Within the context of clinical trials, the section evaluates methodological issues relevant to both research and treatment, such as monitoring drug use. In a previously published study, we found that cocaine's half-life is longer in active street users than in occasional users despite there being no change in the half-life of its main metabolite benzoylecgonine, suggesting that regular use of cocaine alters its the disposition and elimination (Moolchan ET, Cone EJ, Wtsadik A, Huestis MA, Preston KL. J Analytical Toxicology, 24, 458-466, 2000). In another previously published study, we showed that sweat patches could be an alternate method for monitoring drug use, with the advantage of a week-ly window of detection (Huestis MA, Preston KL, Wong CJ, Umbricht A, Cone EJ,. J Analytical Toxicology, 24, 509-521, 2000). In a third study, we assessed the performance of a new urine assay for 6-acetylmorphine (6-AM), a heroin metabolite that is a specific marker for heroin use. 6-AM detection is clinically important because the ingestion of poppy seeds or licit opiate analgesics can produce positive results on urine opiate tests that screen only for heroin-nonspecific metabolites such as morphine and codeine. In the federally mandated workplace drug-testing program, 6-AM GC-MS analysis is now required. Similarly, the Department of Health and Human Services (HHS) requires morphine-positive specimens to be retested by GC/MS for 6-AM at a cutoff concentration of * 10 ng/mL. (In both sets of guidelines, the screening cutoff for morphine and codeine has been raised from * 300 ng/mL to * 2000 ng/mL.) One drawback of screening for 6-AM is its half-life of only 0.6 hours, which makes it detectable in urine for only a few hours after heroin exposure. We collected urine specimens three times per week from 44 participants in a methadone-maintenance program in order to assess the new assay and its performance at the new cutoff concentrations. Of the 1377 urine specimens screened, 261 or 18.9% were positive for opiates at * 300 ng/mL, 153 or 11.1% were positive for opiates at * 2000 ng/mL, and 55 or 4.0% were positive for 6AM at * 10 ng/mL. Of the 253 specimens * 300 ng/mL and available for GC/MS analysis, 231 or 91.3% were confirmed for morphine or codeine at * 300 ng/mL. Of the 151 * 2000 ng/mL and available for GC/MS analysis, 122 or 80.8% were confirmed for morphine or codeine at * 2000 ng/mL. All specimens screening positive for 6-AM also confirmed positive by GC/MS at * 10 ng/mL. Furthermore, none of the specimens screening at * 300 but less than 2000 ng/mL for opiates confirmed positive for 6-AM at * 10 ng/mL. Forty-four (80%) of the 55 positive 6AM urine specimens had concentrations between 201 and 9096 ng/mL, suggesting recent heroin use. Increasing the opiate screening and confirmation cutoffs for the federal workplace drug-testing program from 300 to 2000 ng/mL, resulted in 8% fewer opiate positive tests in individuals participating in a methadone maintenance treatment program. However, recent heroin use, as defined by a urine concentration of 6-AM * 10 ng/mL, was not affected by this change. Although the 6-AM screening assay identified far fewer positive opiate tests, 4% as compared to 11% in the opiate * 2000 ng/mL assay, it clearly identified heroin, as compared to possible poppy seed or codeine use. In addition, although there was a significant correlation between 6-AM and total morphine concentrations, total urinary morphine could not be reliably predicted from the GC/MS 6-AM concentrations. Replacement of an opiate screening assay directed at the measurement of total morphine with an assay directed toward 6-AM would result in the detection of fewer opiate positive tests. The 6-AM assay could be useful in detection of recent heroin exposure and in reducing potential "carryover" positives in consecutive urine tests in treatment and employee assistance programs. In a large study now nearing completion, we are comparing the utility of therapeutic drug monitoring for methadone across a variety of biological matrices, including plasma, saliva, and sweat; we are also planning to assay levels of cortisol and prolactin as possible markers of methadone's pharmacodynamic efficacy.