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Smoking one cigarette produces rapid nicotine dose-related increases in hypothalamic–pituitary–adrenal (HPA) axis hormones, mood, and heart rate, but relatively little is known about the effects of smoking several cigarettes successively. Twenty-four healthy adult men who met Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) criteria for nicotine dependence provided informed consent. After overnight abstinence from smoking, men smoked three low- or high-nicotine cigarettes for 4 min each at 60 min intervals. Samples for nicotine and hormone analysis, Visual Analog Scale (VAS) ratings of subjective effects and heart rate were collected at 4, 8, 12, 16, 20, 30, 40, and 50 min after each cigarette. After low-nicotine cigarettes, nicotine levels, adrenocorticotropin hormone, and heart rate did not increase significantly, cortisol and dehydroepiandrosterone decreased significantly, and positive VAS ratings were lower but parallel to ratings after high-nicotine cigarette smoking. After high-nicotine cigarettes, peak nicotine levels increased monotonically. HPA axis hormones increased after smoking, but peak levels did not differ significantly after successive high-nicotine cigarettes. Positive VAS ratings and heart rate increased after each high-nicotine cigarette, but peak levels were lower after smoking the second and third cigarette. ‘Craving’ decreased significantly after smoking both low- and high-nicotine cigarettes, then gradually increased during the 60 min interval between cigarettes. These data are consistent with clinical reports that the first cigarette after overnight nicotine abstinence is most salient. Tolerance to the subjective and cardiovascular effects of nicotine developed rapidly during repeated cigarette smoking, but nicotine-stimulated increases in HPA axis hormones did not change significantly.Neuropsychopharmacology (2008) 33, 749–760; doi:10.1038/sj.npp.1301455; published online 16 May 2007 [ABSTRACT FROM AUTHOR]

Exercise-associated hyponatraemia (EAH) is an acute-onset imbalance in the tonicity of extracellular fluids during or after endurance exercise which results in a blood sodium concentration <135 mmol/L. Both excessive fluid intake and a concurrent decrease in urine formation contribute to this rapid-onset, predominantly dilutional, decrease in serum sodium, which can result in life-threatening pulmonary and cerebral oedema. Marathon runners with hypotonic encephalopathy related to EAH. including two cases with fatal cerebral oedema, demonstrated non-osmotic secretion of arginine vasopressin and fulfilled the essential diagnostic criteria for the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The pathophysiology of SIADH as the proximate cause of EAH accounts for otherwise puzzling clinical observations such as cases occurring after only moderate fluid intake or presenting hours after races. This formulation provides a framework for enhancing prevention by monitoring weight changes during races to detect positive fluid balance before the onset of mental status changes. Most importantly, SIADH supports a strategy for use of oral and intravenous hypertonic solutions, including 3% sodium chloride, for the emergent treatment of moderate and life-threatening symptoms of hypotonic encephalopathy, respectively. [ABSTRACT FROM AUTHOR]

The acute effects of smoking a Iow- or high-nicotine cigarette on hypothalamic-pituitary-adrenal (HPA) hormones, subjective responses, and cardiovascular measures were studied in 20 healthy men who met American Psychiatric Association Diagnostic and Statistical Manual IV criteria for nicotine dependence. Within four puffs (or 2 min) after cigarette smoking began, plasma nicotine levels and heart rate increased significantly (P<0.01), and peak ratings of 'high' and 'rush' on a Visual Analogue Scale were reported. Reports of 'high,' 'rush,' and 'liking' and reduction of 'craving' were significantly greater after smoking a high-nicotine cigarette than a Iow-nicotine cigarette (P<0.05). Peak plasma nicotine levels after high-nicotine cigarette smoking (23.9 ± 2.6 ng/ml) were significantly greater than after Iownicotine cigarette smoking (3.63 ± 0.59 ng/ml) (P<0.001). After smoking a Iow-nicotine cigarette, adrenocorticotropin hormone (ACTH), cortisol, dehydroepiandrosterone (DHEA), and epinephrine did not change significantly from baseline. After high-nicotine cigarette smoking began, plasma ACTH levels increased significantly above baseline within 12 min and reached peak levels of 21.88 ± 5.34 pml/l within 20 min. ACTH increases were significantly correlated with increases in plasma nicotine (r = 0.85; P < 0.0001), DHEA (r=0.66; P = 0.002), and epinephrine (r = 0.86; P < 0.0001). Cortisol and DHEA increased significantly within 20 min (P < 0.05) and reached peak levels of 424 ± 48 and 21.13 ± 2.55 ng/ml within 60 and 30 min, respectively. Thus cigarette smoking produced nicotine dose-related effects on HPA hormones and subjective and cardiovascular measures. These data suggest that activation of the HPA axis may contribute to the abuse-related effects of cigarette smoking. [ABSTRACT FROM AUTHOR]

Kappa opioid agonists functionally antagonize some abuse-related and locomotor effects of cocaine, and reduce cocaine self-administration by rhesus monkeys. We compared the cardiovascular and subjective effects of acute doses of the mu/kappa opioid nalbuphine alone (5 mg/70 kg, intravenous (i.v.)), with cocaine alone (0.2 mg/kg, i.v.), and with nalbuphine + cocaine in combination, under placebo-controlled, double-blind conditions. Subjects met American Psychiatric Association Diagnostic and Statistical Manual (DSM-IV) criteria for current cocaine abuse. Nalbuphine serum levels exceeded 50 ng/ml within 10 min after injection, and cocaine plasma levels exceeded 130 ng/ml within 4 min. Cocaine's pharmacokinetic profile did not change after concurrent nalbuphine administration. The nalbuphine + cocaine combination was safe and without synergistic effects on heart rate and systolic or diastolic blood pressure, Moreover, the addition of cocaine did not increase the subjective effects of nalbuphine. Visual Analog Scale (VAS) ratings of High, Euphoria, Stimulated, and Good Effect were equivalent after nalbuphine + cocaine and nalbuphine alone, and both were significantly higher than after cocaine alone (area under the curve analysis) (p < 0.05-0.01). Peak VAS ratings of High, Stimulated, Good Effect, and Drug Effect were also significantly higher after nalbuphine + cocaine than after cocaine alone (p < 0.01). Addiction Research Center Inventory (ARCI) scores were equivalent for narbuphine+cocaine and nalbuphine alone, but the PCAG, MBG, and amphetamine scores were significantly higher after both nalbuphine + cocaine and nalbuphine alone than after cocaine alone (p < 0.01-0.003). Thus, there were no additive interactions between nalbuphine and cocaine on cardiovascular, subjective, or drug level measures after acute administration. [ABSTRACT FROM AUTHOR]