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Biomedical subjects

R R Griffiths

Publications and source records attributed to R R Griffiths.

At least 73 records · Page 4Linked to original sources
PubMed1995

Abecarnil and alprazolam in humans: behavioral, subjective and reinforcing effects.

Abecarnil, a novel beta-carboline, is under development for the treatment of Generalized Anxiety Disorder. This study compared the behavioral, subjective and reinforcing effects of abecarnil to those of the benzodiazepine alprazolam in 14 healthy males with histories of sedative drug abuse. Placebo, abecarnil (10, 20, 40 mg) and alprazolam (1.0, 2.0, 4.0 mg) were administered p.o. in a double-blind, cross-over design. Abecarnil and alprazolam produced comparable dose-dependent decreases in behavioral performance on balance, circular lights, digit-recall and digit-symbol-substitution tasks that peaked 2-4 hr after drug administration. Both drugs produced a profile of sedative effects and were categorized by subjects as predominantly barbiturate- or benzodiazepine-like. However, the high dose of alprazolam increased subject-ratings of sleepy, fatigued and tired; these ratings were significantly different from both placebo and all doses of abecarnil. Abecarnil and alprazolam produced comparable dose-dependent increases in ratings of drug strength. The highest dose of alprazolam produced increases in Next Day ratings of drug liking, good effects, monetary value of the drug, and desire to take the drug again that were significantly greater than placebo and the highest dose of abecarnil. Abecarnil, but not alprazolam, produced increases in Next Day ratings of "bad effects" that were significantly greater than placebo. The highest dose of alprazolam produced increases in a direct measure of drug reinforcement (drug vs. money Multiple-Choice Procedure) that were significantly greater than placebo and all doses of abecarnil. Collectively, these data suggest that abecarnil may have less potential for abuse than alprazolam in a sedative-abusing population.

Adult↗
PubMed1994

Caffeine dependence syndrome. Evidence from case histories and experimental evaluations.

OBJECTIVE: The extent to which daily caffeine use is associated with a substance dependence syndrome similar to that associated with other psychoactive drugs is unknown. The purpose of this study was to assess volunteers who reported problems with their use of caffeine for evidence suggesting a diagnosis of caffeine dependence based on the generic criteria for substance dependence from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). DESIGN: Case-series evaluations. SETTING: An academic research center. PARTICIPANTS: Self-identified adults who believed they were psychologically or physically dependent on caffeine. MAIN OUTCOME MEASURE: Diagnoses made by a psychiatrist using a structured clinical interview that included a section on caffeine dependence based on genetic criteria for DSM-IV substance dependence. SECONDARY OUTCOME MEASURE: Double-blind caffeine-withdrawal evaluation. RESULTS: Ninety-nine subjects were screened for the study, and 16 were identified as having a diagnosis of caffeine dependence. Median daily caffeine intake was 357 mg, and 19% of subjects consumed less than the national (US) daily average of caffeine. Criteria used for making diagnoses (and rates of their prevalence) were as follows: withdrawal (94%), use continued despite knowledge of a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by caffeine use (94%), persistent desire or unsuccessful efforts to cut down or control use (81%), and tolerance (75%). Eleven subjects underwent the double-blind caffeine-withdrawal evaluation portion of the study, and nine (82%) of the 11 showed objective evidence of caffeine withdrawal, including eight of 11 with functional impairment. CONCLUSIONS: These results, together with other experimental evidence, suggest that caffeine exhibits the features of a typical psychoactive substance of dependence. It is valuable to recognize caffeine dependence as a clinical syndrome, since some people feel compelled to continue caffeine use despite desires and recommendations to the contrary.

Adult↗
PubMed1994

Discriminative stimulus and subjective effects of theobromine and caffeine in humans.

Theobromine versus placebo discrimination and caffeine versus placebo discrimination were studied in two consecutive experiments in seven volunteers who abstained from methylxanthines. Daily sessions involved PO double-blind ingestion of two sets of capsules sequentially, one of which contained drug and the other placebo. Subjects attempted to identify, and were later informed, which set of capsules contained the drug. In each experiment subjects were exposed to progressively lower doses. Five subjects acquired the theobromine discrimination; the lowest dose discriminated ranged from 100 to 560 mg. All seven subjects acquired the caffeine discrimination; the lowest dose discriminated ranged from 1.8 to 178 mg. A final experiment evaluated subjective effect ratings following 560 mg theobromine, 178 mg caffeine and placebo, which were administered double-blind in capsules once daily, five times each in mixed sequence. Caffeine produced changes in both group and individual ratings (e.g. increased well-being, energy, social disposition and alert). Theobromine did not produce changes in group ratings but changed ratings in some subjects. Across subjects, sensitivity to caffeine discriminative effects in the discrimination experiment correlated significantly with the number and magnitude of caffeine subjective effects in the final experiment. This study documents modest discriminative effects of theobromine in humans, but the basis of the discrimination is unclear. This study suggests that commonly consumed cocoa products contain behaviorally active doses of caffeine and possibly theobromine.

Adult↗
PubMed1994

Modulation of drug reinforcement by behavioral requirements following drug ingestion.

Eight volunteers with histories of drug abuse participated in two experiments examining the modulation of drug choice by behavioral requirements following drug ingestion. Each morning subjects ingested color-coded capsules containing triazolam (0.25 mg), d-amphetamine (15 mg), or placebo and then engaged in a relaxation or a computer vigilance activity. Experiment 1 involved two phases (i.e. a triazolam and a d-amphetamine phase), presented in counterbalanced order. Within each phase, subjects were first exposed to each of two compounds (placebo and either triazolam or d-amphetamine) once with each activity. Then every other day for 20 days subjects chose which compound they ingested with the vigilance and relaxation activities, with the restriction that they could not choose the same compound with both activities. Seven of eight subjects reliably chose d-amphetamine with the vigilance activity; all subjects always chose triazolam with the relaxation activity. In experiment 2 (5 days' duration), after re-exposure to the color-coded compounds used in experiment 1, subjects chose which compound (placebo, d-amphetamine or triazolam) they ingested with the vigilance activity, and on another occasion (in counterbalanced order), which they ingested with relaxation activity. Seven of eight subjects chose d-amphetamine with the vigilance activity; all subjects chose triazolam with the relaxation activity. The relaxation and vigilance activities modulated triazolam and d-amphetamine reinforcement, thereby demonstrating a new class of environmental variable that can influence drug self-administration.

Adult↗
PubMed1994

Enhancing caffeine reinforcement by behavioral requirements following drug ingestion.

Each morning eight adults with caffeine versus placebo discrimination histories ingested letter-coded capsules containing 100 mg caffeine or placebo and then engaged in a relaxation or vigilance activity. Subjects were first exposed to caffeine and placebo once each with each activity. Then each day for 10 days subjects made two choices; they chose which compound they would prefer if vigilance were scheduled and which they would prefer if relaxation were scheduled, with the restriction that they could not choose the same compound with both activities; only one choice (randomly selected) was reinforced. Eight of eight subjects always chose caffeine with vigilance. The next choice condition was identical, except that subjects were free to take either compound with both activities. Six of six subjects reliably chose caffeine with vigilance. Four reliably chose placebo with relaxation. In the final condition, each day for 10 days subjects chose between each drug and each of 52 monetary values; those choices were made separately for vigilance and relaxation; only one choice (randomly selected) was reinforced. For six of seven subjects, the maximum dollar value at which subjects chose drug over money was higher for caffeine in vigilance than for placebo in either activity. For five subjects, the maximum value at which subjects chose caffeine over money was higher in vigilance than in relaxation. Overall, this study demonstrates enhanced caffeine reinforcement when a vigilance activity followed drug ingestion.

Adult↗
PubMed1994

Intravenous self-injection of methcathinone in the baboon.

Methcathinone is a phenylisopropylamine that has been produced by clandestine laboratories and identified in illicit drug traffic. The present study evaluated the intravenous self-administration of methcathinone in three baboons using a cocaine substitution procedure. Intravenous self-injections were available 24 h/day according to a fixed-ratio (FR) schedule with a 3-h timeout following each injection. Doses of racemic methcathinone HCl (0.01-1.0 mg/kg/injection) and its vehicle were substituted for cocaine for 15 or more days. A concurrent FR schedule of food pellet delivery allowed evaluation of any changes in food intake. Self-injection of methcathinone was dose dependent. The lower doses of methcathinone, 0.01 and 0.032, maintained low and intermediate rates of self-injection, respectively, while the higher doses, 0.1, 0.32, and 1.0, maintained rates above vehicle control and comparable to those maintained by cocaine. Acute administration of 3.2 mg/kg to two baboons produced signs of psychomotor stimulant toxicity. Systematic changes in food intake were not observed. The present data indicate that methcathinone functions as a positive reinforcer in baboons and suggests that methcathinone may have abuse potential.

Animals↗
PubMed1994

A procedure for studying the within-session onset of human drug discrimination.

The purpose of the present study was to develop a procedure for measuring the within-session onset of human drug discrimination. During daily sessions, under double-blind conditions, caffeine-abstinent adults ingested a letter-coded capsule containing 178 mg caffeine or placebo. Trials were presented at 30-s intervals, beginning immediately after drug ingestion and continuing for 60 min. On each trial, subjects could guess which of their two letter-coded drugs they had received by pressing a left button (for one drug) or right button (for the other drug); subjects could also press a center "no guess" button instead of guessing. Each trial ended after one button press. After each session, subjects were told which drug they had received. Subjects earned one point (worth $0.10 per point) for each correct guess. Subjects lost either 0, 1, or 10 points for each incorrect guess; the point-loss contingencies were varied in random order across sessions. Discrimination earnings accumulated across all sessions. The point-loss contingencies decreased random responding and delayed the discrimination time course. Overall, this procedure provided an orderly and relatively continuous measure of the within-session onset of drug discrimination and should have a range of applications in understanding the human behavioral pharmacology of drugs.

Caffeine↗
PubMed1994

Tandospirone and alprazolam: comparison of behavioral effects and abuse liability in humans.

Tandospirone is a novel nonbenzodiazepine anxiolytic/antidepressant that acts primarily at the serotonin-1A receptor. In the present study, the behavioral effects and abuse liability of tandospirone were characterized relative to those of the benzodiazepine, alprazolam. In an outpatient setting, the acute effects of placebo, tandospirone citrate (40, 80 and 160 mg) and alprazolam (0.5, 1.0 and 2.0 mg) were assessed with a double-blind, cross-over design in 14 male volunteers with histories of sedative drug abuse. Drug effects were assessed on behavioral performance tasks; observer ratings of drug effect; and subject ratings of strength of drug effect, mood and drug liking. Both alprazolam and tandospirone produced comparable dose-related increases in subject- and observer-rated strength of drug effect. The peak drug effect occurred approximately 2 hr after drug administration; the time to peak did not differ between the two drugs. Alprazolam produced greater impairments on psychomotor performance than did tandospirone. Alprazolam produced dose-related increases in subject-rated drug liking; tandospirone, in contrast, produced dose-related increases in subject-rated drug disliking. The highest dose of alprazolam was predominantly classified by subjects as being a benzodiazepine or a barbiturate (71%) in contrast to the highest dose of tandospirone (29%). Across subjects, tandospirone plasma concentrations after a single dose of 160 mg were significantly correlated with several subjective and behavioral measures. The present study demonstrates that tandospirone and alprazolam can be clearly differentiated on the basis of subjective effects and performance measures. The overall profile indicates that tandospirone has a significantly lower abuse liability than does alprazolam.

Adult↗
PubMed1993

Drug discrimination analysis of endogenous neuroactive steroids in rats.

Rats were trained in a two-lever procedure to discriminate either pentobarbital (10 mg/kg), ethanol (1.5 g/kg), diazepam (1 mg/kg), or lorazepam (1 mg/kg) from the no-drug condition. Consistent with previous reports, rats in the pentobarbital, ethanol, and diazepam training conditions all showed complete dose-dependent generalization to pentobarbital under test conditions, but rats trained to discriminate lorazepam did not. Administration of the neuroactive steroids 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-THDOC) and 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha,5 alpha-P) also produced complete generalization in rats trained to discriminate pentobarbital, ethanol, and diazepam, but not in rats trained to discriminate lorazepam. These results further indicate the specificity of the lorazepam training condition and are consistent with neurochemical data indicating that these neuroactive steroids are similar to barbiturates in modulating gamma-aminobutyric acid (GABA)A receptors. In the context of previous data, the results from the four training groups suggest that the discriminative-stimulus effects of the neuroactive steroids are sedative/anxiolytic in nature and probably mediated through a non-benzodiazepine GABAA site.

Animals↗
PubMed1993

Differential sensitivity to midazolam discriminative-stimulus effects following self-administered versus response-independent midazolam.

Interactions between the discriminative and reinforcing effects of midazolam were studied in two baboons trained to discriminate midazolam (0.32 mg/kg, IV) from saline. The midazolam generalization gradient determined after the baboons were permitted to self-administer midazolam (IV) was shifted to the left of that determined before self-administration. In contrast, the midazolam generalization gradient determined after the same doses of midazolam were delivered response-independently, but in the same order and with the same temporal pattern as during self-administration, was shifted to the right of that determined just before the response-independent phase. These data suggest that sensitivity to the discriminative-stimulus effects of a drug can be modulated by behavioral experience with that drug.

Animals↗
PubMed1993

Behavioral pharmacology of tandospirone in baboons: chronic administration and withdrawal, self-injection and drug discrimination.

The behavioral pharmacology of tandospirone (SM 3997), a novel anxiolytic/antidepressant pyrimidinylpiperazine compound with selective pharmacological effects at the 5-HT1A binding site, was investigated in baboons. Animals administered 50 mg/kg/day i.g. tandospirone, showed few behavioral changes (lip droop, ataxia), which decreased over 2 weeks. Substitution of vehicle for tandospirone after 7 weeks produced time-limited suppression of food intake, suggesting a mild withdrawal syndrome. Under an i.v. self-injection procedure, tandospirone (1.0-32 mg/kg/injection) did not maintain responding greater than vehicle, although cocaine and triazolam did. Under a drug discrimination procedure, tandospirone (1-3.2 mg/kg p.o.; 0.1-32 mg/kg, i.m.) did not occasion drug-appropriate responding in baboons trained to discriminate lorazepam or pentobarbital and buspirone (1-18 mg/kg, p.o.; 0.1-1.0 mg/kg, i.m.) did not occasion drug-appropriate responding in the pentobarbital-training group. Tandospirone's profile of effects differs from those for barbiturates and benzodiazepines and suggests low abuse liability.

Animals↗
PubMed1993

Benzodiazepine and sedative use/abuse by methadone maintenance clients.

Clients at three geographically separate methadone maintenance clinics were surveyed regarding their lifetime use of ten commonly used benzodiazepines and barbiturates. In Baltimore (n = 50), 94% reported use of one or more of these drugs in their lifetime, with 66% reporting use in the last 6 months. In Philadelphia (n = 218), 78% reported use in their lifetime, with 53% reporting use in the last 6 months. In New York City (The Bronx) (n = 279), 86% reported use in their lifetime, with 44% reporting use in the last 6 months. Subjects reporting a history of use of at least 7 of 10 of the named sedatives were recruited for a more detailed interview. They reported that, among the benzodiazepines, diazepam, lorazepam, and alprazolam were frequently used for their 'high' producing effects, and for selling to produce income. In contrast, chlordiazepoxide, oxazepam, and phenobarbital, had much lower ratings of 'high' and were much less likely to be obtained for getting 'high' or for resale.

Alprazolam↗
PubMed1993

Alprazolam and benzodiazepine dependence.

The incidence of nonmedical use of alprazolam is very low relative to its widespread legitimate medical use; in fact, given the millions of patients who have received this medication, the incidence is remarkably small. In particular, among patients with anxiety disorders, dependence does not appear to be a clinically important problem. Alprazolam abuse and dependence represent only a small fraction of the large and serious nonmedical use problem in the United States, and when they occur, are among individuals who abuse other drugs. For example, a serious problem of alprazolam abuse may exist among patients in methadone maintenance treatment. A similar problem exists with diazepam. Alcohol abusers and alcohol-dependent individuals are another group among whom concern about benzodiazepine and alprazolam abuse exists. However, more and better information about the extent and nature of this use is needed. Many patients with alcohol or drug abuse also have anxiety disorders for whom effective pharmacotherapy may be needed. In the interim, caution but not prohibition to use should prevail in prescribing alprazolam to such patients. To the extent that nonmedical alprazolam use exists, evidence suggests that the vast majority of such use is the consequence of the inappropriate prescribing of the medication by a small number of physicians. One way to reduce the inappropriate use of benzodiazepines in methadone programs is to drug test the methadone-maintenance patients and to link positive urine tests to contingency-management strategies. The available data provide some support to the idea that alprazolam and diazepam have more abuse liability than other benzodiazepines.

Adult↗
PubMed1993

Behavioral effects of pentobarbital, lorazepam, ethanol and chlorpromazine substitution in pentobarbital-dependent baboons.

Baboons were given continuous intragastric infusions of 100 mg/kg/day of pentobarbital before and during these experiments. The baboons responded under a fixed-ratio (FR) 30-response schedule of food presentation from 10:00 A.M. of one day to 8:00 A.M. of the next day. Terminating pentobarbital administration (i.e., substituting water for pentobarbital) from 8:00 A.M. of one day to 8:00 A.M. of the next day produced large decreases in the number of pellets earned. Repeated 24-h terminations of pentobarbital administration at 1-week intervals produced similar decreases in the pellets earned. In another experiment, the effects of terminating pentobarbital administration for several days were examined. The number of pellets earned decreased within 2 h of terminating pentobarbital administration was maximally suppressed during the first day, and recovered over 3 to 5 days. When different doses of pentobarbital were substituted for 24 h, the disruption of responding seen after pentobarbital termination was attenuated in a dose-dependent manner. In another experiment, the effects of substituting lorazepam, ethanol or chlorpromazine for pentobarbital for 24 h were examined. Lorazepam produced a dose-dependent attenuation of the effects of pentobarbital termination, whereas ethanol did not. Chlorpromazine did not attenuate the effects of pentobarbital termination in two of the three baboons tested, and produced erratic results in the third.

Animals↗
PubMed1993

Intravenous flumazenil following acute and repeated exposure to lorazepam in healthy volunteers: antagonism and precipitated withdrawal.

The effects of i.v. administered flumazenil (3.0 mg) were studied in healthy male subjects who received pretreatment with p.o. placebo or lorazepam. The duration of placebo or lorazepam (3.0 mg single p.o. daily dose) pretreatment before a flumazenil or placebo injection was 1, 3, 7 or 14 days in four sequential groups of subjects. Initial administration of lorazepam produced a classic sedative profile of effects on various psychomotor/behavioral performance, observer-rated and subject-rated measures. Tolerance to repeated daily administration of lorazepam was suggested by a progressive diminution of performance disrupting effects. In subjects pretreated with placebo, flumazenil increased subject-ratings of dizziness over preinjection ratings. Flumazenil produced an immediate reversal of lorazepam effects in subjects who were not tolerant to lorazepam (1- and 3-day pretreatment groups). Flumazenil did not precipitate withdrawal symptoms in subjects who received a single administration of lorazepam. Precipitated withdrawal symptoms were evident after 3 and 7 days of lorazepam pretreatment, and there was a tendency toward precipitated withdrawal symptoms (that included one panic attack) after 14 days of lorazepam pretreatment. Precipitated withdrawal was characterized by an elevation in subject-rated symptoms including dizziness, tenseness, tachycardia, perceptual disturbance and sweating. Symptoms were maximal immediately after injection, usually mild in severity and usually resolved within 1 hr. There was no evidence of precipitated withdrawal on psychomotor/behavioral performance or observer ratings. The present study provides the strongest human experimental evidence to date that flumazenil can precipitate withdrawal symptoms after a history of repeated benzodiazepine exposure.

Adolescent↗
PubMed1992

Withdrawal syndrome after the double-blind cessation of caffeine consumption.

BACKGROUND: People who stop consuming caffeine may have symptoms, but the incidence and severity of caffeine withdrawal are not known. This study was performed to determine the effects in the general population of ending one's dietary intake of caffeine. METHODS: We studied 62 normal adults whose intake of caffeine was low to moderate (mean amount, 235 mg--the equivalent of 2.5 cups of coffee--per day). They completed questionnaires about symptoms and tests of their mood and performance when consuming their normal diets (base-line period) and at the end of each of two two-day periods during which they consumed caffeine-free diets and under double-blind conditions received capsules containing placebo (placebo period) or caffeine (caffeine period) in amounts equal to their daily caffeine consumption. RESULTS: More subjects had abnormally high Beck Depression Inventory scores (11 percent), high scores on the trait scale of the State-Trait Anxiety Inventory (8 percent), low vigor scores (11 percent) and high fatigue scores (8 percent) on the Profile of Mood States, and moderate or severe headache (52 percent) during the placebo period than during either the base-line period (2, 0, 0, 0, and 2 percent, respectively; P less than 0.05) or the caffeine period (3, 2, 2, 0, and 6 percent; P less than 0.05). More subjects reported unauthorized use of medications during the placebo period (13 percent) than during the caffeine period (2 percent, P = 0.017). Performance of a tapping task was slower during the placebo period than during the base-line and caffeine periods (P less than 0.01). CONCLUSIONS: Persons who consume low or moderate amounts of caffeine may have a withdrawal syndrome after their daily consumption of caffeine ceases.

Adult↗
PubMed1992

Oral self-administration of triazolam, diazepam and ethanol in the baboon: drug reinforcement and benzodiazepine physical dependence.

Reinforcing and physical dependence-producing effects of oral diazepam and triazolam (0.01-1.28 mg/ml) were studied in four non-water-deprived baboons in daily 2-3-h sessions. Drinking initially was food-induced, but subsequently it was maintained for greater than year without the inducing procedures; drug intake greater than 10 mg/kg per session was attained. Triazolam and diazepam reinforcement (compared to vehicle) was concluded for only one baboon for each drug under a single-spout procedure and for two baboons for each drug under a two-spout procedure. However, all baboons showed ethanol reinforcement under a two-spout procedure. When a lever-pressing requirement was imposed for each drink (one-spout procedure), ethanol maintained requirements of 128 or 256 responses/drink, and volume of ethanol consumed was greater than vehicle. Neither benzodiazepine maintained lever pressing better than vehicle at any response requirement and drinking was suppressed by requirements of 1-32. Physical dependence to triazolam and diazepam developed after approximately 1 month of daily ingestion, evidenced by a precipitated withdrawal syndrome after injection of the benzodiazepine antagonist flumazenil. A mild spontaneous withdrawal syndrome occurred after substitution of vehicle for triazolam or diazepam. These data indicate a clear dissociation between the reinforcing and physical dependence-producing effects of triazolam and diazepam.

Animals↗