This study shows a plateau on buprenorphine effects, consistent with its partial agonist classification, and that single doses of buprenorphine up to 70 times the recommended analgesic dose are well tolerated by nondependent humans.

Voucher-based reinforcement contingencies can produce sustained cocaine abstinence in injecting polydrug abusers.

delta 9-Tetrahydrocannabinol (THC), the primary psychoactive constituent of marijuana, is rapidly transferred from lungs to blood during smoking. Oxidative metabolism of THC yields the active metabolite, 11-hydroxy-delta 9-tetrahydrocannabinol (11-OH-THC), and the inactive metabolite, 11-nor-9-carboxy-delta 9-tetrahydrocannabinol (THCCOOH). Characterization of THC's absorption phase is important because of the rapidity with which THC penetrates the central nervous system to produce psychoactive effects. This study incorporated a highly automated procedure to sample blood and to capture rapid drug level changes during and following smoking. Human subjects smoked one marijuana cigarette (placebo, 1.75%, or 3.55% THC) once a week according to a randomized, crossover, double-blind Latin square design. Samples were analyzed by GC/MS for THC, 11-OH THC, and THCCOOH. THC levels increased rapidly, peaked prior to the end of smoking, and quickly dissipated. Mean peak 11-OH-THC levels were substantially lower than THC levels and occurred immediately after the end of smoking. THCCOOH levels increased slowly and plateaued for an extended period. The mean peak time for THCCOOH was 113 min and a correspondingly longer time course of detection was observed. This study provides the first complete pharmacokinetic profile of the absorption of THC and appearance of metabolites during marijuana smoking. These findings have implications for understanding the mechanisms underlying the performance-impairing effects of marijuana, as well as for aiding forensic interpretation of cannabinoid blood levels.

SummaryStructure-activlty relationships for cocaine and analog binding at the depamine, norepinephrine and serotonin transporters were determined.Cocaine inhibition of llgand binding to each of these sites has a stereospecific requirement for the levorotatory isomer. Binding potencies of cocaine derivatives involving N-substltution, C2 and C3 substituent modifications, however, revealed differences in structure-activity relationships for cocaine binding at the transporters.Removal of the N-methyl groups produced little change in binding potency at the dopamlne transporter site hut produced increases in binding potency at norepinephrlne and serotonin transporter sites.Changes in structure at the C2 substituent produced changes in binding potency at the dopamlne transporter which were generally similar in direction, but not necessarily in magnitude at the noreplnephrine and serotonin transporters.Modifications to the C3 substituent, especially substitution of a hydroxyl moiety, produce changes in affinity at norepinephrine and serotonin transporters which are much larger than those observed at dopamine transporters.In general, our results indicate that unique structural requirements exist for each transporter site, but that cocaine binding at norepinephrine and dopamine transporters can be described by more similar structure-actlvity relationships than those found for the serotonin transporter.Reguirements for cocaine binding to the dopamine transporter, which we have previously shown to be associated with the reinforcing effects of cocaine, include levorotatory sterospeclficlty, the benzene ring at C3, at least some portions of the tropane ring, and the presence of the C2 methyl ester group in the ~ conformation.

Caffeine is the world's most widely consumed drug with its main source found in coffee. We evaluated the caffeine content of caffeinated and decaffeinated specialty coffee samples obtained from coffee shops. Caffeine was isolated from the coffee by liquid-liquid extraction and analyzed by gas chromatography with nitrogen-phosphorus detection. In this study, the coffees sold as decaffeinated were found to have caffeine concentrations less than 17.7 mg/dose. There was a wide range in caffeine content present in caffeinated coffees ranging from 58 to 259 mg/dose. The mean (SD) caffeine content of the brewed specialty coffees was 188 (36) mg for a 16-oz cup. Another notable find is the wide range of caffeine concentrations (259-564 mg/dose) in the same coffee beverage obtained from the same outlet on six consecutive days.

Buprenorphine is a potent opioid analgesic used in the treatment of moderate to severe pain. At higher doses, it has demonstrated potential for treating heroin dependence. This study was undertaken to investigate buprenorphine pharmacokinetics by different routes of administration at dosages approximating those used in opioid-dependence studies. Six healthy men who were nondependent but who had a history of heroin use were administered buprenorphine in a crossover design study by intravenous (1.2 mg), sublingual (4.0 mg), and buccal (4.0 mg) routes of administration. Plasma samples were collected up to 96 h and assayed for buprenorphine and norbuprenorphine by negative chemical ionization tandem mass spectrometry. Plasma concentrations of buprenorphine and norbuprenorphine were analyzed by nonlinear regression analysis with standard noncompartmental methods. Buprenorphine biovailability by the sublingual and buccal routes was estimated as 51.4% and 27.8%, respectively, although there was considerable interindividual variability by both routes of administration. The terminal elimination half-lives were longer for the sublingual and buccal routes than for the intravenous route. The extended elimination half-lives may be due to a shallow depot effect involving sequestration of buprenorphine in the oral mucosa. Norbuprenorphine mean peak plasma concentrations were less than 1 ng/mL and were highly variable among different routes of administration and individuals. The terminal elimination half-life of norbuprenorphine was longer than buprenorphine.

Understanding the relationship of Delta(9)-tetrahydrocannabinol (THC) concentrations in oral fluid and plasma is important in interpretation of oral fluid test results. Current evidence suggests that THC is deposited in the oral cavity during cannabis smoking. This "depot" represents the primary or sole source of THC found when oral fluid is collected and analyzed. In this research, oral fluid and plasma specimens were collected from six subjects following smoking of cannabis cigarettes containing 1.75% and 3.55% THC. There was at least one week between each cannabis administration. Plasma specimens were analyzed by gas chromatography-mass spectrometry (GC-MS) and paired oral fluid specimens were analyzed by radioimmunoassay (RIA). In addition, one individual's oral fluid specimens were also analyzed by GC-MS. These data are unique in that they represent simultaneous or near simultaneous collection of oral fluid and plasma specimens in subjects following controlled cannabis dosing. The first oral fluid specimen, collected from one subject at 0.2 h following initiation of smoking, contained a THC concentration of 5800 ng/mL (GC-MS). By 0.33 h, the THC concentration in oral fluid had fallen to 81 ng/mL. From approximately 0.3 h through 4.0 h, the mean (+/- SD) THC ratio of oral fluid to plasma THC concentrations was 1.18 (0.62) with a range of 0.5 to 2.2. Within 12 h, both oral fluid and plasma THC concentrations generally declined below 1 ng/mL. RIA analyses of oral fluid specimens for six subjects demonstrated the same pattern of initial high levels of contamination immediately after smoking, followed by rapid clearing, and a slower decline over 12 h. Mean THC oral fluid concentrations by RIA at 0.2 h were 864 ng/mL and 4167 ng/mL compared to plasma concentrations of 52 ng/mL and 230 ng/mL at 0.27 h following the low- and high-dose cannabis cigarettes, respectively. The similarity in oral fluid and plasma THC concentrations following the dissipation of the initial "contamination" indicates the likelihood of a physiological link between these specimens. Recent studies have shown that sublingual or transmucosal administration of pure THC results in direct absorption of intact THC into the bloodstream, thereby bypassing the gastrointestinal tract. The current study demonstrates that THC is deposited in the oral cavity and remains for up to 24 h following cannabis smoking. The decline in THC oral fluid concentration over this time suggests that there may be absorption of THC into blood as previously shown with pure THC. Passive cannabis exposure studies appear to indicate that positive oral fluid tests for THC can occur shortly after cannabis smoke exposure, but results were negative within 1 h. Consequently, when very recent passive exposure to cannabis smoke can be ruled out, it is concluded that a positive oral fluid test provides credible evidence of active cannabis use.

Key Points Question How does smoked and vaporized cannabis acutely influence subjective drug effects, cognitive and psychomotor performance, and cardiovascular measures in healthy adults who infrequently use cannabis (>30 days since last use)? Findings In a crossover trial of 17 healthy adults, inhalation of smoked and vaporized cannabis containing 10 mg of Δ9-tetrahydrocannabinol (THC) produced discriminative drug effects and modest impairment of cognitive functioning, while inhalation of a 25-mg dose of THC was associated with pronounced drug effects, increased incidence of adverse effects, and significant impairment of cognitive and psychomotor ability. Vaporized cannabis produced greater pharmacodynamic effects and higher concentrations of THC in blood compared with equal doses of smoked cannabis. Meaning Significant, sometimes adverse, drug effects can occur at relatively low THC doses in infrequent cannabis users, and accordingly these data should be considered with regard to regulation of retail cannabis products and education for individuals initiating cannabis use.