 hours of fasting. Subjects completed several subjective effects questionnaires as well as psychomotor tasks prior to, and at regular intervals, following the intravenous injection for a 3-hour period. An observer-rated behavioral checklist was completed at regular intervals during the session and several physiological measures (including measurement of pupil size) were recorded. Fentanyl induced opiate-like mood changes, miosis (pupil constriction), and impairment of extraocular muscle control, and 4 of the 6 subjects reported liking the effects; however, fasting had no impact on any of fentanyl's effects. We conclude that food deprivation up to 24 hours does not alter the subjective, psychomotor, or physiological response to the opiate, fentanyl.     

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.     

Amnesic effects and subjective ratings during repeated dosing of flunitrazepam to healthy volunteers

Summary Flunitrazepam (1 mg) or placebo was administered once daily over a treatment period of 8 days to healthy, male volunteers to study the time course of the effects on memory functions and on subjective ratings of alertness and tension. The plasma level of flunitrazepam increased by approximately 40% (P<0.05) during the treatment period. The mean pre-dose level of flunitrazepam on day 4 and day 8 was approximately 0.005 M, and no residual effects on memory functions were observed. Intake of flunitrazepam decreased the number of freely recalled words by about 85% (P<0.05) and significantly affected the subjects' rating of attention when tested during the first few hours after drug intake on day 1 of treatment. However, no significant effect on the subjects' rating of relaxation was observed. When tested similarly after 8 days treatment, flunitrazepam significantly affected the subjects' rating of relaxation (P<0.01). Furthermore, no tolerance developed for the effect of flunitrazepam on free recall (P>0.3) and the subjects' rating of attention (P>0.7), and these effects had nearly equal time courses during the treatment period. This may indicate that the amnesic effect of benzodiazepines is at least partially mediated through the effects on attention or general arousal. Two of the subjects in the active drug group reported adverse reactions or incidents of discomfort during the 1st week following the treatment period, whereas none in the placebo group reported such reactions.     

Cardiovascular responses to metipranolol and timolol eyedrops in healthy volunteers.

1. Intraocular pressure and cardiovascular responses to metipranolol 0.1% and 0.3% and timolol 0.25% eyedrops were measured in a balanced single dose placebo-controlled crossover study in eight healthy volunteers aged 34-58 years. 2. Timolol 0.25% and metipranolol 0.3% reduced intraocular pressure throughout the 6 h period of observation to a similar extent. Metipranolol 0.1% was marginally less effective, significantly reducing pressure up to 4 h only. 3. No drug treatment significantly altered resting heart rate or blood pressure. Timolol 0.25% significantly reduced exercise tachycardia (P less than 0.05), an effect which was not shown by metipranolol 0.1 or 0.3%. Exertional pain in the legs occurred more frequently after timolol 0.25% and metipranolol 0.3% than after metipranolol 0.1% or placebo eyedrops. 4. Octan-1-ol/pH 7.4 buffer distribution coefficients at 37 degrees C were found to be: metipranolol 5.19, timolol 0.84, indicating that metipranolol has an approximately 6-fold greater lipid solubility. 5. It is concluded that, by comparison with timolol, metipranolol in eyedrop concentrations up to 0.3%, despite its greater lipid solubility, reaches concentrations in the systemic circulation which are less likely to affect the heart.     

Personality and the subjective effects of acute amphetamine in healthy volunteers.

Individual differences in the positive mood and other subjective effects of d-amphetamine have been linked to personality traits related to sensation seeking. The current study extends these associations to separate personality traits of reward sensitivity, physical fearlessness, and impulsivity. A total of 128 healthy volunteers received oral doses of d-amphetamine (10 and 20 mg) or placebo in counterbalanced order. Their responses to the drug were measured using the Profile of Mood States, Addiction Research Center Inventory, and Drug Effects Questionnaire. Participants completed the Multidimensional Personality Questionnaire Brief Form to assess personality traits related to reward sensitivity (Agentic Positive Emotionality and Social Potency (SP)), physical fear (Harm Avoidance (HA)), and impulsivity (Control (CL)). Participants were rank ordered on each trait, and individuals with scores in the top and bottom thirds of scores on each trait were compared using ANCOVA. High trait physical fearlessness (low HA) was associated with greater positive activational effects of 10 mg d-amphetamine. High trait reward sensitivity (high SP) was marginally associated with greater positive activational effects of 20 mg d-amphetamine. High trait impulsivity (low CL) was unrelated to positive drug effects in response either dose. The two separate personality traits of physical fearlessness and reward sensitivity are associated with d-amphetamine effects on mood in healthy volunteers. Implications for the vulnerability to psychostimulant addiction in healthy nonaddicts are discussed.     

Subjective,behavioral and physiological responses to intravenous meperidine in healthy volunteers

Meperidine is a mu opiate agonist that is frequently used to treat pain. We examined in healthy volunteers (N=10) the effects of intravenous meperidine (0, 0.25, 0.5, and 1.0 mg/kg) on mood and psychomotor performance. A randomized, placebo-controlled, crossover design was used in which subjects were injected with meperidine or saline in a double-blind fashion. Subjects completed several subjective effects questionnaires commonly used in abuse liability testing studies before drug injection and at periodic intervals for up to 5 h after drug injection. Subjects also completed several psychomotor tests. Meperidine produced a constellation of subjective effects in a dose-related fashion, including increases in ratings of “sedated,” “coasting or spaced out” and “feel drug effect” ratings. Many of the drug's subjective effects persisted up to 4 or 5 h after administration of the 1.0 mg/kg dose. Drug liking ratings assessed on a visual analog scale were increased after meperidine injection in about half of the subjects (P=0.09). Eye-hand coordination was affected slightly by meperidine but other indices of psychomotor functioning were unaffected. Miosis increased in a dose-related fashion. Other physiological parameters, such as vital signs, were not affected by meperidine. We conclude that meperidine in healthy volunteers has robust and long-lasting effects on mood, but may have weaker effects on psychomotor performance.     

Effect of pindolol on endocrine and temperature responses to buspirone in healthy volunteers

Ten healthy subjects received buspirone (30 mg orally) with and without pre-treatment with the 5-HT1A receptor antagonist, pindolol (80 mg over 3 days). Following pindolol treatment the growth hormone and hypothermic responses to buspirone were significantly decreased. There was also a delay in the onset of the prolactin response to buspirone but the total amount of prolactin secretion, calculated as area under the curve, was not significantly reduced. The data suggest that the growth hormone and hypothermic responses to buspirone in humans are mediated by 5-HT1A receptors, but an explanation founded on pharmacokinetic factors cannot presently be excluded. Both this latter possibility and the lack of selectivity of pindolol for 5-HT receptors indicate the need for the further neuroendocrine studies of the mode of action of buspirone, preferably with more selective 5-HT1A receptor antagonists.     

Effects of labetalol and propranolol on responses to adrenaline infusion in healthy volunteers

The effects of labetalol and propranolol were compared in eight healthy human volunteers using pulse rate and blood pressure changes in response to low rates of adrenaline infusion. Propranolol not only blocked but reversed the positive chronotropic and vasodepressor effects of adrenaline. Labetalol appeared to block these effects only partially. The alpha blocking property of labetalol may have contributed to this difference and hence is unlikely to cause alpha receptor mediated side-effects of endogenously released adrenaline in stress. This model is able to differentiate with great sensitivity between pure beta blockers and alpha beta blocking agents.     

Memantine produces modest reductions in heroin-induced subjective responses in human research volunteers

Rationale Previous studies have demonstrated an interaction between opioids and noncompetitive antagonists at N-methyl-d-aspartate (NMDA) receptors, but few studies have examined the utility of these medications for treating opioid dependence. Objective In this 8-week inpatient study, participants were maintained on the low-affinity, noncompetitive NMDA receptor antagonist memantine (0, 30, and 60 mg per day, PO) and under each maintenance dose condition, the effects of intranasal heroin (0, 12.5, and 50 mg, IN) were examined. Methods During the first week after admission to the hospital, participants were detoxified from heroin. All of the volunteers received all of the memantine and heroin dose combinations. Participants (N = 8) first sampled a dose of heroin and $20. During a subsequent choice session, participants could self-administer heroin and/or money. Responses, which consisted of finger presses on a computer mouse, were made under a modified progressive ratio schedule (PR 50, 100, 200, 400, 800, 1,200, 1,600, 2,000, 2,400, and 2,800) during a ten-trial self-administration task. Subjective, performance, and physiological effects were measured repeatedly during laboratory sessions. Results Memantine produced modest reductions in subjective ratings of drug quality, liking, willingness to pay for the drug, and craving for heroin. However, memantine produced few changes in the reinforcing effects of heroin. Conclusions These data demonstrate that memantine was well tolerated and modestly effective in reducing the subjective but not the reinforcing effects of heroin. Although it is unlikely that memantine will be useful as a stand-alone maintenance medication for opioid dependence, it may have some utility as an adjunct treatment medication.