Cocaethylene formation following ethanol and cocaine administration by different routes.

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d5) was administered in all conditions. Oral cocaine-d5 2.0 mg/kg, intravenous cocaine-d5 1.0 mg/kg, and smoked cocaine-d5 (200 mg) were administered after oral ethanol 1.0 g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d3) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d5, cocaethylene-d5, cocaethylene-d3, and benzoylecgonine-d5 were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs.

A phase 1 trial of pharmacologic interactions between transdermal selegiline and a 4-hour cocaine infusion.

BACKGROUND: The selective MAO-B inhibitor selegiline has been evaluated in clinical trials as a potential medication for the treatment of cocaine dependence. This study evaluated the safety of and pharmacologic interactions between 7 days of transdermal selegiline dosed with patches (Selegiline Transdermal System, STS) that deliver 6 mg/24 hours and 2.5 mg/kg of cocaine administered over 4 hours. METHODS: Twelve nondependent cocaine-experienced subjects received deuterium-labeled cocaine-d5 intravenously (IV) 0.5 mg/kg over 10 minutes followed by 2 mg/kg over 4 hours before and after one week of transdermal selegiline 6 mg/24 hours. Plasma and urine were collected for analysis of selegiline, cocaine, catecholamine and metabolite concentrations. Pharmacodynamic measures were obtained. RESULTS: Selegiline did not change cocaine pharmacokinetic parameters. Selegiline administration increased phenylethylamine (PEA) urinary excretion and decreased urinary MHPG-sulfate concentration after cocaine when compared to cocaine alone. No serious adverse effects occurred with the combination of selegiline and cocaine, and cocaine-induced physiological effects were unchanged after selegiline. Only 1 peak subjective cocaine effects rating changed, and only a few subjective ratings decreased across time after selegiline. CONCLUSION: No pharmacological interaction occurred between selegiline and a substantial dose of intravenous cocaine, suggesting the combination will be safe in pharmacotherapy trials. Selegiline produced few changes in subjective response to the cocaine challenge perhaps because of some psychoactive neurotransmitters changing in opposite directions.

The clinical pharmacology of intranasal l-methamphetamine.

BACKGROUND: We studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant. METHODS: 12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 microg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured. RESULTS: Plasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 +/- 56.1, 124.7 +/- 106.6, and 268.1 +/- 220.5 microg for ascending exposures (mean 4.2 +/- 3.3 microg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen. CONCLUSION: Inhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant.

Expanding treatment of tobacco dependence.

Nicotine dependence is the leading preventable cause of adult morbidity and mortality in the world. New research on the treatment of this disorder ranges from studies evaluating access to treatment to studies elucidating the molecular mechanisms of nicotine addiction. As our understanding of the neurobiology of tobacco addiction grows, the number of potential therapeutic targets by which we can intervene in this pernicious disorder also increases. This paper presents an overview of recent research trends in the treatment of tobacco dependence. We review several novel mechanisms of action that may serve as therapeutic targets for the pharmacologic treatment of tobacco dependence, including drugs that affect monamine oxidase, selective nicotinic receptors, glutamate and gamma-aminobutyric acid receptors, and the endocannabinoid system. For each of these therapeutic targets, we discuss medications in development that affect these pathophysiologic mechanisms.

Repeated psychological stress testing in stimulant-dependent patients.

Decreasing response to stress has been one goal of interventions aimed at reducing relapse to substances of abuse. A laboratory stress test that can be repeated would be helpful in testing the efficacy of interventions in decreasing the response to stress before more extensive trials are begun. The effects of two types of psychological stress tests, the Trier Social Stress Test (TSST) and a stress imagery test, on psychological, physiological, and hormonal responses (salivary cortisol and DHEA) were examined when each test was given twice to cocaine- or methamphetamine-dependent human subjects, 24 of whom completed at least one session. The stress imagery test produced significant changes in several of the subjective response measures in both first and second sessions, including several measures of negative affect and a craving measure. The TSST produced significant changes only in the second session. The stress imagery protocol showed better replicability across two sessions. Cocaine users and methamphetamine users did not respond similarly in their craving responses. Reported craving for methamphetamine after stress testing showed decreases or much smaller increases compared to that for cocaine. Neither stress test significantly increased salivary cortisol or DHEA, and changes in hormone concentrations were not related to subjective responses. These results suggest that stress imagery testing procedures may be useful as provocative tests of stress-induced affect and stimulant drug craving. Although less convincing because of the heterogeneity of the subjects, they also suggest that HPA axis responsivity is not clearly linked to acute stress-induced stimulant craving or affective response.

Fluoxetine attenuates adrenocortical but not subjective responses to cocaine cues.

Preclinical data suggest a link between stress reactivity and cocaine self-administration by rodents. Serotonin appears to modulate the hypothalamic-pituitary-adrenal (HPA) axis. We studied the effects of chronic treatment with the serotonin reuptake inhibitor fluoxetine 40 mg/day on subjective and hormonal responses to cocaine cues in 22 subjects participating in a controlled clinical trial for cocaine dependence. Fluoxetine antagonized the cue-induced increase in cortisol but increased subjects' ratings of the likelihood of cocaine use in response to cocaine cues. Cortisol response to cocaine cues was not related to subjective craving. Activation of the HPA axis by cocaine cues does not appear to be a necessary mediator of cue-induced craving.

Pharmacokinetics and subjective effects of sublingual buprenorphine, alone or in combination with naloxone: lack of dose proportionality.

OBJECTIVE: Buprenorphine and buprenorphine/naloxone combinations are effective pharmacotherapies for opioid dependence, but doses are considerably greater than analgesic doses. Because dose-related buprenorphine opioid agonist effects may plateau at higher doses, we evaluated the pharmacokinetics and pharmacodynamics of expected therapeutic doses. DESIGN: The first experiment examined a range of sublingual buprenorphine solution doses with an ascending dose design (n = 12). The second experiment examined a range of doses of sublingual buprenorphine/naloxone tablets along with one dose of buprenorphine alone tablets with a balanced crossover design (n = 8). PARTICIPANTS: Twenty nondependent, opioid-experienced volunteers. METHODS: Subjects in the solution experiment received sublingual buprenorphine solution in single ascending doses of 4, 8, 16 and 32 mg. Subjects in the tablet experiment received sublingual tablets combining buprenorphine 4, 8 and 16 mg with naloxone at a 4 : 1 ratio or buprenorphine 16 mg alone, given as single doses. Plasma buprenorphine, norbuprenorphine and naloxone concentrations and pharmacodynamic effects were measured for 48-72 hours after administration. RESULTS: Buprenorphine concentrations increased with dose, but not proportionally. Dose-adjusted areas under the concentration-time curve for buprenorphine 32 mg solution, buprenorphine 1 6 mg tablet and buprenorphine/naloxone 16/4 mg tablet were only 54 +/- 16%, 70 +/- 25% and 72 +/- 17%, respectively, of that of the 4 mg dose of sublingual solution or tablet. No differences were found between dose strengths for most subjective and physiological effects. Pupil constriction at 48 hours after administration of solution did, however, increase with dose. Subjects reported greater intoxication with the 32 mg solution dose, even though acceptability of the 4 mg dose was greatest. Naloxone did not change the bioavailability or effects of the buprenorphine 16 mg tablet. CONCLUSION: Less than dose-proportional increases in plasma buprenorphine concentrations may contribute to the observed plateau for most pharmacodynamic effects as the dose is increased.

Quantitative drug levels in stimulant psychosis: relationship to symptom severity, catecholamines and hyperkinesia.

To examine the relationship between quantitative stimulant drug levels, catecholamines, and psychotic symptoms, nineteen patients in a psychiatric emergency service with a diagnosis of amphetamine- or cocaine-induced psychosis were interviewed, and plasma and urine were collected for quantitative assays of stimulant drug and catecholamine metabolite levels. Methamphetamine or amphetamine levels were related to several psychopathology scores and the global hyperkinesia rating. HVA levels were related to global hyperkinesia but not to psychopathology ratings. Although many other factors such as sensitization may play a role, intensity of stimulant-induced psychotic symptoms and stereotypies appears to be at least in part dose-related.

The pharmacology of cocaethylene in humans following cocaine and ethanol administration.

BACKGROUND: Concurrent use of cocaine and alcohol results in formation of a cocaine homolog and metabolite-cocaethylene. METHODS: To characterize cocaethylene pharmacology, ten paid volunteer subjects were given deuterium-labeled (d(5)) cocaine (0.3, 0.6, and 1.2 mg/kg and cocaine placebo) by a 15-min constant rate intravenous injection 1 h after a single oral dose of ethanol (1 g/kg) or ethanol and cocaine placebo using a double-blind, crossover design. Six of the same volunteers subsequently received a 1.2 mg/kg dose of cocaine alone. A small (7.5 mg) nonpharmacologically active dose of deuterium-labeled cocaethylene-d(3) was concurrently administered with the cocaine to enable calculation of absolute cocaethylene formation and clearance. Plasma and urine cocaine, cocaethylene, and benzoylecgonine concentrations, physiologic and subjective effects were measured. RESULTS: When co-administered with ethanol, 17+/-6% (mean+/-S.D.) of the cocaine was converted to cocaethylene. Cocaethylene peak plasma concentrations and AUC increased proportionally to the cocaine dose. Ethanol ingestion prior to cocaine administration decreased urine benzoylecgonine levels by 48% and increased urinary cocaethylene and ecgonine ethyl ester levels. Subjects liked and experienced more total intoxication after the combination of cocaine and ethanol than after either drug alone. CONCLUSIONS: In the presence of ethanol, the altered biotransformation of cocaine resulted in 17% of an intravenous cocaine dose being converted to cocaethylene and relatively lower urinary concentrations of benzoylecgonine.

The bioavailability of intranasal and smoked methamphetamine.

BACKGROUND: Patients in harm-reduction treatment programs are switching from intravenous to other routes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally. METHODS: Eight experienced methamphetamine users were administered smoked or intranasal methamphetamine concurrently with an intravenous dose of deuterium-labeled methamphetamine. Plasma and urine concentrations were measured for calculation of bioavailability and other pharmacokinetic parameters by noncompartmental methods. RESULTS: Methamphetamine was well absorbed after smoking or intranasal administration, with bioavailabilities of 79% after intranasal administration and 67% of the estimated delivered dose or 37.4% of the absolute (pipe) dose after smoking. Maximum methamphetamine concentrations occurred at 2.7 and 2.5 hours after intranasal and smoked doses. The elimination half-life was similar for intravenous (11.4 hours), intranasal (10.7 hours), and smoked (10.7 hours) methamphetamine. Clearance (272 mL x h(-1) x kg(-1)), steady-state volume of distribution (4.2 L/kg), and mean residence time (16 hours) of the intravenous dose were similar to previously reported values. Dextroamphetamine (INN, dexamfetamine) half-life (all routes) was 16.2 hours. Methamphetamine and dextroamphetamine renal clearances (all routes) were about 100 and 1100 mL x h(-1) x kg(-1), respectively. CONCLUSIONS: Intranasal and smoked methamphetamine are well absorbed. Although intranasal or smoked routes may decrease the risk of transmission of blood-borne diseases, exposure to methamphetamine and the possibility of drug-related complications remain substantial.

Altering cortisol level does not change the pleasurable effects of methamphetamine in humans.

Preclinical studies have linked corticosteroid secretion and levels with drug self-administration by animals. In a double-blind, cross-over study, subjective, physiological, and endocrine responses to intravenous doses of methamphetamine 0.5 mg/kg or placebo were assessed in eight methamphetamine-experienced subjects after three cortisol-modifying premedication conditions: augmenting cortisol level with oral hydrocortisone 50 mg, blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone 1500 mg orally, or no premedication. Although the pharmacologic manipulations produced the expected hormonal changes, subjective response to the methamphetamine showed few differences. Diminishing cortisol response by pharmacologic blockade did not alter the pleasurable effects of methamphetamine. Hydrocortisone did increase self-reported 'bad drug effect' and decreased craving after saline placebo relative to the period following methamphetamine. Metyrapone was associated with significant premature ventricular complexes in two subjects during methamphetamine administration and may not be safe for those who use methamphetamine.

Subjective and hormonal effects of 3,4-methylenedioxymethamphetamine (MDMA) in humans.

RATIONALE: 3,4-Methylenedioxymethamphetamine (MDMA) is a widely used phenethylamine. Reports have described the effects of MDMA in a controlled laboratory setting, but the full range of effects of MDMA in humans is still not completely characterized. OBJECTIVES: To describe the physiological, subjective, and hormonal changes after single doses of MDMA in a laboratory setting and examine relationships between these effects. METHODS: Eight MDMA-experienced volunteers each received placebo, 0.5 mg/kg, and 1.5 mg/kg oral doses of MDMA in a double-blind crossover study. RESULTS: The 1.5 mg/kg dose (comparable to that typically used by most participants) produced significant subjective effects, peaking at about 2 h after dosing, including some effects commonly associated with stimulant drugs, hallucinogens, and entactogens. MDMA significantly increased plasma cortisol, prolactin, and dehydroepiandrosterone (DHEA) levels. Increase in plasma cortisol after the 1.5 mg/kg dose correlated with increased heart rate, rate-pressure product, and drug liking. Rise in DHEA correlated with euphoria. CONCLUSIONS: A typically used dose of MDMA produced effects commonly associated with stimulants and hallucinogens. Subjects liked MDMA. Correlations between cortisol and DHEA levels and some physiological and psychological effects are consistent with animal data suggesting that hormones modulate some responses to drugs of abuse.