Biomedical subjects

M W Fischman

Publications and source records attributed to M W Fischman.

At least 37 records · Page 2Linked to original sources

PubMed1999

Fluoxetine-maintained obese humans: effect on food intake and body weight.

The effects of fluoxetine on food intake, body weight, and mood of obese individuals was examined in a 16-week inpatient/outpatient study. Six male and eight female obese volunteers began the study (four male and five females completed all phases of the study). They lived in a residential laboratory during three one-week inpatient periods separated by a 5-week and an 8-week outpatient period. Following an initial 4-day placebo baseline, participants were maintained on fluoxetine (60 mg/day) for the remainder of the study. Food intake parameters (total daily energy intake, macronutrient intake, mean number of eating bouts, interbout interval), body weight, subjective effects, and task performance were measured several times during the day during inpatient periods; food intake questionnaires were completed daily during the outpatient periods. Fluoxetine significantly reduced daily energy intake derived from fat, carbohydrate, and protein by decreasing the mean number of eating bouts per day throughout the study. No other food intake parameter was affected. Body weight was significantly reduced after 7 weeks, but not after 16 weeks of daily fluoxetine administration. These results indicate that fluoxetine reduced food intake for at least 16 weeks in nondepressed obese individuals without specifically affecting carbohydrate intake. Weight that was lost during the first few weeks of daily fluoxetine administration was subsequently regained even though food intake remained reduced. Therefore, fluoxetine maintenance does not appear promising as a sole long-term therapy for obesity.

Adult↗

PubMed1999

Limited sex differences in response to "binge" smoked cocaine use in humans.

The subjective and physiological effects of repeated smoked cocaine self-administration were compared in 11 men and 9 women. Twice a day, on 2 consecutive days, participants smoked up to six 50-mg doses of cocaine base, at 14 min intervals. Men and women self-administered a similar number of cocaine doses (21.7 and 21.6, respectively). The most striking sex difference was that women had higher cocaine plasma concentrations than men (632.7 ng/ml vs. 376.7 mg/ml) after the sixth cocaine dose of the first session. After the first cocaine dose, women reported that they would spend significantly less for the dose than men ($1.58 vs. $3.15). Although cocaine produced similar effects in men and women 4 min after each dose, 15 min after the last dose of the session, heart rate and blood pressure remained elevated in women, but ratings of "I want cocaine" were lower in women as compared to men. Thus, smoking cocaine produced similar acute subjective effects in men and women, but prolonged cardiovascular effects and higher cocaine plasma concentrations in women.

Adult↗

PubMed1999

Blockade of cocaine-induced increases in adrenocorticotrophic hormone and cortisol does not attenuate the subjective effects of smoked cocaine in humans.

Surgical or pharmacological ablation of the hypothalamic-pituitary-adrenal (HPA) axis reduces the discriminative stimulus and reinforcing effects of cocaine in laboratory rodents. We have recently reported that attenuation of cocaine-induced increases in cortisol does not modulate the subjective effects of smoked cocaine in humans. To examine whether attenuation of HPA function at the pituitary level reduces the effects of cocaine in humans, eight 'crack' cocaine abusers were pre-treated with the synthetic glucocorticoid, dexamethasone (0 and 2 mg), 10 h before receiving cocaine. Three doses of smoked cocaine (0, 12 and 50 mg) were administered in counterbalanced order under each pre-treatment condition. Dexamethasone alone increased heart rate and blood pressure, and completely abolished cocaine-induced adrenocorticotrophic hormone and cortisol release. Maximal heart rate following cocaine administration was significantly increased by dexamethasone. However, the subjective effects of cocaine were not affected by dexamethasone pre-treatment. These results extend our earlier findings with humans, indicating that the role of the HPA axis in mediating the effects of cocaine is limited. These data are concordant with findings in non-human primates, but contrast with findings in laboratory rodents, thus underscoring the importance of validation of rodent models with laboratory studies in humans.

Adrenocorticotropic Hormone↗

PubMed1998

Effects of an alternative reinforcer on intravenous heroin self-administration by humans.

Five heroin-dependent research volunteers, maintained on divided daily oral morphine doses, participated in an inpatient study designed to evaluate intravenous (i.v.) heroin self-administration when money ($10, $20 or $40) was concurrently available. Each morning participants received a single injection of heroin (placebo, 6.25, 12.5, 25, or 50 mg/70 kg, i.v.) and each afternoon, they had the opportunity to self-administer all or part of the morning dose. Participants responded under a progressive-ratio schedule (50, 100, ..., 2800) during a 10-trial self-administration task. During each trial, participants could respond for 1/10th of the sampled heroin dose or 1/10th of a single money value. The progressive-ratio value increased independently for each option. The total amount of heroin and/or money chosen during the self-administration task was administered at the end of the task. Heroin dose-dependently increased ratings of 'good drug effect' and 'high', impaired task performance and decreased pupil diameter and blood oxygen saturation. Heroin also dose-dependently increased progressive-ratio break point values, which varied as a function of the alternative money amount. Consistent with previous studies, the present results demonstrate that alternative reinforcers, depending on magnitude, are effective in reducing heroin use in opioid-dependent individuals.

Administration, Oral↗

PubMed1998

Effects of pergolide on intravenous cocaine self-administration in men and women.

Clinical evidence suggests that pergolide, a D1/D2 dopamine receptor agonist, may be useful in maintaining cocaine abstinence. We investigated pergolide's effects in a laboratory model of IV cocaine self-administration by humans. Twelve inpatient volunteers (7M, 5F), who reported spending an average of $170/week on cocaine, received pergolide (0.05 mg BID) for 8 days and placebo for 8 days, with drug order balanced across subjects. Self-administration sessions occurred on the last 4 days of maintenance on each medication. A modified seven-trial progressive ratio choice procedure (0, 8, 16, 32 mg/70 kg cocaine versus $5) was utilized, with sessions consisting of: (a) two sample trials, where participants responded to receive the dose and tokens available that day, and (b) five choice trials, where participants chose between the available dose and tokens. Following each trial, the response requirement for the chosen option increased by 400. Maintenance on pergolide 1) decreased cocaine-induced increases in ratings of "High," "Stimulated," cocaine "Potency," estimates of street value, and heart rate, 2) increased ratings of "I want cocaine," and 3) had no effect on cocaine self-administration. The increased desire to use cocaine during pergolide maintenance suggests that it has limited treatment utility at this dose, but given the attenuation of cocaine's subjective and cardiovascular effects, an investigation of a wider range of pergolide doses on cocaine self-administration and subjective effects is warranted.

Adult↗

PubMed1998

Effects of methysergide and loratadine on food intake, mood, and performance of humans living in a residential laboratory.

The effects of loratadine, a peripherally acting histamine (H1) antagonist, and methysergide, a serotonin (5-HT) antagonist, were evaluated in seven normal-weight, male research volunteers, participating in a placebo-controlled, double-blind, 17-day residential study. Participants received oral loratadine (10 or 20 mg), methysergide (4 or 8 mg), or placebo at 1000 and 1700 hours daily. Active drug was administered on Days 4, 5, 7, 8, 11, 12, 15, and 16; placebo was administered on all other days. Drug and dose order were counterbalanced across participants. Food intake, performance, and subjective ratings were measured repeatedly throughout the day. Loratadine had no effect on food intake, performance, or subjective ratings. In contrast, total caloric intake significantly decreased from approximately 3500 kcal during placebo administration to 3065 kcal on the first but not the second day of methysergide administration. Consumption of carbohydrate (p < 0.055), protein, and fat decreased on the first day of methysergide administration. This decrease in food intake was due to a decrease in meal size; the number of meals consumed was not affected. The proportion of calories derived from carbohydrates significantly increased on the first day of methysergide administration. Methysergide also significantly impaired performance of a psychomotor task on the first day of high-dose administration and increased ratings of several subjective measures, including "Vomiting," "Stomach Pain," and "Miserable." These results suggest that the anorectic effect occurred as a result of the somatic and mood changes produced by methysergide. In addition, the inability of loratadine to affect food intake indicates that antagonism of central histamine receptors may be responsible for the increases in food intake produced by other antihistamines (e.g., diphenhydramine).

Adult↗

PubMed1998

Mood and performance changes in women with premenstrual dysphoric disorder: acute effects of alprazolam.

This study determined if women with premenstrual dysphoric disorder (PMS) showed impaired mood and performance when they were experiencing their premenstrual symptoms, and if the effects of alprazolam varied as a function of menstrual cycle phase. Under double-blind conditions, the acute effects of placebo and alprazolam (0.25, 0.50, 0.75 mg) were tested during both luteal and follicular phases. Women with confirmed PMS experienced substantial changes in mood as a function of menstrual cycle phase. However, under controlled laboratory conditions, acute doses of alprazolam did not improve negative premenstrual mood, but rather increased negative mood in the follicular phase. Alprazolam impaired task performance, although this impairment was generally similar in both phases when baseline phase differences were taken into consideration. Consistent with the failure of alprazolam to improve mood premenstrually, subjective measures indicative of abuse liability were not increased following alprazolam. Taken together, these data suggest that acute administration of alprazolam doses are not clinically useful for the treatment of PMS.

Adult↗

PubMed1998

Smoked cocaine self-administration in females and voucher incentives for abstinence.

UNLABELLED: There are three purposes for this study: (1) To extend the laboratory study of heavy smoked cocaine use to women, (2) to assess cocaine withdrawal symptoms and (3) to assess the utility of voucher incentives for achieving and maintaining cocaine and other drug abstinence in female cocaine abusers. METHODS: Ten non-treatment seeking female cocaine smokers resided inpatient for 4-5 days and could smoke up to 6 doses of cocaine base (50 mg each) twice a day (at 1200 h and again at 1600 h) for 2 consecutive days. During the following 2-week outpatient phase, women were given US $40 in merchandise vouchers if urinalysis indicated lower drug levels from the previous day. RESULTS: Women self-administered 20.4 out of 24 possible doses. Compared to the 1200 session, heart rate and blood pressure, but not subjective effects, were still significantly increased prior to the 1600 session. Nine women completed the outpatient phase, attending 98% of their appointments. Using the One-Half Rule, 56% of urines indicated no new cocaine or other drug use. IMPLICATIONS: Although a US $40 voucher incentive for a "clean" urine was not sufficient to eliminate cocaine use, the possibility of earning the voucher was sufficient to maintain nearly perfect attendance.

Adult↗

PubMed1998

Effects of "binge" use of intravenous cocaine in methadone-maintained individuals.

AIMS: To examine the effects of heavy cocaine use followed by abstinence. DESIGN: During self-administration sessions, which occurred in the afternoon and again in the evening, participants could after self-administer up to six doses of intravenous cocaine (32 mg/70 kg) at 14-minute intervals. All volunteers participated in a 2-day and a 3-day series of self-administration sessions (cocaine binges). No cocaine was available for at least 2 days following each cocaine binge. PARTICIPANTS: Five adult methadone-maintained cocaine abusers. SETTING: Inpatient clinical research unit. MEASUREMENTS: Cardiovascular and subjective effects. FINDINGS: The first cocaine dose in a session produced substantial subjective and cardiovascular effects and, with the exception of blood pressure and ratings of "irritable", administering up to five more cocaine doses did not increase these effects. Additional cocaine doses, however, did increase ratings of "bad drugs effect" and decrease ratings of "I want cocaine". Maximal subjective and cardiovascular effects of cocaine did not vary across sessions on the same day or between days. Ratings of "depressed" and "miserable" were increased the first day after each period of cocaine use, and presentation of cocaine-related stimuli increased ratings of "I want cocaine" and "I want heroin" during cocaine abstinence. CONCLUSION: Acute tolerance developed to many of the effects of cocaine during a cocaine binge in methadone-maintained individuals, next-day residual changes in mood were subtle, and no prolonged effects of a cocaine binge were observed.

Adult↗

PubMed1998

Ethical and practical issues involved in behavioral pharmacology research that administers drugs of abuse to human volunteers.

Researchers carrying out non-therapeutic research that involves the administration of drugs of abuse to human volunteers can be faced with many ethical and practical questions. The history of this type of research is relatively brief, with little in the way of published information relevant to carrying out behavioral pharmacological research with human participants. The aim of this article is to raise issues that occur in most studies of this type and to provide solutions that we have found acceptable and which have been approved by a variety of institutions and regulatory agencies. Clearly, there are other approaches that would work equally as well, and we are not attempting to provide 'the' answer to many of the issues raised. We believe that raising these issues and providing our perspectives is important for stimulating others to discuss them and for all of us to strive, where possible, to reach a consensus concerning ethical practices and to become aware of gaps and pitfalls. The topics discussed range from the nuts and bolts of acquiring and keeping track of drugs, to selecting research participants and designing ethical studies that protect our volunteers while still collecting scientifically useful data.

Behavior↗

PubMed1998

Ketoconazole attenuates the cortisol response but not the subjective effects of smoked cocaine in humans.

Attenuation of hypothalamo-pituitary-adrenal (HPA) function in laboratory rodents has been found to reduce the reinforcing effects of cocaine. To examine whether attenuation of HPA function reduces the effects of cocaine in humans, one female and seven male 'crack' cocaine abusers were pretreated with three doses of ketoconazole (0, 600, 1200 mg), an inhibitor of adrenocorticoid biosynthesis, 1 h before receiving cocaine. Three doses of smoked cocaine (0, 12, 50 mg) were administered in counterbalanced order under each ketoconazole condition. Ketoconazole dose-dependently reduced cocaine-induced cortisol, but not adrenocorticotropin (ACTH) release, and attenuated the cocaine-induced increase in heart rate and blood pressure. Plasma ACTH levels were more predictive of blood pressure changes than either cocaine or cortisol levels. Suppression of cortisol secretion was not associated with a reduction in ratings of the subjective effects of cocaine. These results support a role for the HPA axis in the cardiovascular effects of cocaine, but do not support a role for the HPA axis in the subjective effects of cocaine. To the extent that self-administration can be predicted by subjective effects, these results further argue that the HPA axis does not play a critical role in cocaine self-administration by humans.

Administration, Inhalation↗

PubMed1998

The effects of memantine on the subjective, reinforcing and cardiovascular effects of cocaine in humans.

Eight male frequent cocaine smokers participated in a 44- to 47-day inpatient and outpatient study to assess the effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, memantine, on cocaine self-administration, subjective effects, and psychomotor performance. Participants were maintained on memantine (0 and 20 mg daily) for 7-10 days prior to laboratory testing, using a double-blind crossover design. Under each medication condition, participants smoked four doses of cocaine base (0, 12, 25 and 50 mg), and were subsequently given five opportunities, 14 min apart, to self-administer that dose of cocaine or receive a merchandise voucher ($5.00). Each cocaine dose was tested twice under each medication condition, and the order of medication condition and cocaine dose was systematically varied. Vital signs were recorded every 2 min, and subjective effects were assessed at baseline and after each cocaine or voucher delivery. In addition, psychomotor performance was assessed before and after each self-administration session. Memantine maintenance was not associated with changes in psychomotor performance or the number of cocaine doses chosen each session. Memantine maintenance was, however, associated with significant increases in some subjective effects of cocaine, including ratings of 'good drug effect', 'high', 'potency', 'quality', and street value. These data suggest that NMDA antagonists may have limited usefulness as treatment medications for cocaine abuse.

Adult↗

PubMed1997

Residual effects of repeated cocaine smoking in humans.

A total of nine adult 'crack' cocaine users completed a protocol investigating changes in behavior on days following the self-administration of smoked cocaine. During self-administration sessions, participants could take up to six doses of smoked cocaine (50 mg; 25 mg for two participants). Both 2 and 3 day conditions were tested. During the 2 day condition, a cocaine self-administration session occurred in the afternoon and again in the evening on 2 consecutive days, while during the 3 day condition, self-administration sessions occurred twice a day-on 3 consecutive days. Participants reported greater cocaine craving (estimated using ratings of 'I want cocaine') and feeling more 'anxious,' 'confused,' 'of a good drug effect,' 'high,' 'sedated' and less 'friendly' the first day after using cocaine for 3 days compared to the first day after using cocaine for 2 days. Exposure to stimulus cues associated with smoked cocaine (e.g. participants preferred type of crack pipe) did not elicit cocaine craving or other behavioral changes after either 2 or 3 days of cocaine use. These data demonstrate that the cessation of heavy cocaine use under controlled laboratory conditions produced modest changes in mood and cocaine craving that were related to the length of the binge, and varied as a function of time since last cocaine use.

Adult↗

PubMed1997

Relationship between subjective effects of cocaine and dopamine transporter occupancy.

Cocaine is believed to work by blocking the dopamine transporter (DAT) and thereby increasing the availability of free dopamine within the brain. Although this concept is central to current cocaine research and to treatment development, a direct relationship between DAT blockade and the subjective effects of cocaine has not been demonstrated in humans. We have used positron emission tomography to determine what level of DAT occupancy is required to produce a subjective 'high' in human volunteers who regularly abuse cocaine. We report here that intravenous cocaine at doses commonly abused by humans (0.3-0.6 mg kg(-1)) blocked between 60 and 77% of DAT sites in these subjects. The magnitude of the self-reported high was correlated with the degree of DAT occupancy, and at least 47% of the transporters had to be blocked for subjects to perceive cocaine's effects. Furthermore, the time course for the high paralleled that of cocaine concentration within the striatum, a brain region implicated in the control of motivation and reward. This is the first demonstration in humans that the doses used by cocaine abusers lead to significant blockade of DAT, and that this blockade is associated with the subjective effects of cocaine. Although these findings provide justification to target the DAT for medication development they suggest that for drugs to be effective in blocking cocaine's effects they would have to be given at doses that achieve almost complete DAT occupancy.

Adult↗

PubMed1997

Concentration and occupancy of dopamine transporters in cocaine abusers with [11C]cocaine and PET.

The concentration (Bmax) of the dopamine transporter (DAT) and the maximum and effective occupancies by cocaine doses of 0.1 mg/kg or 0.05 mg/kg were measured in the striatum of cocaine abusers (n = 12) by using [11C]cocaine as a radiotracer for the DAT and positron emission tomography (PET). Two methods based on a three-compartment model with one binding site (the nonlinear least squares (NLSQ) and the Farde pseudoequilibrium method) were used to estimate Bmax. Effective occupancies and maximum occupancies were calculated from the distribution volume ratios (DVR) and a three-compartment model, respectively. The NLSQ and Farde methods gave similar values of Bmax (average, 650 +/- 350 pmol/ml and 776 +/- 400 pmol/ml, respectively), but the individual estimates of Bmax were found to be very sensitive to small variations in other model parameters and were not correlated with the parameter Bmax/Kd (r = .07). The average maximum (and effective) occupancies were found to be 67% (50%) and 52% (39%) for the 0.1-mg/kg and the 0.05-mg/kg studies, respectively. The ED50 based on the effective occupancy corresponds to 0.1 mg/kg, which is significantly smaller than the ED50 of 3 mg/kg calculated from studies in which [123]beta-CIT is displaced by cocaine. The effect on the Bmax estimate of two binding sites with different Kd's is also considered by simulation. We conclude (1) that the lack of robustness in the Bmax estimate limits the usefulness of any one subject's Bmax and suggests that the combination parameter Bmax/Kd (or the DVR), which has been used extensively, is a more stable measure of free receptor/transporter concentration. The average Bmax may, however, provide an estimate of the expected concentration in humans. (2) The DVR can be used as a measure of DAT occupancy without applying an explicit model.

Adult↗

PubMed1997

Alprazolam increases food intake in humans.

The present study investigated the effect of alprazolam on the pattern of food intake in seven male participants living in a residential laboratory for 17 days. A wide selection of meals, snacks and beverages was freely available. Capsule administration occurred at 1300 and 1730 hours. Food intake on days when alprazolam (0.75 mg) was administered (days 2, 11) was compared to days when no capsule (days 1, 9) or placebo (days 3, 10) was administered. Alprazolam increased total caloric intake by approximately 975 kcal from a baseline of 2800 kcal. Alprazolam increased the number of eating occasions occurring in the evening (1700-2330 hour), without altering the size of eating occasions (kcal), or the proportion of total calories derived from carbohydrate, fat and protein. These data demonstrate alprazolam's robust effects on food intake in humans.

Adult↗

PubMed1997

Binge cocaine self-administration in humans: intravenous cocaine.

Cocaine is frequently used in intermittent cycles of repeated dosing, or "binges." This pattern of cocaine use has been difficult to study in humans because currently available laboratory models use only one daily session during which a single dose or multiple doses are administered. In the present study, seven adult male IV cocaine users completed a protocol investigating changes in cardiovascular and subjective responses during the repeated self-administration of cocaine. Volunteers participated in a 2-day and a 3-day access condition. On each day of access, they participated in two 2.5-h sessions, one at 1200 and another at 1600 hours. In the 2- and 3-day conditions, participants had access to cocaine on 2 or 3 consecutive days, respectively. During sessions, participants could self-administer up to six doses of IV cocaine (32 mg/70 kg) every 14 min. Participants chose not to self-administer cocaine on only 10% of the 420 trials. Acute tolerance developed to the cardiovascular and several subjective effects of cocaine. Heart rate was the only measure that tended to decrease across days of repeated cocaine self-administration. Ratings of "I want cocaine" decreased at the end of the last self-administration session during both 2- and 3-day conditions. There was no difference between the 2- and 3-day conditions for any measure. The laboratory model of "binge" cocaine use established in this study can be used to describe changes in cardiovascular and subjective effects of cocaine within and between bouts of repeated cocaine use.

Adult↗

PubMed1997

Cyproheptadine produced modest increases in total caloric intake by humans.

Four male and three female normal-weight research volunteers, participating in an 18-day residential study, received oral cyproheptadine (4 mg) or placebo at 0930, 1245, and 1730 hours daily. Food intake, performance, and subjective ratings were measured throughout the day. The interaction between cyproheptadine and carbohydrate consumption was examined by providing subjects diets that engendered varied levels of carbohydrate intake. Three diet conditions were tested for 6 days each: a regular diet, a low-carbohydrate (high-fat) diet, and a high-carbohydrate diet. Placebo was given on days 1, 2, 3, and 6, while cyproheptadine was given on days 4 and 5 of each diet condition. When subjects received placebo and had access to a regular diet, they consumed 2500 kcal/day (59% carbohydrate 28% fat, 13% protein). Total caloric intake decreased (p < 0.007) when subjects received placebo and had access to the low-carbohydrate diet (40% carbohydrate, 43% fat, 17% protein) and increased (p < 0.056) when subjects received placebo and had access to a high-carbohydrate diet (70% carbohydrate, 19% fat, 11% protein). Cyproheptadine significantly increased total daily caloric intake by 20%, to 3000 kcal, only under the regular diet condition. The increase in caloric intake was due to an increase in the number of eating occasions without a change in eating occasion size. Although subjects consumed more food under the regular diet and cyproheptadine condition, cyproheptadine had no effect on the relative contribution of macronutrients to total daily caloric intake. There was no evidence for a modulation of the food-intake increasing effects of cyproheptadine by the macronutrient mix of the available diet. Cyproheptadine also significantly altered self-reported mood: compared to placebo, cyproheptadine produced significant increases in ratings of "Tired", "Sleepy", "Headache", "Can't Concentrate", and "Bad Drug Effect" and decreases in "Alert". Furthermore, cyproheptadine produced small decrements in psychomotor task performance.

Adult↗