Edward J. Cone

Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects

Four healthy male subjects smoked two marijuana cigarettes or one marijuana cigarette and one placebo cigarette, or two placebo cigarettes on separate days in a random order crossover design. Each marijuana cigarette contained 2.8% delta-9-tetrahydrocannabinol (THC). Plasma hormones and THC were measured before and after each smoking session. Plasma LH was significantly depressed and cortisol was significantly elevated after smoking marijuana. Nonsignificant depressions of prolactin, FSH, testosterone and free testosterone and elevation of GH also occurred. Concurrent measures of subjective effects via subscales of the Addiction Research Center Inventory, Single Dose Questionnaire and a Visual Analog Scale were generally elevated. Significant impairment on a psychomotor performance task paralleled elevations in subjective effects, hormone effects and peak THC determinations. Although all the hormone effects were within normal basal ranges, interactions between these systems, and their effects on behavior cannot be discounted.

Effects of high-dose intravenous buprenorphine in experienced opioid abusers.

Abstract: Sublingual buprenorphine, a long-acting, partial mu-opioid agonist, is as effective as methadone in the treatment of heroin dependence, with a better safety profile due to its antagonist activity. However, the safety of therapeutic doses (8 to 16 mg) that might be diverted for intravenous (IV) use has not been demonstrated. To evaluate the safety and possible ceiling effects of buprenorphine administered IV to experienced opioid users, buprenorphine was administered to 6 nondependent opioid abusers residing on a research unit; the doses tested, in separate sessions, were 12 mg buprenorphine sublingual, IV/sublingual placebo, and escalating IV buprenorphine (2, 4, 8, 12, and 16 mg). Physiologic and subjective measures were collected for 72 hours post-drug administration. Buprenorphine minimally but significantly increased systolic blood pressure. Changes in heart rate or oxygen saturation among the 7 drug conditions were not statistically significant. The mean maximum decrease in oxygen saturation from baseline was greatest for the 8-mg IV dose. Buprenorphine produced positive mood effects, although with substantial variability among participants. Onset and peak effects occurred earlier following IV administration: peak IV effects occurred between 0.25 and 3 hours; peak sublingual effects occurred at 3 to 7 hours. Duration of effects varied among the outcome measures. The dose-response curves were flat for most parameters, particularly subjective measures. Side effects were mild except in one participant who experienced severe nausea and vomiting after the 12-mg IV dose. Buprenorphine appears to have a ceiling for cardiorespiratory and subjective effects and a high safety margin even when taken by the IV route.

Cerebral Responses to Single and Multiple Cocaine Injections in Newborn Sheep

ABSTRACT: Newborn infants exposed to cocaine near birth display a wide range of neurologic abnormalities, but the mechanism or mechanisms for these injuries remain unknown. We studied the cerebral effects of a single acute dose (4 mg/kg; n = 7) and multiple binge doses (4 mg/kg hourly for 5 h; n = 7) of i.v. cocaine in unancsthetized newborn (5 ± 1 d old) sheep. We measured cerebral blood flow, mean arterial blood pressure, arterial blood gases, and cerebral O2 metabolism. Measurements were made at baseline; 30 s; and 5,15, and 60 min after a single injection of cocaine in the acute group and at the same time intervals after the 5th dose of cocaine in the binge group. CBF increased by 98 ± 68% (mean ± SD) at 30 s after a single acute dose and by 97 ± 94% at 30 s after the 5th of five hourly binge doses. Although it returned to baseline by 5 min in the acute group, cerebral blood flow remained elevated 5, 15, and 60 min after the 5th cocaine dose in the binge group. At 30 s, mean arterial blood pressure increased by 57 ± 21% in the acute group and 46 ± 15% in the binge group. In both groups, mean arterial blood pressure remained elevated at 5 min. Although no change occurred in cerebral O2 metabolism in the acute group, an increase in cerebral O2 consumption (7.4 ±1.3 mL/100 g/ min versus 5.5 ± 1.1 at baseline) was observed at 5 min in the binge group. Thus, injection of cocaine as a single acute dose or after multiple binge doses results in acute cerebral vasodilation and hypertension in newborn sheep. Acute cerebral vasodilation, when combined within hypertension, may partially explain the pathogenesis of cocaine-associated neonatal neurologic abnormalities.

Risk Management Implications of Abuse Potential Assessment

Pharmaceutical risk management can be considered to be any strategies for minimizing risks and enabling the realization of the benefits of medications. Historically, risk management has been achieved through the drug label, which includes the US Controlled Substances Act (CSA) drug scheduling placement if abuse and dependence are considered sufficiently serious to warrant special restrictions. Since the late 1990s, additional strategies for addressing abuse- and dependence-related risks have been developed, including various postmarketing requirements for surveillance and reporting to the Food and Drug Administration. These strategies have been described in guidance documents and include risk assessment, risk management, and postmarketing surveillance. Preclinical abuse potential assessment provides early signals of potential risks and scheduling. Such studies are also considered in the premarket risk evaluation that guides recommendations concerning risk management strategies that go beyond drug scheduling along with the evaluation of abuse-deterrent drug products and how such evaluation might be informed by preclinical studies.