Chronic administration of lipophilic drugs can result in accumulation and prolonged elimination during abstinence. It has been suggested that cocaine and/or metabolites can be detected in saliva and urine for an extended period following long-term, high-dose administration. The effects of chronic oral cocaine administration in healthy volunteer subjects with a history of cocaine abuse were investigated. Subjects were housed on a closed clinical ward and were administered oral cocaine in up to 16 daily sessions. In each session, volunteers received five equal doses of oral cocaine with 1 h between doses. Across sessions, cocaine was administered in ascending doses from an initial dose of 100 mg (500 mg/day) up to 400 mg (2 g/day), increasing by 25 mg/dose/session (125 mg/session). Participation in the study was terminated if cardiovascular safety parameters were exceeded. Plasma and saliva specimens were collected periodically during the dosing sessions and during the one-week withdrawal phase at the end of the study. All urine specimens were collected throughout the entire study. Specimens were analyzed for cocaine and metabolites by solid-phase extraction followed by gas chromatographic-mass spectrometric analysis in the SIM mode. The limit of detection for each analyte was approximately 1 ng/mL. The analytes measured included benzoylecgonine (BZE), ecgonine methyl ester, cocaine, benzoylnorecgonine, norcocaine, m- and p-hydroxycocaine, and m- and p-hydroxybenzoylecgonine. Noncompartmental analysis was employed for the determination of plasma and saliva pharmacokinetic parameters. Urinary elimination half-lives for cocaine and metabolites were determined by constructing ARE (amount remaining to be excreted) plots. Two phases of urinary elimination of cocaine and metabolites were observed. An initial elimination phase was observed during withdrawal that was similar to the elimination pattern observed after acute dosing. The mean (N = 6) plasma, saliva, and urine cocaine elimination half-lives were 1.5 +/- 0.1 h, 1.2 +/- 0.2 h, and 4.1 +/- 0.9 h, respectively. For three subjects, the mean cocaine urinary elimination half-life for the terminal phase was 19.0 +/- 4.2 h. There was some difficulty in determining if a terminal elimination phase for cocaine was present for the remaining three subjects because of interference by high concentrations of BZE. A terminal elimination phase was also observed for cocaine metabolites with half-life estimates ranging from 14.6 to 52.4 h. These terminal elimination half-lives greatly exceeded previous estimates from studies of acute cocaine administration. These data suggest that cocaine accumulates in the body with chronic use resulting in a prolonged terminal elimination phase for cocaine and metabolites.

The goal of this study was to determine whether slowly infused, response-independent cocaine would reduce cocaine self-administration in an animal model of drug abuse. Seven male rhesus monkeys self-administered i.v. cocaine on a fixed-ratio 30 schedule (5-min time-out). With unit dose (0.056 mg/kg per infusion for one monkey and 0.032 mg/kg per infusion for the rest) and infusion volume (0.5 ml) held constant, the rate of delivery was manipulated (0.125, 0.1875, 0.375, 0.75 and 3 ml/min, with infusions lasting 240, 160, 80, 40, and 10 s, respectively). Response rates increased monotonically as a function of delivery rate. Responding for cocaine at the slowest delivery rate did not differ from saline. The effects of infusing additional cocaine (starting 30 min prior to the session) at this non-reinforcing rate (0.125 ml/min) were then determined. Delivery rate of the self-administered infusion was manipulated as before. Non-contingent cocaine significantly increased responding for cocaine (at the fastest delivery rate) and for saline. While non-contingent cocaine reduced responding for cocaine in two of the seven monkeys, it also significantly reduced responding in three monkeys that responded for food on the same schedule. Plasma levels of cocaine delivered at rates of 0.125 and 3 ml/min were compared in five other monkeys. While a higher peak was reached with the faster infusion, levels did not differ after 5 min. Thus, when an infusion became available (after the 5-min time-out) in the self-administration experiments, plasma levels should not have differed regardless of the delivery rate. These results suggest that a low-dose, slow-delivery treatment with cocaine might prime or reinstate drug seeking rather than decrease it.

Drugs derived from amphetamine, methamphetamine and their methylenedioxy- analogues, although being sold as plant food or bath salts, are being used as legal alternatives to scheduled amphetamine stimulants. These products often contain methylone, mephedrone and methylenedioxypyrovalerone (MDPV)--three amphetamine derivatives shown to have strong pharmacological effects. Four postmortem cases were analyzed for methylone, mephedrone and MDPV, with drug levels quantitated in multiple biological matrices. All four cases had detectable levels of methylone, with heart blood concentrations of 0.740, 0.118, 0.060 and 1.12 mg/L. Analysis of several tissue samples shows that methylone does not sequester in a particular tissue type after death. The average liver-to-blood ratio was 2.68. Two cases also had MDPV present, but insufficient data were collected to formulate a hypothesis on postmortem sequestration or redistribution. Two different extraction methods, as well as analysis of derivatized and underivatized methylone, show that the drug is suitable for analysis in either method. The cases are believed to show one instance of chronic methylone use, with a urine concentration of 38 mg/L.

Detection times reported for single-dose studies may not predict detection times following repeated cocaine dosing. Although repeated cocaine administration can result in drug accumulation and extended excretion time, there is a paucity of data from controlled dosing studies with repeated drug administration. We compared detection times for cocaine and benzoylecgonine (BZE) in oral fluid and BZE in urine following single and repeated cocaine dosing. Two groups of cocaine-experienced subjects participated in these studies. The single-dose group received cocaine by intravenous, intranasal, and smoked administration. The repeated dose group received daily escalating oral cocaine doses culminating in a total of 1,250-2,000 mg. Oral fluid and urine specimens following the last dosing were analyzed by gas chromatography-mass spectrometry. Detection times were determined as the time to the last positive specimen. The effect of repeated dosing was to extend oral fluid detection times for cocaine approximately fourfold and BZE detection times sevenfold, whereas urine BZE detection times were extended twofold. Because cocaine abusers frequently self-administer higher and repeated doses, we conclude that the short detection times observed in single-dose studies underestimate the utility of oral fluid for detection of cocaine abuse in realistic settings.

Long-term use of cocaine may produce neurophysiological and metabolic alterations that differ from acute drug use. A laboratory model that was capable of evaluating the effects of chronic cocaine administration in human subjects was needed. Chronic oral administration of cocaine was considered a feasible route because of the ease of administration, control of dosing patterns, and possible reduction in medical risks compared with the intravenous and smoked routes. This clinical study was conducted to evaluate chronically administered oral cocaine as a means of studying cocaine addiction and withdrawal in humans. Cocaine-abusing volunteers were given multiple doses of oral cocaine each day in up to 16 daily sessions (including three placebo sessions). In each daily session, volunteers received five equal doses separated by hourly intervals. Across sessions, the dose was increased from an initial dose of 100 mg (500 mg/day) to 400 mg (2000 mg/day) in the last session. The dose for each consecutive cocaine session was increased by 25 mg/dose/session (125-mg total increase per session). Twelve subjects were enrolled in the study; however, three subjects dropped out prior to completion of at least three sessions. Two subjects completed all 13 cocaine sessions. The remaining seven subjects completed from 3 to 11 sessions; their participation was terminated early for safety and behavioral reasons. Plasma was collected during all sessions and analyzed for cocaine and metabolites by solid-phase extraction followed by gas chromatography-mass spectrometry. Oral cocaine administration resulted in peak plasma concentrations of cocaine approximately 1 h after administration. Accumulation of cocaine was evident between hourly doses and there was evidence of dose-proportional increases in area under the curve (AUC) measures across sessions. A variety of cocaine metabolites was measured in plasma including benzoylecgonine, ecgonine methyl ester, norcocaine, benzoylnorecgonine, and p and m-hydroxy metabolites of cocaine and benzoylecgonine. During chronic oral dosing, there appeared to be a trend for AUC ratios (AUCmetabolite/AUCcocaine) of benzoylecgonine and ecgonine methyl ester to decrease and norcocaine to increase, indicating the possibility of dose-, time-, or route-dependent changes in the absorption and/or metabolism of cocaine. Overall, this study demonstrated that chronic oral dosing of cocaine produced dose-related increases in plasma cocaine concentration, and this model could be useful for studying the effects of chronic cocaine use in human subjects.