Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (D-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of D-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous D-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. D-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of 'high'; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of D-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.

Introduction-Cannabinoids produce a spectrum of effects in humans including euphoria, cognitive impairments, psychotomimetic effects, and perceptual alterations. The extent to which dopaminergic systems contribute to the effects of Δ-9-tetrahydrocannabinol (Δ-9-THC) remains unclear. This study evaluated whether pretreatment with a dopamine receptor antagonist altered the effects of Δ-9-THC in humans.

These data provide prospective, empirical evidence that the DHEA-S level is increased by acute stress in healthy humans and that the DHEA-S-cortisol ratio may index the degree to which an individual is buffered against the negative effects of stress.

Acid extrusion is essential for osteoclast (OC) activity. We examined Na + and HCO3 --independent H + extrusion in ratand mouse OCs by measuring intracellular pH (pH1) changes, with the pH1 indicator BCECF (biscarboxyethyl-5-(6) carboxyfluorescein) after H+ loading with an ammonium pulse. 90% of OCs attached to glass do not possess HCO3-and Na+-independent H +-extrusion (rate of pH1 recovery = 0.043±0.007 (SEM) pH U/min, n = 26). In contrast, in OCs attached to bone, the pH1 recovery rate is 0.228±0.011 pH. U/min, n = 25. OCs on bone also possess a NH4+-permeable pathway not seen on glass. The boneinduced H+ extrusion was inhibited by salmon calcitonin (10-8 M, for 2 h), and was not present after pretreating the bone slices with the aminobisphosphonate alendronate (ALN). At ALN levels of 0.22 nmol/mm2 bone, H+ extrusion was virtually absent 12 h after cell seeding (0.004±0.002 pH U/min) and 50% inhibition was observed at 0.022 pmol ALN/mm2 bone. The Na+-independent H+ extrusion was not inhibited by bafilomycin Al (up to i-O M), although a bafilomycin Al (10-8 M) -sensitive H+ pump was present in membrane vesicles isolated from these osteoclasts. These findings indicate that Na+-independent acid extrusion is stimulated by osteoclast attachment to bone and is virtually absent when bone is preincubated with ALN, or when osteoclasts are treated with salmon calcitonin. (J. Clin. Invest.