A medication that has been tested in the rat reinstatement model of relapse is aripiprazole, a D2 partial agonist used clinically to treat schizophrenia. In rats, aripiprazole blocks psychostimulant seeking induced by drug cues. To determine whether it would have this effect in humans, we enrolled cocaine-using methadone-maintained outpatients in a randomized clinical trial. To assist initial abstinence prior to randomization, participants earned vouchers for providing two weeks worth of thrice-weekly cocaine-negative urine specimens. Participants who achieved that criterion were randomized to receive aripiprazole (15/mg per day) or placebofor 25 weeks along with their daily methadone. The main outcome measure was latency to relapse, based on urine drug screens. We stopped the trial because too few (18 of 41) participants met the abstinence criterion. The results suggested that aripiprazole delayed lapse and relapse, but the effects did not reach statistical significance. Unexpectedly, the proportion of participants reporting cocaine craving was higher in the aripiprazole group, though frequency of craving was similar in the aripiprazole and placebo groups. These results did not support the utility of aripiprazole in recently abstinent cocaine users: it might delay relapse, but might also slightly increase craving. Difficulty in trial implementation underscores the fact that initial abstinence from cocaine is not a trivial hurdle. We also used EMA to investigate relationships among drinking, other drug use, and drug craving in a sample of 114 polydrug users who were not heavy drinkers and did not meet DSM criteria for alcohol abuse or dependence. Participants responded to 2-5 random prompts per day to report on their moods, cravings, and activities, and initiated entries when they used or acutely craved heroin or cocaine. Drinking alcohol was assessed in both types of entries. Breath alcohol was measured three times weekly. Participants reported drinking alcohol in 1.6% of random-prompt entries, 3.7% of event-contingent entries when craving cocaine and/or heroin, and 11.6% of event-contingent entries when using cocaine and/or heroin. Drinking was also associated with higher craving ratings, and with frequency of pre-study drinking. More drinking was detected by ambulatory self-report than by in-clinic breath testing. Even though we had screened out heavy drinkers from our sample of polydrug users, drinking was associated with heroin and cocaine craving and actual use. Stress-induced resumption or exacerbation of several unhealthy behaviors involves brain receptors for the neurotransmitter corticotropin-releasing factor (CRF). In a rat model of relapse, drugs that block CRF1 receptors prevent stress-induced reinstatement of responding for heroin, cocaine, alcohol, and nicotine, as well as palatable food. Therefore, we set out to assess the anticraving properties of the CRF1-receptor antagonist pexacerfont. Because the safety of pexacerfont given to people who are likely to use cocaine or heroin has not yet been established, we conducted a test of concept study evaluating pexacerfont for protection against stress-induced eating and food craving. The study was conducted as a randomized, double-blind trial with two groups, pexacerfont and placebo, at our outpatient clinic. We enrolled 31 healthy adults scoring high on a measure of dietary restraint (food preoccupation and chronic unsuccessful dieting), with body-mass index (BMI) > 22. Participants were randomized to pexacerfont (300mg/day for 7 days, then 100mg/day for 21 days) or placebo. Outcome measures were kilocalories of snack-food consumption in bogus taste tests after laboratory stressors and food-cue exposures, and nightly ratings of food problems/preoccupation on the Yale Food-Addiction Scale (YFAS). Although the study was stopped early for administrative reasons unrelated to safety or outcome, the available data from the bogus taste test suggested some protective effect of pexacerfont against eating after a laboratory stressor. Similarly, nightly YFAS ratings were lower with pexacerfont than placebo, but this effect should be interpreted with caution because it was present from the first night of pill ingestion, despite pexacerfonts slow pharmacokinetics. Though not definitive, the findings support further investigation of the anticraving properties of pexacerfont or other CRF1 antagonists, especially for food. Our study was, to our knowledge, the only one of several translational studies of pexacerfont to show some signal, perhaps due to our careful choices of population and behavioral measures. We are continuing to evaluate patient characteristics that may guide developments in personalized medicine. Using inducible pluripotent stem cells (iPSCs), we produced DA neurons from opioid-dependent and control participants carrying different 3 VNTR (variable number tandem repeat) polymorphisms in the gene for the dopamine transporter (DAT or SLC6A3). We found that the 3 VNTR polymorphism affected DAT expression and that treatment of the neurons with valproic acid alters the expression of several genes important for dopaminergic functioning, including DAT, Nurr1 and TH. Valproic acid also significantly increased expression of D2 receptors, especially in cell lines derived from the opioid-dependent participants. Our data suggest that human iPSC-derived DA neurons are a useful in vitro experimental model to examine the effects of genetic variation on gene regulation, to examine underlying mechanisms of addiction and other disorders, and to serve as a platform for treatment development. One of the factors affecting the health of drug users is exposure to adulterants in street drugs. These adulterants, which may or may not have pharmacological effects, are often added to increase volume of powdered drug in order to increase profits. Levamisole, an anthelmintic drug with cholinergic properties, has been implicated in cases of drug-induced vasculitis when added to cocaine for profit purposes. We are collaborating with investigators in the National Institute of Arthritis and Musculoskeletal and Skin Diseases to understand the mechanisms of levamisole- and other drug-induced autoimmunity. The results of the collaboration highlight a novel causal role for cholinergic neuroimmunomodulation of the innate immune system in drug-induced autoimmunity and suggest potential novel therapeutic targets in environmental triggers of inflammatory diseases, in cocaine users and others. Finally, we continue to develop Geographical Momentary Assessment (GMA), an approach to measurement and understanding of the relationships among mood, drug use, and environmental exposure to psychosocial stressors in participants daily travels. GMA is largely a descriptive technique, but we remain committed to transforming description into intervention. For example, we have shown that electronic-diary studies can provide amazing insight into the daily lives of substance abusers during treatment and data that are sensitive to behavioral changes during even brief periods of abstinence. The technologies that enable us to collect data on drug use, craving, and stress in the field may also be used for delivery of treatment in the field, perhaps in response to the patients movement toward previously identified triggers.
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