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Biomedical subjects

R R Griffiths

Publications and source records attributed to R R Griffiths.

At least 127 records · Page 7Linked to original sources
PubMed1988

Caffeine physical dependence: a review of human and laboratory animal studies.

Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been poorly characterized in laboratory animals and only moderately well characterized in humans. In humans, a review of 37 clinical reports and experimental studies dating back to 1833 shows that headache and fatigue are the most frequent withdrawal symptoms, with a wide variety of other signs and symptoms occurring at lower frequency (e.g. anxiety, impaired psychomotor performance, nausea/vomiting and craving). When caffeine withdrawal occurs, severity can vary from mild to extreme (i.e. incapacitating). The withdrawal syndrome has an onset at 12-24 h, peak at 20-48 h, and duration of about 1 week. The pharmacological specificity of caffeine withdrawal has been established. The proportion of heavy caffeine users who will experience withdrawal symptoms has been estimated from experimental studies to range from 25% to 100%. Withdrawal symptoms have been documented after relatively short-term exposure to high doses of caffeine (i.e. 6-15 days of greater than or equal to 600 mg/day). Although animal and human studies suggest that physical dependence may potentiate the reinforcing effects of caffeine, human studies also demonstrate that a history of substantial caffeine intake is not a necessary condition for caffeine to function as a reinforcer. The similarities and differences between caffeine and classic drugs of abuse are discussed.

Animals↗
PubMed1988

Reinforcing properties of caffeine: studies in humans and laboratory animals.

Three types of experimental studies are reviewed: (1) intravenous and oral caffeine self-administration by laboratory animals, (2) oral caffeine self-administration by humans, and (3) human subjective effects of caffeine relevant to reinforcing effects. These studies show that, under appropriate conditions, caffeine can serve as a reinforcer and can produce elevations in subjective drug liking and/or euphoria. In this regard, caffeine can be distinguished from a wide range of behaviorally active compounds, such as the amphetamine analog fenfluramine and the major tranquilizer chlorpromazine, which do not produce such effects. Caffeine can also be distinguished from classic drugs of abuse such as cocaine, d-amphetamine or pentobarbital which generally maintain high levels of self-administration (or liking) in contrast to caffeine which tends to maintain lower levels of self-administration (or liking) or maintain self-administration under a more narrow range of parametric conditions. Several human studies and one animal experiment suggest that physical dependence substantially potentiates the reinforcing effects of caffeine. Other human and animal studies indicate that there may be substantial differences between individual subjects in the reinforcing effects of caffeine. An important challenge for future human and animal drug self-administration research will be to delineate more precisely the conditions under which caffeine does and does not serve reliably as a reinforcer.

Animals↗
PubMed1988

Relative abuse liability of lorazepam and diazepam: an evaluation in 'recreational' drug users.

The subjective, psychomotor and cognitive effects of oral doses of lorazepam (0, 1.5, 3 and 6 mg) and diazepam (0, 10, 20 and 40 mg) were studied under double-blind conditions in 14 volunteers with histories of 'recreational' benzodiazepine use/abuse. For each subject, drug was administered over 4 test days in a 2 (drug) by 4 (dose level) mixed design. Drug was the between-groups factor while dose was the within-subjects factor. Test days were separated by at least 1 week. The results showed that subjective ratings of drug 'liking' and the psychomotor and cognitive effects of lorazepam were generally similar to those of diazepam over the range of doses studied. Lorazepam, however, tended to produce effects of longer duration than diazepam. Since previous studies have shown that diazepam has a relatively high abuse liability among the benzodiazepines, the present findings suggest that lorazepam shares this property with diazepam is subjects with a history of 'recreational' drug use/abuse.

Adult↗
PubMed1988

Amantadine: evaluation of reinforcing properties and effect on cocaine self-injection in baboons.

The ability of amantadine to maintain self-injection behavior and to alter self-administration of cocaine was examined in baboons using a standard intravenous cocaine self-injection procedure. Responding was maintained under a FR 80- or 160-response schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections/day. Vehicle or amantadine doses were substituted for cocaine for a period of 15 or more days. Evaluation of a wide range of amantadine doses (0.32-32 mg/kg per injection) showed that this compound did not maintain self-administration behavior above vehicle control levels. In another experiment using the cocaine self-injection baseline, amantadine (10 or 32 mg/kg per day) was administered via a chronic intravenous infusion. Cocaine self-injection behavior was maintained and re-initiated during chronic amantadine exposure, suggesting that the reinforcing efficacy of cocaine was not modified by chronic amantadine administration.

Amantadine↗
PubMed1988

Reinforcing effects of caffeine in humans.

The reinforcing and subjective effects of caffeine were studied under double-blind conditions in 12 normal humans. After 2 forced exposure days on which subjects received color-coded capsules containing either caffeine (100, 200, 400 or 600 mg) or placebo, subjects had a choice day on which they chose which one of the two types of color-coded capsules would be ingested. Subjects were exposed to 10 experimentally independent choices (i.e., involving exposure and choice between novel color-coded capsule conditions) at each of several dose levels. All forced exposure and choice opportunities occurred when subjects were overnight abstinent from their normal dietary caffeine intake (mean, 116 mg/day). Significant caffeine positive reinforcement was demonstrated in 5 of 12 subjects at one or more doses. Percentage of selection of caffeine was inversely related to dose, with four subjects showing significant caffeine avoidance at 400 and/or 600 mg. Choice behavior was correlated positively with feelings of contentedness and was correlated negatively with prestudy trait anxiety scores and with ratings of capsule disliking. Compared to placebo, caffeine produced increases in subjective ratings indicating arousal while producing decreases in headache and "craving" for caffeine-containing foods, even at the lowest dose of 100 mg. At higher doses caffeine produced dysphoric anxiety-like subjective effects. Overall, this study provides the first demonstration in humans of the positive reinforcing effects of caffeine alone (i.e., in capsules) and documents individual differences among normal subjects in both caffeine positive reinforcement and caffeine avoidance.

Adult↗
PubMed1987

Effects of Ro 15-1788 and CGS 8216 in diazepam-dependent baboons.

Baboons received continuous intragastric infusions of diazepam (20 mg/kg per day) for one or more months. While diazepam treatment continued, baboons received intragastric doses of Ro 15-1788 (0.032-32.0 mg/kg) or CGS 8216 (1.0-100.0 mg/kg) at intervals of two or more weeks. Baboons were observed following administration of these antagonists for the presence of precipitated withdrawal signs. The following results were obtained: (1) both Ro 15-1788 and CGS 8216 produced signs of precipitated withdrawal in the baboon; (2) a more severe overall withdrawal syndrome was precipitated with Ro 15-1788 than with CGS 8216 at testable doses; (3) Ro 15-1788 produced dose-related increases in the overall severity of withdrawal, while CGS 8216 did not produce a clear dose-related increase in the overall severity of withdrawal; (4) dose-effect curves for Ro 15-1788 for certain signs (e.g. limb-tremor) were monotonicly increasing, while for other signs dose-effect curves plateaued at lower doses of Ro 15-1788 (e.g. retching and vomiting) or were an inverted U-shape (e.g. scratching). CGS 8216 precipitated withdrawal signs were less clearly dose-dependent; (5) onset of Ro 15-1788 precipitated withdrawal signs were rapid (5-15 min) and reliable, while the onset of CGS 8216 precipitated withdrawal signs were generally slower (approximately 30 min) and more variable; (6) at doses of Ro 15-1788 and CGS 8216 that produced equal levels of vomiting and retching, Ro 15-1788 produced more limb-tremor than CGS 8216. These studies indicate that Ro 15-1788 and CGS 8216 may produce quantitatively and qualitatively different precipitated withdrawal syndromes.

Animals↗
PubMed1987

Phenylpropanolamine: effects on subjective and cardiovascular variables at recommended over-the-counter dose levels.

Two controlled clinical studies evaluated the effects of phenylpropanolamine HCL (PPA) on measures of blood pressure, pulse, and subjective state (mood). One hundred fifty subjects participated in a parallel groups design that compared a 75-mg sustained release (SR) preparation with a 25-mg tid. dosing regimen and placebo. Fifty-nine of these subjects participated in an additional cross-over component that compared SR PPA 75 mg with placebo. Measures of blood pressure, pulse, and subjective drug effect were obtained nine times throughout the course of a 12-hour session. Data analysis revealed no clinically and few statistically significant effects due to drug treatment. As expected, most measures showed circadian changes on both the cardiovascular and mood variables, which were not related to drug treatment. No euphorogenic or "amphetamine-like" effects were noted. Although further work is warranted regarding the effects of chronic or higher-than-normal doses of PPA, the current studies suggest that PPA, at currently recommended dose levels, is not associated with adverse effects on either cardiovascular or subjective functioning.

Adult↗
PubMed1987

Nicotine gum: dose-related effects on cigarette smoking and subjective ratings.

The effects of nicotine-containing chewing gum on cigarette smoking and subjective and physiological response were evaluated in eight normal volunteers. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Before 90-min smoking sessions subjects chewed two pieces of placebo or nicotine-containing gum (0, 2, 4, or 8 mg) under double-blind conditions. Each subject received each treatment four times in a mixed order across days. Analysis of the chewed gum for remaining nicotine revealed that the mean delivered nicotine doses were 0, 1.02, 2.39, and 5.20 mg nicotine. Nicotine preloading produced dose-related increases in plasma nicotine, while producing dose-related decreases in various measures of cigarette smoking including number of cigarettes smoked, number of puffs taken, expired air carbon monoxide level, and ratings of smoking satisfaction. Nicotine preloading produced dose-related increases in ratings of gum dose-strength, while producing decreases in ratings of gum dose acceptability and liking. Heart rate and blood pressure were not significantly affected by nicotine gum. Taken together, the present results confirm that responses to nicotine in the gum preparation are orderly and related to dose, and the results suggest that the efficacy of treating tobacco dependence with nicotine gum may be enhanced by increasing the administered dose.

Adult↗
PubMed1987

Self-injection of d,1-3,4-methylenedioxymethamphetamine (MDMA) in the baboon.

MDMA (d,1-3,4-Methylenedioxymethamphetamine HCl; "ecstasy") self-injection (0.1-3.2 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time out allowing a maximum of eight injections per day. MDMA or MDMA vehicle (saline) was substituted for cocaine for a period of 14 or more days followed by a return to the cocaine baseline. MDMA (0.32-3.2 mg/kg/inj) maintained more injections and higher responses rates than were maintained by saline. The maximal number of injections maintained by MDMA and the maximal response rate maintained by MDMA were less than those maintained under baseline conditions with cocaine. The highest dose of MDMA tested maintained a cyclic pattern of self-injection, i.e., days of high numbers of injections intermixed with days of low numbers of injections. At the highest dose of MDMA tested, concurrent food maintained behavior was suppressed to an extent that food intake was also decreased.

3,4-Methylenedioxyamphetamine↗
PubMed1987

An examination of the intravenous self-administration of phenylpropanolamine using a cocaine substitution procedure in the baboon.

Intravenous self-administration of phenylpropanolamine HCl (0.10 to 10.0 mg/kg/injection) was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a FR 160-response schedule of intravenous injection. Each drug injection was followed by a 3-hr time-out allowing a maximum of eight injections per day. Phenylpropanolamine or phenylpropanolamine vehicle (saline) was substituted for cocaine for a period of 15 days followed by a return to the cocaine baseline. Response rates after phenylpropanolamine substitution were similar to those maintained by saline substitution, and lower than those maintained under cocaine baseline conditions. At the two highest doses of phenylpropanolamine tested (3.2 and 10.0 mg/kg/injection) concurrent food maintained behavior was suppressed.

Animals↗
PubMed1987

Self-administration of barbiturates and benzodiazepines: a review.

Studies of barbiturate and benzodiazepine self-administration are categorized by species and route of administration. Reinforcement, defined as self-administration of drug greater than of a non-drug control, has been demonstrated most often in studies employing the IV route, and there has been greater reliability in this result for a given drug among barbiturates rather than among benzodiazepines. Most studies of PO self-administration in rodents have not demonstrated reinforcement, despite a number of behavioral manipulations to induce drug intake. Studies of PO barbiturate self-administration in monkeys have demonstrated reinforcement but recent studies of PO benzodiazepine self-administration in baboons have not, although physical dependence was demonstrated. Reinforcement via the IG route has not been reliably demonstrated. Behavioral variables, including interreinforcement interval and drug self-administration history, appear to be important determinants of whether or not reinforcement will be demonstrated, particularly among the benzodiazepines; but the range of conditions under which behavioral and pharmacological variables interact to promote or lessen the likelihood of self-administration of these drugs remains to be determined experimentally.

Animals↗
PubMed1987

Interactions of diazepam and caffeine: behavioral and subjective dose effects in humans.

The effects of diazepam (DZ) (0, 10, and 20 mg) and caffeine (CAF) (0, 200, 400, and 600 mg) alone and in combination were examined in nine healthy male subjects using a within-subject experimental design in which all subjects received all twelve possible dose combinations. Drug effects were assessed using various psychomotor and cognitive performance tasks, staff (observer) ratings of subject behavior, and subject ratings of mood and drug effect. DZ treatment alone impaired performance on all tasks and produced staff and subject ratings indicative of sedative drug effects. CAF treatment alone facilitated performance on two psychomotor tasks requiring rapid reaction speed and increased staff ratings of subject restlessness and subject ratings of tension, alertness, arousal, and CAF symptoms. CAF generally antagonized the DZ-induced ratings of sedation and impairment of psychomotor performance; however, CAF did not consistently antagonize the DZ impairment of immediate recall or delayed recognition memory performance. DZ antagonized the CAF-induced staff-rated restlessness, and subject-ratings of tension, alertness, arousal and CAF symptoms. The results generally support the hypothesis that DZ and CAF produce antagonistic effects through functionally opposing mechanisms, however, the observed effects of drug combinations are dependent on the specific doses being tested and on the measures of drug effect being examined.

Adolescent↗
PubMed1987

Lorazepam and meprobamate dose effects in humans: behavioral effects and abuse liability.

On a residential research ward, the acute effects of placebo, lorazepam (LZ) (1.5-9.0 mg) and meprobamate (MEP) (600-3600 mg) were examined using a within-subject double-blind Latin Square design in nine male subjects with histories of drug abuse. Drug effects were assessed with objective performance tasks, subject estimates of performance, staff ratings of drug effects and subject ratings of drug effects, sleep, mood, drug liking and monetary street value. Generally, both LZ and MEP produced comparable dose-related effects; LZ had a more rapid onset of action and on several measures showed a more shallow dose-response curve than MEP. With LZ, but not MEP, subjects under-estimated the degree to which their performance was impaired and under-rated drug effects as compared to analogous staff ratings. Both drugs produced sedation-like subject ratings of mood and sleep but generally did not produce tranquilization-like ratings. MEP produced subject ratings of drug liking and monetary street value which were equal to or in some cases greater than those of LZ. Relative potency estimations showed that LZ was 510 to 783 times more potent than MEP in producing performance impairment but was only 370 times more potent than MEP in producing subject ratings of drug liking. Overall, these data indicate that the likelihood of abuse of MEP is at least equal to if not greater than that of LZ although LZ may have a greater likelihood of producing adverse behavioral effects such as a performance impairment and under-estimates of the degree of impairment. These data in conjunction with previous results from this laboratory show that the behavioral effects of benzodiazepines can be differentiated from those of other types of sedative/anxiolytics and that MEP displays characteristics of a barbiturate-like profile of action.

Adult↗
PubMed1987

Human cigarette smoking: effects of puff and inhalation parameters on smoke exposure.

This study determined effects of three smoking behavior components: puff volume, inhalation volume and lung exposure duration on biological measures of smoke exposure. A microcomputer-based auditory feedback system allowed subjects (N = 9 or 10 per experiment) to control puff and inhalation parameters as they smoked usual brand cigarettes. In each of four experiments, one smoking parameter was manipulated across sessions while two other parameters were held constant. Biological samples were obtained before and after each 8-puff smoking session conducted under a given set of behavioral parameters for analysis of plasma nicotine and expired air carbon monoxide (CO) levels. In Experiment I, both nicotine and CO levels were influenced systematically as puff volume was varied from 15 to 60 ml (inhalation volume = 50% of vital capacity, lung exposure time = about 9 sec). Nicotine boost (post- minus presession levels) increased 4-fold and CO boost increased 9-fold over this range of puff volume values. In Experiment II, nicotine levels were unaffected when average lung exposure times varied from 5 to 21 sec (puff volume = 50 ml, inhalation volume = 50% of vital capacity), suggesting that all the nicotine available may be absorbed during a normal smoking inhalation cycle with no breathholding. CO levels increased systematically with longer breathholds. In Experiments III and IV, inhalation volumes from 10% and 20% to 60% of vital capacity had no effect on either nicotine or CO levels, and this was true whether lung exposure time was about 8 sec (Experiment III) or about 4 sec (Experiment IV). This series of studies has shown that puff volume is an important determinant of tobacco smoke exposure, but that inhalation components of smoking behavior, at least within the range of parameters tested, have no effect on nicotine exposure levels.

Adult↗
PubMed1986

Naloxone does not affect cigarette smoking.

In order to provide information about the hypothesis that endogenous opioids mediate the reinforcing properties of cigarette smoking, the present study examined the effects of naloxone, an opioid antagonist, on cigarette smoking in seven normal volunteers. The study used experimental procedures that had previously been shown sensitive for detecting the effects of other drugs, (including a nicotine antagonist) on smoking. Isolated subjects smoked their regular brand of cigarettes freely in a naturalistic laboratory environment while watching television or reading. Sixty minutes before each 2 h smoking session subjects received an IM injection of naloxone HCl (0.0625, 0.25, 1.0, or 4.0 mg/kg) or placebo. Each subject received each treatment three times in a mixed order across days. Naloxone did not significantly affect any measure of cigarette smoking including number of cigarettes, number of puffs, or expired air carbon monoxide level. Naloxone did, however, produce significant dose-related increases in subject ratings of yawning, stretching, and relaxation. The results of the present study provide no support for the endogenous opioid theory of smoking reinforcement.

Adult↗
PubMed1986

Effects of mecamylamine on human cigarette smoking and subjective ratings.

Multiple measures of cigarette smoking, subjective effect and physiological effect were collected during 90-min test sessions in normal volunteers. Before sessions subjects received oral doses of mecamylamine (2.5, 5.0, 10, 20 mg) or placebo. Each dose and placebo was given three times in a randomized block sequence. Mecamylamine increased several measures of cigarette smoking, including number of cigarettes, number of puffs per cigarette, and expired air carbon monoxide level. Mecamylamine also produced modest, dose-related decreases in standing blood pressure and increases in standing heart rate. The subjective effects produced by mecamylamine were not characteristic of those of psychoactive drugs. Mecamylamine appears to have increased cigarette smoking by decreasing the effective dose level of nicotine available from cigarette smoking.

Adult↗
PubMed1986

Effects of marijuana smoking on subjective ratings and tobacco smoking.

Multiple measures of tobacco cigarette smoking and subjective and physiological effect were collected during 90 minute test sessions in volunteer cigarette smokers who also had histories of recreational marijuana use. Before sessions, subjects smoked one marijuana cigarette (placebo or 1.29%, 2.84%, 4.00%) using a standardized puffing procedure. Each dose and placebo was given four times to each subject in a randomized block sequence. Marijuana smoking produced dose-related increases in heart rate, ratings of dose strength and drug liking. However, marijuana produced no significant alterations in tobacco cigarette smoking. Puff duration within each marijuana cigarette varied in a fashion similar to that observed in previous studies of tobacco cigarette smoking: puff duration progressively decreased as the cigarette was smoked. This effect is probably due to progressive decreases in resistance to draw as the cigarette is smoked. Expired air carbon monoxide (CO) levels following marijuana smoking were inversely related to marijuana dose, suggesting the occurrence of some compensatory changes in marijuana smoking in response to dose manipulations. It is concluded that, although marijuana produces dose-related effects on physiological and subjective effects and on marijuana smoking behavior, marijuana differs from a variety of other psychoactive drugs previously studied in this paradigm in that no reliable changes in tobacco smoking were produced.

Adolescent↗