Oral glycine administration increases brain glycine/creatine ratios in men: a proton magnetic resonance spectroscopy study.

Oral high-dose glycine administration has been used as an adjuvant treatment for schizophrenia to enhance glutamate neurotransmission and mitigate glutamate system hypofunction thought to contribute to the disorder. Prior studies in schizophrenia subjects documented clinical improvements after 2 weeks of oral glycine administration, suggesting that brain glycine levels are sufficiently elevated to evoke a clinical response within that time frame. However, no human study has reported on brain glycine changes induced by its administration. We utilized a noninvasive proton magnetic resonance spectroscopy ((1)H-MRS) technique termed echo time-averaged (TEAV) (1)H-MRS, which permits noninvasive quantification of brain glycine in vivo, to determine whether 2 weeks of oral glycine administration (peak dose of 0.8 g/kg/day) increased brain glycine/creatine (Gly/Cr) ratios in 11 healthy adult men. In scans obtained 17 h after the last glycine dose, brain (Gly/Cr) ratios were significantly increased. The data indicate that it is possible to measure brain glycine changes with proton spectroscopy. Developing a more comprehensive understanding of human brain glycine dynamics may lead to optimized use of glycine site agonists and glycine transporter inhibitors to treat schizophrenia, and possibly to treat other disorders associated with glutamate system dysfunction.

Reduced Plasma Nitric Oxide End Products in Cocaine-dependent Men.

Chronic cocaine abusers experience brain and peripheral vascular dysfunction, the severity of which tends to be greater in men than women. The mechanisms underlying these effects of cocaine are unknown. Because nitric oxide (NO) abnormalities play key roles in development of vascular dysfunction in several disorders, we determined whether vascular nitric oxide end product (NOx) levels, which can serve as markers of systemic vascular NO production, are reduced in cocaine-dependent (CD) subjects. Plasma samples from 24 CD men, 12 CD women, and matched comparison subjects (19 men, 14 women) were analyzed with a Sievers 280i nitric oxide chemiluminescence detection analysis system. NOx levels in comparison in women and men were 24.9 ± 6.6 and 23.3 ± 5.7 µmol/L, and in CD women and men were 22.5 ± 8.4 and 13.0 ± 9.6 µmol/L, respectively. ANCOVA analysis, adjusted for lifetime smoking, indicated group (P < 0.0005) and sex (P = 0.04) effects, both of which survived posthoc Scheffe tests. Reduced NOx levels in CD men drove the group difference. These data suggest that chronic cocaine abuse is associated with reduced NOx levels in men, although the finding also may be attributable to factors indirectly related to cocaine abuse, including cohort differences in other drug use or lifestyle factors. These findings warrant additional studies to more directly characterize vascular NO turnover in cocaine abusers and to establish whether NO abnormalities contribute to cocaine-associated vascular dysfunction and to sex differences in cocaine's effects.

Antiandrogen pretreatment alters cocaine pharmacokinetics in men.

Among cocaine users, men experience more adverse brain and vascular effects than their female counterparts. This could be caused by testosterone, which may potentiate some of cocaine's effects. We examined whether antiandrogen (flutamide, FL) pretreatment alters cocaine's acute behavioral, physiologic, and pharmacokinetic effects in men with histories of occasional cocaine use. Participants (N = 8) were pretreated with oral FL (250 mg) and placebo on separate study days followed by intravenous (IV) cocaine (0.4 mg/kg). Vital signs, subjective ratings, and blood samples for cocaine and metabolites were obtained at baseline and for 90 minutes after cocaine administration. FL, itself, had no effects on physiologic or subjective responses; however, after cocaine, heart rate recovered faster with FL pretreatment. Flutamide reduced peak plasma cocaine levels (Wilcoxon signed-rank z = 2.1, P < 0.04) and area under the curve (AUC; z = 1.96, P < 0.05). Additionally, FL reduced EME levels (z = 1.96, P < 0.05) and AUC for BE and EME (z = 2.38, P < 0.02 and z = 1.96, P < 0.05, respectively). These results suggest that FL may alter cocaine pharmacokinetics in men. Because cocaine and BE are vasoconstrictive, the data imply that FL might reduce some of cocaine's cardiovascular effects.