Clinical pharmacology of drugs of abuse and of potential treatment medications

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The section is studying the clinical pharmacology of drug of abuse and potential treatment medications as part of our program to evaluate new treatments. Potential treatment medications are tested for abuse potential and screened for interactions with drug of abuse that might have efficacy and/or safety implications. The first phase of a study evaluating the safety and abuse potential of buprenorphine, a partial opioid agonist under development for treatment of opioid dependence, has been completed. Although the safety of SL buprenorphine in experienced opioid users without physical dependence has been reported at doses up to 32 mg, concerns have been raised about the potential acute health risk of buprenorphine if diverted and used by the IV route at doses equivalent to those used for maintenance. Buprenorphine was tested in a single-blind, double-dummy design in doses up to 16 mg IV and 12 mg SL. Vital signs and oxygen saturation and subjective and behavioral effects were monitored for up to 72 hours. There were no significant changes in oxygen saturation and only mild effects on blood pressure. Buprenorphine produced increases in positive subjective measures compared to placebo, but these effects did not increase in an orderly dose-related manner. The results are consistent with a ceiling effect and partial agonist activity. The abuse potential of IV buprenorphine does not appear to increase with dose, nor does there appear to be a substantial difference in abuse potential between IV and SL buprenorphine at the doses tested. Buprenorphine also appears to have a ceiling for cardio-respiratory effects and a high safety margin when administered by the IV route in the absence of other drugs. Other studies in the section have examined the influence of instructions and expectations on the reactions of humans to psychoactive drugs. Instructions and expectations have been shown to influence consumption levels, the ability of a drug to function as a reinforcer, its subjective effects, as well as other physiological effects. To further examine the influence of instructions of drug response, recreational drug users were trained to discriminate between 75 mg tripelennamine and placebo in two experiments differing in instructional set in a standard drug discrimination paradigm. Participants were instructed that one of the two drugs was more sedative-like than the other drug and during the other experiment one of the two drugs was more stimulant-like. Discrimination of diazepam and amphetamine was then tested in each experiment. The results indicated that instructions designed to give participants expectations as to the types of drugs they would be administered produced no effect on discrimination and only a few significant changes in subjective effects. On the other hand, when participants were asked to name (label) the drug they believed they received, their answers reflected the instructional set of the experiment. The study has implications for drug discrimination methology and for the factors that influence drug taking in humans.