The role of sex in daily levels of high-risk alcohol and cannabis co-use.

Background: Co-use of alcohol and cannabis is highly prevalent and may be associated with negative outcomes. The intersection between alcohol and cannabis use remains poorly understood. The present study assessed this intersection and the moderating effects of sex on the daily levels of high-risk alcohol and cannabis co-use. Methods: A secondary analysis of an experimental pharmacology study specifically designed to recruit individuals using both alcohol and cannabis was conducted. Thirty-three non-treatment seeking subjects (19 M/14F) reporting high-risk levels of alcohol and cannabis use completed a 30-day Timeline Follow-back (TLFB) assessment for alcohol and cannabis use, resulting in a total of N = 990 observations. Logistic models tested the probability of same day cannabis use as predicted by alcohol use (any use, total drinking, and binge drinking), sex, and alcohol use by sex interactions. Results: Drinking any alcohol on a given day was associated with a significant increase in the likelihood of same-day cannabis use (b = 0.61, p = 0.001) as was amount of alcohol consumed on a given day (b = 0.083, p = 0.012). These relations were significantly moderated by sex (b = 1.58, p<0.001; b = 0.14, p = 0.044). Male-identifying individuals demonstrated an increased probability of concurrent cannabis use with any alcohol use on a given day, and this relationship increased linearly as the number of drinks consumed increased. Conclusions: The present study investigated the patterns associated with co-using alcohol and cannabis in individuals reporting high-risk levels of both alcohol and cannabis use. The sex-dependent findings suggest that males are at higher risk for co-using alcohol and cannabis compared with females.

Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers.

Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30mg, PO, QID) for two weeks and received placebo ibudilast (0mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N=10/group) were randomized to receive ibudilast (20 or 40mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50mg/70kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4°C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p≤0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p≤0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.

Paradoxical effects of chronic morphine treatment on the temperature and pituitary-adrenal responses to acute restraint stress: a chronic stress paradigm.

Body temperature and pituitary-adrenal responses to restraint (15 min or 4 h) stress were evaluated in nondependent and morphine-dependent rats. Male Sprague-Dawley rats were treated twice daily with increasing doses of morphine (10-100 mg/kg, s.c.) for 16 days. Transmitters were implanted in the peritoneal cavity to monitor body temperature and blood was collected for hormone assays. Acute withdrawal from chronic morphine treatment was associated with reduced body weight, increased adrenal weight and decreased thymus weight. Sixteen days after termination of chronic morphine treatment, rats had recovered normal adrenal size, but still displayed marked thymus involution and reduced body weight. Restraint-induced hyperthermia was attenuated in morphine-dependent rats that had undergone 12-h withdrawal. Sixteen days after withdrawal, rats still had not fully recovered the hyperthermic response to restraint. Chronic morphine treatment resulted in a marked elevation of basal corticosterone concentrations. Despite the negative-feedback effects of elevated basal corticosterone concentrations, morphine-dependent rats that had undergone 12-h withdrawal displayed a potentiated and prolonged corticosterone response to restraint stress. In contrast, rats that had undergone 8-day and 16-day morphine withdrawal had recovered normal basal pituitary-adrenal activity, but displayed significantly reduced and shorter adrenocorticotropic hormone and corticosterone responses to restraint. These results suggest that chronic morphine dependence is a chronic stressor, resulting in profound and long-lasting changes in the temperature and pituitary-adrenal responses to acute restraint stress in a time-dependent manner. This morphine-dependence model may be useful in understanding the role that hormonal stress responses play in the maintenance and relapse to opioid use in humans.