[I've included information on ethanol toxicity to illustrate the possible connections between hangovers and toxicity. The dangers represented by factors involved in alcoholic beverage induced hangovers should be better acknowledged by the medical research community.]

Wall TL, Horn SM, Johnson ML, Smith TL, Carr LG.
Hangover symptoms in Asian Americans with variations in the aldehyde dehydrogenase (ALDH2) gene.
J Stud Alcohol 2000 Jan;61(1):13-7
"OBJECTIVE: Hangovers are not experienced by all people and whether they contribute to the development of alcoholism is unclear. One population that might provide some insight into the role of hangover in the etiology of alcohol use disorders is that of individuals of Asian heritage. Certain Asians have lower rates of alcohol use and alcoholism, findings associated with a mutation in the aldehyde dehydrogenase (ALDH2) gene. Asians with ALDH2*2 alleles drink less and are less likely to be alcoholic than Asians without this mutation. Following alcohol ingestion, they exhibit more intense reactions to alcohol and generate higher levels of the metabolite acetaldehyde. This study evaluated hangover symptoms in Asian Americans with variations in the ALDH2 gene. METHOD: Men and women of Chinese, Japanese and Korean heritage (N = 140) were asked about their drinking history and a blood sample was collected for genotyping at the ALDH2 locus. Subjects used a Likert-type scale to estimate their severity of hangover and completed a 13-item hangover scale assessing the frequency of hangover symptoms during the previous 6 months. RESULTS: With abstainers (n = 17) excluded and with the effects of gender and recent drinking history controlled, ALDH2 genotype accounted for a significant amount of additional variability in the estimated severity of hangover score with a similar, but nonsignificant, trend for a five-item subscale score derived from the hangover scale. CONCLUSIONS: These results suggest that Asian Americans with ALDH2*2 alleles may experience more severe hangovers that may contribute, in part, to protection against the development of excessive or problematic drinking in this population." [Abstract]

Mantle D, Preedy VR.
Free radicals as mediators of alcohol toxicity.
Adverse Drug React Toxicol Rev 1999 Nov;18(4):235-52
"In this article we have reviewed recent evidence in support of the hypothesis that acute/chronic alcohol toxicity is mediated primarily via the generation of damaging free radical species in various tissues. Studies in man, animal model or in vitro experimental systems have shown: (1) the demonstration of alcohol-induced free radical species directly via esr spectroscopic analysis; (2) increases in indirect markers of ethanol-induced free radical damage in tissues, such as lipid peroxides and protein carbonyl; (3) ethanol-induced alterations in the levels of endogenous tissue antioxidants. These data show the induction of free radicals by ethanol to be a complex interactive process. The classical pathway for ethanol metabolism, catalysed by alcohol dehydrogenase to form acetaldehyde, results in the formation of free radicals, resulting from concomitant changes in NADH levels and NADH/NAD+ redox ratios, which in turn modulate the activity of the free radical generating enzyme xanthine oxidase. The induction of CYP 2E1 in the microsomes results in the generation of HER, another major route by which ethanol induces free radical formation. In addition to the above, ethanol may also induce free radical formation via the reaction of aldehyde oxidase with acetaldehyde or NADH to generate oxyradicals via disturbance in the metabolism of the pro-oxidant iron, or via increased efflux from mitochondria following altered mitochondrial oxidative metabolism." [Abstract]

Zimatkin SM, Liopo AV, Deitrich RA.
Distribution and kinetics of ethanol metabolism in rat brain.
Alcohol Clin Exp Res 1998 Nov;22(8):1623-7
"It was found that the accumulation of acetaldehyde produced from 50 mM ethanol in rat brain homogenates takes place in all major brain regions. The velocity varied between 3.5 to 7.1 nmol/mg of protein/hr. The rate increased in the following order: brain hemispheres, striatum, brainstem, hypothalamus, and cerebellum. Significant regional differences in this process were found: in the initial period of incubation (5 min), acetaldehyde accumulation was maximal in the brain hemispheres; but, in the 30- to 60-min period, it became significantly higher in the cerebellum. Inhibition of this process by the catalase inhibitor, 3-amino-1,2,4-triazole (8 mM), was minimal in the brainstem (27%) and maximal (57%) in the cerebellum, despite nearly complete inhibition of catalase. This would indicate that processes other than catalase activity must contribute to acetaldehyde accumulation." [Abstract]

Galter, Dagmar, Carmine, Andrea, Buervenich, Silvia, Duester, Gregg, Olson, Lars
Distribution of class I, III and IV alcohol dehydrogenase mRNAs in the adult rat, mouse and human brain
Eur J Biochem 2003 270: 1316-1326
"The localization of different classes of alcohol dehydrogenases (ADH) in the brain is of great interest because of their role in both ethanol and retinoic acid metabolism. Conflicting data have been reported in the literature. By Northern blot and enzyme activity analyses only class III ADH has been detected in adult brain specimens, while results from riboprobe in situ hybridization indicate class I as well as class IV ADH expression in different regions of the rat brain. Here we have studied the expression patterns of three ADH classes in adult rat, mouse and human tissues using radioactive oligonucleotide in situ hybridization. Specificity of probes was tested on liver and stomach control tissue, as well as tissue from class IV ADH knock-out mice. Only class III ADH mRNA was found to be expressed in brain tissue of all three investigated species. Particularly high expression levels were found in neurons of the red nucleus in human tissue, while cortical neurons, pyramidal and granule cells of the hippocampus and dopamine neurons of substantia nigra showed moderate expression levels. Purkinje cells of cerebellum were positive for class III ADH mRNA in all species investigated, whereas granular layer neurons were positive only in rodents. The choroid plexus was highly positive for class III ADH, while no specific signal for class I or class IV ADH was detected. Our results thus support the notion that the only ADH expressed in adult mouse, rat and human brain is class III ADH." [Abstract]

Kinoshita, Hiroshi, Jessop, David S., Finn, David P., Coventry, Toni L., Roberts, David J., Ameno, Kiyoshi, Jiri, Iwao, Harbuz, Michael S.
Acetaldehyde, a metabolite of ethanol, activates the hypothalamic-pituitary-adrenal axis in the rat
Alcohol Alcohol. 2001 36: 59-64
"— Cyanamide is a potent inhibitor of aldehyde dehydrogenase (ALDH: EC 1.2.1.3) used in the treatment of alcoholics. In the presence of ethanol, cyanamide causes an accumulation of acetaldehyde, a highly toxic metabolite of ethanol, with unpleasant side-effects. A similar accumulation is seen in some Oriental people with low ALDH activity. We have investigated the effects of ethanol and cyanamide administration on the activation of the hypothalamic–pituitary–adrenal (HPA) axis using in situ hybridization histochemistry and radioimmunoassay. Ethanol plus cyanamide resulted in a significant increase in corticotrophin-releasing factor and arginine vasopressin mRNA in the paraventricular nucleus, and pro-opiomelanocortin mRNA in the anterior pituitary. Plasma corticosterone concentrations were also significantly elevated following ethanol plus cyanamide administration. The blood concentration of acetaldehyde in the ethanol plus cyanamide group increased significantly. These results suggest that acetaldehyde, induced by blocking ethanol metabolism, is able to activate the HPA axis operating through a central mechanism." [Full Text]

Jones AW.
Elimination half-life of methanol during hangover.
Pharmacol Toxicol 1987 Mar;60(3):217-20
"This paper reports the elimination half-life of methanol in human volunteers. Experiments were made during the morning after the subjects had consumed 1000-1500 ml red wine (9.5% w/v ethanol, 100 mg/l methanol) the previous evening. The washout of methanol from the body coincided with the onset of hangover. The concentrations of ethanol and methanol in blood were determined indirectly by analysis of end-expired alveolar air. In the morning when blood-ethanol dropped below the Km of liver alcohol dehydrogenase (ADH) of about 100 mg/l (2.2 mM), the disappearance half-life of ethanol was 21, 22, 18 and 15 min. in 4 test subjects respectively. The corresponding elimination half-lives of methanol were 213, 110, 133 and 142 min. in these same individuals. The experimental design outlined in this paper can be used to obtain useful data on elimination kinetics of methanol in human volunteers without undue ethical limitations. Circumstantial evidence is presented to link methanol or its toxic metabolic products, formaldehyde and formic acid, with the pathogenesis of hangover." [Abstract]

Dobrzynska I, Skrzydlewska E, Kasacka I, Figaszewski Z.
Protective effect of N-acetylcysteine on rat liver cell membrane during methanol intoxication.
J Pharm Pharmacol 2000 May;52(5):547-52
"Methanol is oxidized in-vivo to formaldehyde and then to formate, and these processes are accompanied by the generation of free radicals. We have studied the effect of N-acetylcysteine on liver cell membrane from rats intoxicated with methanol (3.0 g kg(-1)). Evaluation of the effect was achieved by several methods. Lipid peroxidation and surface charge density were measured. An ultrastructural study of the liver cells was undertaken. The concentration of marker enzymes of liver damage (alanine aminotransferase and aspartate aminotransferase) in blood serum was measured. Methanol administration caused an increase in lipid peroxidation products (approximately 30%) as well as in surface charge density (approximately 60%). This might have resulted in the membrane liver cell damage visible under electron microscopy and a leak of alanine aminotransferase and aspartate aminotransferase into the blood (increase of approximately 70 and 50%, respectively). Ingestion of N-acetylcysteine with methanol partially prevented these methanol-induced changes. Compared with the control group, lipid peroxidation was increased by approximately 3% and surface charge density by approximately 30%. Alanine aminotransferase and aspartate aminotransferase activity increased by 9 and 8%, respectively, compared with the control group. The results suggested that N-acetylcysteine was an effective antioxidant in methanol intoxication. It may have efficacy in protecting free radical damage to liver cells following methanol intoxication." [Abstract]

Skrzydlewska E.
Decreased antioxidant status and increased lipid peroxidation in rats after methanol intoxication.
Rocz Akad Med Bialymst 1996;41(2):397-404
"The liver is the main metabolic place where the methanol is oxidized to formaldehyde and to formate. The aim of this paper was to study the liver antioxidant system in acute methanol intoxication, after 6, 12, 24 hours and 2, 5 and 7 days of alcohol administration into rats. In liver homogenates the superoxide dismutase, catalase, peroxidase and reductase glutathione activity and content of malondialydehyde (MDA), SH-compounds in protein and non-protein fraction and ascorbate were estimated. Activity of superoxide dismutase and catalase was significantly increased after 6 hours following methanol ingestion and persisted up to 2-5 days of intoxication. It was accompanied by significant decreased of reductase and peroxidase glutathione activities. The protein and non-protein SH-groups were significantly decreased during 6 hours to 5 days following methanol ingestion. The liver MDA content was considerably increased. After 2 days since methanol intoxication the liver vitamin C content was significantly decreased in comparison with the control group. The obtain results demonstrated that during methanol induced liver injury there are increase of lipid peroxidation and impairment of proantioxidant equilibrium in favour to prooxidant." [Abstract]

Bendtsen P, Jones AW, Helander A.
Urinary excretion of methanol and 5-hydroxytryptophol as biochemical markers of recent drinking in the hangover state.
Alcohol Alcohol 1998 Jul-Aug;33(4):431-8
"Twenty healthy social drinkers (9 women and 11 men) drank either 50 g of ethanol (mean intake 0.75 g/kg) or 80 g (mean 1.07 g/kg) according to choice as white wine or export beer in the evening over 2 h with a meal. After the end of drinking, at bedtime, in the following morning after waking-up, and on two further occasions during the morning and early afternoon, breath-alcohol tests were performed and samples of urine were collected for analysis of ethanol and methanol and the 5-hydroxytryptophol (5-HTOL) to 5-hydroxyindol-3-ylacetic acid (5-HIAA) ratio. The participants were also asked to quantify the intensity of hangover symptoms (headache, nausea, anxiety, drowsiness, fatigue, muscle aches, vertigo) on a scale from 0 (no symptoms) to 5 (severe symptoms). The first morning urine void collected 6-11 h after bedtime as a rule contained measurable amounts of ethanol, being 0.09 +/- 0.03 g/l (mean +/- SD) after 50 g and 0.38 +/- 0.1 g/l after 80 g ethanol. The corresponding breath-alcohol concentrations were zero, except for three individuals who registered 0.01-0.09g/l. Ethanol was not measurable in urine samples collected later in the morning and early afternoon. The peak urinary methanol occurred in the first morning void, when the mean concentration after 80 g ethanol was approximately 6-fold higher than pre-drinking values. This compares with a approximately 50-fold increase for the 5-HTOL/5-HIAA ratio in the first morning void. Both methanol and the 5-HTOL/5-HIAA ratio remained elevated above pre-drinking baseline values in the second and sometimes even the third morning voids. Most subjects experienced only mild hangover symptoms after drinking 50 g ethanol (mean score 2.4 +/- 2.6), but the scores were significantly higher after drinking 80 g (7.8 +/- 7.1). The most common symptoms were headache, drowsiness, and fatigue. A highly significant correlation (r = 0.62-0.75, P <0.01) was found between the presence of headache, nausea, and vertigo and the urinary methanol concentration in the first and second morning voids, whereas 5-HTOL/5-HIAA correlated with headache and nausea. These results show that analysing urinary methanol and 5-HTOL furnishes a way to disclose recent drinking after alcohol has no longer been measurable by conventional breath-alcohol tests for at least 5-10h. The results also support the notion that methanol may be an important factor in the aetiology of hangover." [Abstract]

Yoshimoto K, Komura S, Kawamura K.
Occurrence in vivo of 5-hydroxytryptophol in the brain of rats treated with ethanol.
Alcohol Alcohol 1992 Mar;27(2):131-6
"The effect of ethanol (EtOH) on the release of dopamine (DA) and 5-hydroxytryptamine (5-HT) and the efflux of their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindol-3-ylacetic acid (5-HIAA) and 5-hydroxytryptophol (5-HTOL) from the striatum of the freely moving rat were studied in vivo using brain microdialysis. Striatal DA and 5-HT release was maximally enhanced at first fraction after the administration of EtOH (2 g/kg, i.p.). The level of the DA-oxidized metabolite, DOPAC, decreased significantly. In the 5-HT metabolic pathway, the oxidized metabolite, 5-HIAA, did not show significant changes, whereas levels of the biogenic alcohol 5-HTOL were increased to 180% at 90 min following EtOH administration. It is suggested that EtOH, most probably via acetaldehyde, could shift 5-HT metabolism from the oxidative to the reductive pathway in the rat brain." [Abstract]

Some M, Svensson S, Hoog JO, Helander A.
Studies on the interaction between ethanol and serotonin metabolism in rat, using deuterated ethanol and 4-methylpyrazole.
Biochem Pharmacol 2000 Feb 15;59(4):385-91
"The metabolic interaction between ethanol and serotonin (5-hydroxytryptamine) via alcohol dehydrogenase (ADH; EC 1.1.1.1) was studied in tissue homogenates of Sprague-Dawley rats by following the transfer of deuterium from deuterated ethanol over endogenous NADH to 5-hydroxytryptophol (5HTOL). Homogenates of whole brain, lung, spleen, kidney, liver, stomach, jejunum, ileum, colon, and caecum were incubated in the presence of [2H2]ethanol and 5-hydroxyindole-3-acetaldehyde (5HIAL), and the [2H]5HTOL formed was identified and quantified using gas chromatography-mass spectrometry. ADH activity was most abundant in liver, kidney, and within the gastrointestinal tract. The highest incorporation of deuterium was obtained in homogenates of kidney, lung, and colon, whereas in brain, which contains very low ADH activity, no incorporation could be demonstrated. Addition of extra NAD+ (2.4 mM) increased the formation of [2H]5HTOL 2.6-fold in liver homogenates, but only 1.2-fold in kidney homogenates. 4-Methylpyrazole, a potent inhibitor of class I ADH, inhibited the 5HIAL reduction in homogenates of lung, kidney, jejunum, ileum, and colon, and caused a marked drop in 5HTOL oxidation in all tissues except stomach and spleen. These results demonstrate that in the rat a metabolic interaction between ethanol and serotonin via the ADH pathway may take place in several tissues besides the liver, which is the main tissue for ethanol detoxification." [Abstract]

Airaksinen MM, Kari I.
Beta-carbolines, psychoactive compounds in the mammalian body. Part I: Occurrence, origin and metabolism.
Med Biol 1981 Feb;59(1):21-34
"1-Methyltetrahydro-beta-carboline (tetrahydroharman) is formed in the body as the acetaldehyde condensate after alcohol intake and its concentration is usually greatest at the time of hang-over. Its oxidation product, 1-methyl-beta-carboline (harman), has also been found in human urine and platelets." [Abstract]

Nagy L, Zsadanyi O, Csoban G.
[Comparative analysis of the effects of alcoholic drinks of different qualities (author's transl)]
Z Rechtsmed 1978 Mar 28;81(1):31-43
"The authors compared the effects of alcoholic drinks rich in fusel oil with the effects of diluted pure alcohol of the same quantity on 19 clinically healthy university students. The investigations utilized EEG and physiopsychic testing methods. The clinical symptoms were observed both under the effect of drinks and in a crapulous state ("hang-over"). It was found that alcoholic drinks rich in fusel oil can produce a more deviating EEG curve, an increased worsening of physiopsychic performance and of clinical and subjective symptoms. The necessity of regular quality control of alcoholic beverages is pointed out." [Abstract]

Hori H, Fujii W, Hatanaka Y, Suwa Y.
Effects of fusel oil on animal hangover models.
Alcohol Clin Exp Res. 2003 Aug; 27(8 Suppl): 37S-41S.
"BACKGROUND: Fusel oil has been reported to have undesirable side effects such as hangover. However, the relationship between fusel oil and hangover has been investigated insufficiently. In this study, we investigated the effects of fusel oil and their ingredients contained in alcoholic beverages by using animal hangover models. METHODS: Ethanol and fusel oil were simultaneously administered to Suncus murinus, and emetic responses were observed for 60 min. Ethanol and fusel oil were simultaneously administered to mice immediately after intake of saccharin solution; on the next day, the mouse's saccharin solution intake was measured. RESULTS: The volatile fraction (fusel oil) of whisky had no remarkable effect on ethanol-induced emetic responses in suncus. Whisky had the most suppressive effect on ethanol-induced conditioned taste aversion in mice among the various alcoholic beverages tested. The volatile fraction (fusel oil) of whisky suppressed the ethanol-induced conditioned taste aversion. In contrast, the nonvolatile fraction of whisky had no effect. The administration of isoamyl alcohol (5 mg/kg) and isoamyl acetate (10 and 40 microg/kg), ingredients of fusel oil, significantly suppressed the ethanol-induced conditioned taste aversion. CONCLUSIONS: The fusel oil in whisky had no effect on the ethanol-induced emetic response, but it suppressed taste-aversion behavior in animal models of hangover symptoms. These results suggest that the fusel oil in whisky alleviates hangover, contrary to the common belief." [Abstract]

Upadhya SC, Ravindranath V.
Detection and localization of protein-acetaldehyde adducts in rat brain after chronic ethanol treatment.
Alcohol Clin Exp Res 2002 Jun;26(6):856-63
"BACKGROUND: Ethanol is metabolized to acetaldehyde in the cell, which is potentially deleterious because it can react with cellular proteins and form protein-acetaldehyde adducts, which can interfere with normal cellular function. Because the primary site of ethanol action is the brain, the present study was carried out to determine whether protein-acetaldehyde adducts are formed in rat brain after chronic ethanol administration. METHODS: Rats were treated with ethanol for 1 year, and the formation of protein-acetaldehyde adducts was examined by immunoblot analysis and localized in brain by immunohistochemical analysis by using affinity purified antibody to acetaldehyde-hemocyanin adduct. RESULTS: In the brain of rats administered ethanol for up to 1 year, protein-acetaldehyde adducts were detectable by immunoblot analysis. In brain, mitochondria was the primary site of adduct formation, unlike the liver, where the major protein-acetaldehyde adduct has been detected in the cytosol. Immunohistochemical localization of protein-acetaldehyde adducts in chronic ethanol-treated rat brain demonstrated the selective presence of adducts in cortical neurons, granule cell layer of dentate gyrus, neurons in the midbrain, and granular cell layers of cerebellum. CONCLUSIONS: These results demonstrate the significant formation of protein-acetaldehyde adducts in rat brain after ethanol ingestion. The modification of mitochondrial proteins in brain by protein-acetaldehyde adduct formation is significant because mitochondrial dysfunction has been implicated in neurodegeneration." [Abstract]

Nakamura K, Iwahashi K, Itoh M, Ameno K, Ijiri I, Takeuchi Y, Suwaki H.
Immunohistochemical study on acetaldehyde adducts in alcohol-fed mice.
Alcohol Clin Exp Res 2000 Apr;24(4 Suppl):93S-96S
"BACKGROUND: Acetaldehyde binds to some proteins, which results in Schiff base formation. It is assumed that acetaldehyde binds to the proteins after the consumption of ethanol, to form an adduct. Such acetaldehyde adducts are related to organ disease. METHODS: We examined 8-week-old male BALB/c mice, which were given a liquid diet for 7 days. The diet consisted of vitamins, minerals, amino acids, and a 5% (v/v) ethanol solution. After the 7 days, we took tissue samples from the brain, liver, and adrenal cortex to investigate the distribution of acetaldehyde adducts. We performed immunohistochemical staining of the cerebral cortex, liver, and adrenal cortex from the mice by using antibodies against acetaldehyde adducts. RESULTS: Our study showed that acetaldehyde adducts formed in the cerebral cortex in the early phase in alcohol-fed mice. CONCLUSIONS: Because acetaldehyde in the liver has been shown to cause liver damage, our study suggests a relationship between acetaldehyde adducts in the brain and brain damage." [Abstract]

Rintala, Jyrki, Jaatinen, Pia, Parkkila, Seppo, Sarviharju, Maija, Kiianmaa, Kalervo, Hervonen, Antti, Niemela, Onni
EVIDENCE OF ACETALDEHYDE-PROTEIN ADDUCT FORMATION IN RAT BRAIN AFTER LIFELONG CONSUMPTION OF ETHANOL
Alcohol Alcohol. 2000 35: 458-463
"Acetaldehyde, the first metabolite of ethanol, has been shown to be capable of binding covalently to liver proteins in vivo, which may be responsible for a variety of toxic effects of ethanol. Acetaldehyde–protein adducts have previously been detected in the liver of patients and experimental animals with alcoholic liver disease. Although a role for acetaldehyde as a possible mediator of ethanol-induced neurotoxicity has also been previously suggested, the formation of protein–acetaldehyde adducts in brain has not been examined. This study was designed to examine the occurrence of acetaldehyde–protein adducts in rat brain after lifelong ethanol exposure. A total of 27 male rats from the alcohol-preferring (AA) and alcohol-avoiding (ANA) lines were used. Four ANA rats and five AA rats were fed 10–12% (v/v) ethanol for 21 months. Both young (n = 10) and old (n = 8) rats receiving water were used as controls. Samples from frontal cortex, cerebellum and liver were processed for immunohistochemical detection of acetaldehyde adducts. In four (two ANA, two AA rats) of the nine ethanol-exposed rats, weak or moderate positive reactions for acetaldehyde adducts could be detected both in the frontal cortex and cerebellum, whereas no such immunostaining was found in the remaining five ethanol-treated rats or in the control rats. The positive reaction was localized to the white matter and some large neurons in layers 4 and 5 of the frontal cortex, and to the molecular layer of the cerebellum. Interestingly, the strongest positive reactions were found among the ANA rats, which are known to display high acetaldehyde levels during ethanol oxidation. We suggest that acetaldehyde may be involved in ethanol-induced neurotoxicity in vivo through formation of adducts with brain proteins and macromolecules." [Full Text]

Gonthier B, Jeunet A, Barret L.
Electron spin resonance study of free radicals produced from ethanol and acetaldehyde after exposure to a Fenton system or to brain and liver microsomes.
Alcohol 1991 Sep-Oct;8(5):369-75
"Free radical formation from ethanol and acetaldehyde was studied in the presence of a spin-trap and a NADPH generating system with a chemical model, Fenton's reagent, or by enzymatic oxidation of these solvents by rat liver and brain microsomes. The free radicals were detected by electron spin resonance spectroscopy (E.S.R.), using the spin-trapping agent, alpha-(4-pyridyl l-oxide)-N-tertbutyl-nitrone (POBN). Under such conditions, the hydroxyethyl radical derived from ethanol was obtained after both incubation in liver and brain microsomes as well as after exposure to the Fenton system. Enzymatic inhibition and activation showed that the mixed function oxidase system plays an important role in the generation of such a radical, even in the brain. Under all the experimental conditions acetaldehyde could also generate a free radical deriving directly from the parent molecule and modified by enzymatic activation or inhibition. A second, longer lasting radical was also observed in the presence of acetaldehyde. On the basis of a comparative study to a known process causing lipoperoxidation, its lipidic origin was suggested." [Abstract]

Phillips SC.
Can brain lesions occur in experimental animals by administration of ethanol or acetaldehyde?
Acta Med Scand Suppl 1987;717:67-72
"In a series of experimental studies involving ethanol vapour administration to rats, sustained blood alcohol levels in the range 89-115 mM for nine hours of each day over a two week period did not lead to neural degeneration detactable with either light or electron microscopy. A single nine hours exposure to ethanol and disulfiram giving rise to 20-41 mM alcohol and 52-76 microM acetaldehyde in the blood did lead to degeneration; and that with repeated exposures of this later type, the damage was found to be accumulative. The lowest levels of blood acetaldehyde which led to neural degeneration in the present study were not distant from clinically observed levels." [Abstract]

Hamby-Mason R, Chen JJ, Schenker S, Perez A, Henderson GI.
Catalase mediates acetaldehyde formation from ethanol in fetal and neonatal rat brain.
Alcohol Clin Exp Res 1997 Sep;21(6):1063-72
"Fetal ethanol (E) exposure has well documented deleterious effects on brain development, yet it is uncertain if the neurotoxicity of maternal E consumption is generated by E itself, by its primary metabolite acetaldehyde (AcHO), or both. The current studies present evidence that homogenates of immature rat brains can generate AcHO via a catalase (CAT)-mediated reaction and that AcHO may be produced in vivo by this system. Homogenates of day 19 fetal rat brain were incubated with E (50 mM). When incubated with CAT inhibitors (sodium azide or 3-aminotriazole), AcHO formation was blocked, whereas neither the alcohol dehydrogenase inhibitor, 4-methylpyrazole, nor P-450 inhibitors decreased AcHO production. Three hours after one oral dose of E (4 g/kg) to a pregnant dam (gestation day 19), AcHO levels in fetal brain increased to 14.28 +/- 1.82 nM/g tissue. Baseline CAT activity in day 19 fetal brains was 4.5 times adult values (p < 0.05). Western blot analysis determined that CAT protein level in the day 19 fetal brain exceeded that in adult brain by 2.5 times. One hour after a single dose of E, CAT activity in day 19 fetal brain increased by 8.2 units/mg protein. In 5-day-old neonatal brains during the "third trimester" brain growth spurt, baseline CAT activity was twice the adult values (p < 0.05) and a 2-day in vivo E regimen increased AcHO levels to four times the control values, with a concomitant 1.7-fold increase in CAT activity. This was prevented by administration of a CAT inhibitor (3-amino-1,2,4-triazole). Immunohistochemical staining of neonatal brains exposed to E illustrated the presence of acetaldehyde-protein adducts. We conclude that AcHO is likely produced in rat fetal and neonatal brain via CAT-mediated oxidation of E. This phenomenon may be an important factor in the neurotoxic effects of in utero E exposure." [Abstract]

Eysseric H, Gonthier B, Soubeyran A, Richard MJ, Daveloose D, Barret L.
Effects of chronic ethanol exposure on acetaldehyde and free radical production by astrocytes in culture.
Alcohol 2000 Jun;21(2):117-25
"In a previous study, the production of acetaldehyde and free radicals derived from ethanol was characterized in astrocytes in primary culture. In the present study, the effects of chronic exposure on the production of both compounds as well as on the main antioxidant system were compared with those of an acute exposure. This was done to better understand the different ways the brain reacts to these modes of exposure. Under these conditions, both a time-dependent increase in the accumulation of acetaldehyde and a decreased formation of the alpha-hydroxyethyl radical were shown. This was associated with increased activities of catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPX) and with decreased glutathione (GSH) content. These effects, which counteract reactive oxygen species (ROS) formation by stimulating the main enzymes of the antioxidant system, were also associated with the reduced amount of radicals derived from ethanol. This could be a beneficial effect, but this was counter-balanced by the increased rate of acetaldehyde accumulation, whose high toxicity is well known. All these effects underline the crucial role played by catalase which, on one hand converts hydrogen peroxide to water and, on the other hand, ethanol to acetaldehyde." [Abstract]

Holownia A, Ledig M, Mapoles J, Menez JF.
Acetaldehyde-induced growth inhibition in cultured rat astroglial cells.
Alcohol 1996 Jan-Feb;13(1):93-7
"Due to the important role of glial cells in brain maturation and reports on delayed astroglial proliferation following ethanol exposition, it was of great interest to examine the effects of the primary metabolite of ethanol--acetaldehyde--on astroglial cell growth. This was carried out by examining biochemical parameters of astroglial cells cocultured with Chinese hamster ovary cell line (CHO) transfected with alcohol dehydrogenase (ADH), able to generate acetaldehyde from ethanol. Acetaldehyde generated from ethanol by ADH-transfected CHO cells had an inhibitory effect on the growth of astroglial cells as assessed by measuring marker enzyme activities and culture protein levels. Moreover, both acetaldehyde and ethanol altered cell cycle and increased astroglial superoxide dismutase activity. Additionally, acetaldehyde, but not ethanol, increased malondialdehyde levels in cultured astroglia. These results clearly show that acetaldehyde may participate in the development of the Fetal Alcohol Syndrome." [Abstract]

Ohsawa I, Nishimaki K, Yasuda C, Kamino K, Ohta S.
Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells.
J Neurochem 2003 Mar;84(5):1110-7
"Mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a major role in acetaldehyde detoxification. The alcohol sensitivity is associated with a genetic deficiency of ALDH2. We have previously reported that this deficiency influences the risk for late-onset Alzheimer's disease. However, the biological effects of the deficiency on neuronal cells are poorly understood. Thus, we obtained ALDH2-deficient cell lines by introducing mouse mutant Aldh2 cDNA into PC12 cells. The mutant ALDH2 repressed mitochondrial ALDH activity in a dominant negative fashion, but not cytosolic activity. The resultant ALDH2-deficient transfectants were highly vulnerable to exogenous 4-hydroxy-2-nonenal, an aldehyde derivative generated by the reaction of superoxide with unsaturated fatty acid. In addition, the ALDH2-deficient transfectants were sensitive to oxidative insult induced by antimycin A, accompanied by an accumulation of proteins modified with 4-hydroxy-2-nonenal. Thus, these findings suggest that mitochondrial ALDH2 functions as a protector against oxidative stress." [Abstract]

Bondy SC, Guo SX.
Effect of ethanol treatment on indices of cumulative oxidative stress.
Eur J Pharmacol 1994 Aug 3;270(4):349-55
"The effect of ethanol exposure upon several parameters relating to oxidative stress has been examined in brain and liver. A single administration of either acetaldehyde or ethanol was able to enhance rates of generation of reactive oxygen species in liver but this effect was not apparent in the cerebral cortex. Glutamine synthetase is especially sensitive to inactivation by free radicals and evidence for cumulative oxidative damage to this enzyme was found in liver and to a lesser extent in cerebral cortex. This enzyme was depressed in liver after both a single injection of acetaldehyde or ethanol, or after more extended dosing. The liver was also more susceptible than cerebral cortex, to pro-oxidant effects as judged by depression of glutathione after acute dosing with either solvent. Enzyme inhibition representing temporally summated oxidative events may be a more sensitive procedure than direct measurement of rates of formation of active oxygen species and may find especially utility in the detection of prolonged low level pro-oxidant activity." [Abstract]

Quintanilla ME, Callejas O, Tampier L.
Aversion to acetaldehyde: differences in low-alcohol-drinking (UChA) and high-alcohol-drinking (UChB) rats.
Alcohol 2002 Feb;26(2):69-74
"We have previously found the existence of a relation between activity of the brain mitochondrial aldehyde dehydrogenase (ALDH2) and consumption of ethanol in rats of the low-alcohol-drinking (UChA) and the high-alcohol-drinking (UChB) strains. The aim of the present study was to determine whether UChA and UChB rats also differed in sensitivity to the aversive effects of acetaldehyde (AcH). Aversion to AcH was studied by using a conditioned taste aversion (CTA) paradigm. Ethanol naive UChA and UChB rats were administered AcH intraperitoneally (50, 100, or 150 mg/kg) or saline and exposed to a banana-flavored solution during five conditioning trials. A strong dose-dependent CTA to AcH was found in UChA rats, whereas UChB rats did not show a CTA to any dose of AcH. At equal doses of AcH, cerebral venous blood AcH levels in UChA rats were consistently higher than in UChB rats, a finding that may reflect the previously observed differences in the activity of ALDH2 between these strains. However, this observation is unlikely to explain fully the differences observed because aversion to AcH was developed in the UChA strain at blood levels of AcH that did not produce any aversion in the UChB strain. These results support the suggestion that, for the first time, differences in central or systemic effects of AcH per se may play a major role in determining the aversion to AcH in drinker and nondrinker animals." [Abstract]

Correa M, Sanchis-Segura C, Aragon CM.
Brain catalase activity is highly correlated with ethanol-induced locomotor activity in mice.
Physiol Behav 2001 Jul;73(4):641-7
"It has been demonstrated that acute administration of lead to mice enhances brain catalase activity and ethanol-induced locomotion. These effects of lead seem to be related, since they show similar time courses and occur at similar doses. In the present study, in an attempt to further evaluate the relation between brain catalase activity and lead-induced changes in ethanol-stimulated locomotion, the interaction between lead acetate and 3-amino-1H,2,4-triazole (AT), a well-known catalase inhibitor, was assessed. In this study, lead acetate or saline was acutely injected intraperitoneally to Swiss mice at doses of 50 or 100 mg/kg 7 days before testing. On the test day, animals received an intraperitoneal injection of AT (0, 10, or 500 mg/kg). Five hours following AT treatment, ethanol (0.0 or 2.5 g/kg, ip) was injected and the animals were placed in open-field chambers, in which locomotion was measured for 10 min. Neither lead exposure nor AT administration, either alone or in combination, had any effect on spontaneous locomotor activity. AT treatment reduced ethanol-induced locomotion as well as brain catalase activity. On the other hand, ambulation and brain catalase activity were significantly increased by both doses of lead. Furthermore, AT significantly reduced the potentiation produced by lead acetate on brain catalase and on ethanol-induced locomotor activity in a dose-dependent manner. A significant correlation was found between locomotion and catalase activity across all test conditions. The results show that brain catalase activity is involved in the effects of lead acetate on ethanol-induced locomotion in mice. Thus, this study confirms the notion that brain catalase provides the molecular basis for understanding some of the mechanisms of the action of ethanol in the central nervous system." [Abstract]

Life Extension Foundation:
ALCOHOL INDUCED HANGOVER: PREVENTION
"The consumption of alcohol results in the formation of two very toxic compounds: acetaldehyde and malondialdehyde. These compounds generate massive free radical damage to cells throughout the body. ... That is why people feel so sick the day after consuming too much alcohol. If the proper combination of antioxidants is taken at the time the alcohol is consumed or before the inebriated individual goes to bed, the hangover and much of the cellular damage caused by alcohol may be prevented."

Andy Coghlan, Jens Thomas
New Scientist | Alcohol | Desperate remedies
"So, onto N-acetyl-cysteine (NAC), an amino acid supplement sold in health food stores. This proved to be a winner. "Fantastic," said one volunteer. "My head didn't feel fuzzy at all," said another."

Vasdev S, Mian T, Longerich L, Prabhakaran V, Parai S.
N-acetyl cysteine attenuates ethanol induced hypertension in rats.
Artery 1995;21(6):312-6
"All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. N-acetyl cysteine, an analogue of the dietary amino acid cysteine, binds acetaldehyde, thus preventing its damaging effect on physiological proteins. This study examined the effect of oral N-acetyl cysteine on the increased blood pressure, platelet cytosolic free calcium, blood acetaldehyde and adverse renal vascular changes induced by chronic ethanol treatment in rats. Twenty-four male Wistar-Kyoto (WKY) rats, age 7 weeks were divided into four groups of six animals each. Animals in group I were given water and group II 5% ethanol in water for the next 14 weeks. Animals in group III were given 5% ethanol + 1% N-acetyl cysteine for 4 weeks followed by 5% ethanol + 2% N-acetyl cysteine for the next 10 weeks. Animals in group IV were given 5% ethanol for 7 weeks; at that time ethanol was withdrawn and animals were placed on water with 2% N-acetyl cysteine for the next 7 weeks. After 14 weeks systolic blood pressure and platelet cytosolic free calcium were all significantly higher (p<0.001) in rats given ethanol as compared to rats in other groups. N-acetyl cysteine treatment, along with ethanol, significantly (p<0.001) attenuated the increased blood pressure and platelet cytosolic free calcium and adverse renal vascular changes. Discontinuation of ethanol treatment for 7 weeks along with N-acetyl cysteine supplementation also significantly lowered the blood pressure and platelet cytosolic free calcium and attenuated adverse renal vascular changes. There was no significant difference in aortic malonaldehyde among four groups. Increase in blood acetaldehyde with ethanol treatment was significantly attenuated with N-acetyl cysteine treatment. These results suggest that acetaldehyde may be the cause of ethanol-induced hypertension and elevated cytosolic free calcium and renal vascular changes." [Abstract]

Ozaras R, Tahan V, Aydin S, Uzun H, Kaya S, Senturk H.
N-acetylcysteine attenuates alcohol-induced oxidative stess in rats.
World J Gastroenterol 2003 Apr;9(4):791-4
" CONCLUSION: Ethanol-induced liver damage was associated with oxidative stress, and co-administration of n-acetylcysteine attenuates this damage effectively in rat model." [Abstract]

O'Neill PJ, Rahwan RG.
Protection against acute toxicity of acetaldehyde in mice.
Res Commun Chem Pathol Pharmacol 1976 Jan;13(1):125-8
"The ability of several compounds to protect against acetaldehyde-induced loss of righting reflex was studied in mice and compared with previously published results in rats. L-cysteine (3 mMoles/kg), L-ascorbic acid, DL-thioctic acid, or DL-homocysteine (2 mMoles/kg each) was administered orally 30 minutes prior to an intraperitoneal ED90 of acetaldehyde (415 mg/kg). Cysteine, ascorbate, and thioctic acid caused a statistically significant reduction in acetaldehyde-induced toxicity, while homocysteine afforded only little protection. These results are qualitatively, but not quantitatively, similar to those reported for rats." [Abstract]

Ginter E, Zloch Z, Ondreicka R.
Influence of vitamin C status on ethanol metabolism in guinea-pigs.
Physiol Res 1998;47(2):137-41
"Guinea-pigs were maintained for 5 weeks on a diet containing three different concentrations of vitamin C: a) traces (none added), b) medium (0.05% w/w) and high (0.5% w/w). Twenty-four hours before killing the animals received one i.p. dose of 3 g ethanol per kg body weight (a model of short-term acute intoxication). In a parallel experiment which lasted 5 weeks, the animals were treated every week with two i.p. doses of 1 g ethanol per kg body weight followed by the final acute intoxication (3g ethanol/kg) (a model of long-term chronic alcoholization). In both experiments, the guinea-pigs with the highest tissue concentration of vitamin C proved to have significantly decreased residual levels of ethanol and acetaldehyde in the liver and the brain, a decreased activity of alanine- and aspartate aminoacyl transferases in the serum and decreased contents of triacylglycerols and cholesterol in the serum and liver in comparison with the vitamin C-unsupplemented group. The regression curve expressing vitamin C levels versus residual ethanol and acetaldehyde concentrations in the liver confirmed the highly significant negative correlation between them. Administration of the guinea-pigs with large amounts of vitamin C appears to accelerate ethanol and acetaldehyde metabolism and reduce some of their adverse health effects." [Abstract]

Wickramasinghe SN, Hasan R.
In vivo effects of vitamin C on the cytotoxicity of post-ethanol serum.
Biochem Pharmacol 1994 Aug 3;48(3):621-4
"The consumption of alcohol is followed by the development in the serum of a non-dialysable cytotoxic activity against A9 cells. This cytotoxicity has been previously shown to reside mainly in unstable acetaldehyde-albumin complexes from which cytotoxic acetaldehyde molecules can be transferred to target cells. The cytotoxicity developing in serum albumin 8 hr after seven healthy volunteers drank 84 g ethanol over 45 min was abolished when the same volunteers were pre-treated with 1 g vitamin C daily for 3 days prior to alcohol consumption. The cytotoxicity was measured against A9 cells using two different indicators: (i) detachment of adherent cells and (ii) a decrease in the ability of cells to reduce tetrazolium. These data suggest that the administration of vitamin C may be useful in limiting those aspects of alcohol toxicity mediated by circulating acetaldehyde." [Abstract]

Stege TE.
Acetaldehyde-induced lipid peroxidation in isolated hepatocytes.
Res Commun Chem Pathol Pharmacol 1982 May;36(2):287-97
"In an effort to evaluate further the concept of ethanol-induced lipid peroxidation, isolated rat hepatocytes obtained via collagenase perfusion were utilized. Hepatocytes were judged to be functionally intact based on measurements of adenosine-5-triphosphate, gluconeogenesis, bromosulphthalein uptake, and trypan blue exclusion. When hepatocytes were incubated with acetaldehyde, a metabolite of ethanol, at 100 mg% and 10 mg%, significant increases in lipid peroxidation resulted as measured by levels of malonaldehyde. Acetaldehyde-induced increases in malonaldehyde were reduced by pre-incubation with antioxidants such as Vitamin E (200 mg%) or glutathione (100 mg%)." [Abstract]

Pittler, Max H., White, Adrian R., Stevinson, Clare, Ernst, Edzard
Effectiveness of artichoke extract in preventing alcohol-induced hangovers: a randomized controlled trial
CMAJ 2003 169: 1269-1273
"BACKGROUND: Extract of globe artichoke (Cynara scolymus) is promoted as a possible preventive or cure for alcohol-induced hangover symptoms. However, few rigorous clinical trials have assessed the effects of artichoke extract, and none has examined the effects in relation to hangovers. We undertook this study to test whether artichoke extract is effective in preventing the signs and symptoms of alcohol-induced hangover. METHODS: We recruited healthy adult volunteers between 18 and 65 years of age to participate in a randomized double-blind crossover trial. Participants received either 3 capsules of commercially available standardized artichoke extract or indistinguishable, inert placebo capsules immediately before and after alcohol exposure. After a 1-week washout period the volunteers received the opposite treatment. Participants predefined the type and amount of alcoholic beverage that would give them a hangover and ate the same meal before commencing alcohol consumption on the 2 study days. The primary outcome measure was the difference in hangover severity scores between the artichoke extract and placebo interventions. Secondary outcome measures were differences between the interventions in scores using a mood profile questionnaire and cognitive performance tests administered 1 hour before and 10 hours after alcohol exposure. RESULTS: Fifteen volunteers participated in the study. The mean number (and standard deviation) of alcohol units (each unit being 7.9 g, or 10 mL, of ethanol) consumed during treatment with artichoke extract and placebo was 10.7 (3.1) and 10.5 (2.4) respectively, equivalent to 1.2 (0.3) and 1.2 (0.2) g of alcohol per kilogram body weight. The volume of nonalcoholic drink consumed and the duration of sleep were similar during the artichoke extract and placebo interventions. None of the outcome measures differed significantly between interventions. Adverse events were rare and were mild and transient. INTERPRETATION: Our results suggest that artichoke extract is not effective in preventing the signs and symptoms of alcohol-induced hangover. Larger studies are required to confirm these findings." [Full Text]

Skrzydlewska E, Ostrowska J, Stankiewicz A, Farbiszewski R.
Green tea as a potent antioxidant in alcohol intoxication.
Addict Biol 2002 Jul;7(3):307-14
"Ethanol oxidation to acetaldehyde and next to acetate is accompanied by free radical generation. Free radicals can affect cell integrity when antioxidant mechanisms are no longer able to cope with the free radical generation observed in ethanol intoxication. Natural antioxidants are particularly useful in such a situation. The present study was designed to investigate the efficacy of green tea as a source of water-soluble antioxidants (catechins) on the liver and blood serum antioxidative potential of rats chronically (28 days) intoxicated with ethanol. Alcohol caused a decrease in liver superoxide dismutase, glutathione peroxidase and catalase activities and an increase in activity of glutathione reductase. Moreover, a decrease in the level of reduced glutathione, ascorbic acid, vitamins A and E and beta-carotene were observed. The activity of serum glutathione peroxidase decreased while glutathione reductase activity increased. The level of serum non-enzymatic antioxidants was also decreased in the liver. Alcohol administration caused an increase in the liver and serum lipid peroxidation products, measured as thiobarbituric acid-reactive substances. However, green tea prevents the changes observed after ethanol intoxication. Green tea also protects membrane phospholipids from enhanced peroxidation. These results indicate a beneficial effect of green tea in alcohol intoxication." [Abstract]

Vasdev S, Wadhawan S, Ford CA, Parai S, Longerich L, Gadag V.
Dietary vitamin B6 supplementation prevents ethanol-induced hypertension in rats.
Nutr Metab Cardiovasc Dis 1999 Apr;9(2):55-63
"BACKGROUND AND AIMS: All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. Acetaldehyde has been shown to deplete vitamin B6 in chronic alcoholics. It also binds with sulfhydryl groups of membrane proteins, altering membrane Ca2+ channels and increasing vascular cytosolic free calcium, peripheral vascular resistance and blood pressure. The aldehyde-binding thiol compound, N-acetyl cysteine, attenuates elevated blood pressure and associated adverse changes in ethanol-induced hypertensive rats. Vitamin B6 supplementation increases the level of endogenous cysteine. Aim of this work was thus to investigate whether a dietary supplementation of vitamin B6 can prevent ethanol-induced hypertension and associated changes in Wistar-Kyoto (WKY) rats. METHODS AND RESULTS: Starting at 7 weeks of age, WKY rats were divided into three groups of six animals each. The control group received a normal vitamin B6 diet (regular chow) and normal drinking water, the ethanol group, the same diet plus 1% ethanol in the drinking water, and the ethanol + vitamin B6 group a high vitamin B6 diet (20 times normal diet) and 1% ethanol in the drinking water. After 14 weeks, systolic blood pressure, platelet [Ca2+]i and kidney and aortic aldehyde conjugate levels were significantly higher in the ethanol group. These rats also showed smooth muscle cell hyperplasia in the small arteries and arterioles of the kidneys. Dietary vitamin B6 supplementation prevented these changes. CONCLUSIONS: Dietary vitamin B6 supplementation prevented ethanol-induced hypertension and associated changes in WKY rats by normalizing tissue aldehyde conjugate levels." [Abstract]

Altura BM, Altura BT.
Association of alcohol in brain injury, headaches, and stroke with brain-tissue and serum levels of ionized magnesium: a review of recent findings and mechanisms of action.
Alcohol 1999 Oct;19(2):119-30
"Although there is general agreement that chronic ingestion of alcohol poses great risks for normal cardiovascular functions and peripheral-vascular homeostasis, a direct cause and effect between the real phenomena of alcohol-induced headache and risk of brain injury and stroke is not appreciated. "Binge drinking" of alcohol is associated with an ever-growing number of strokes and sudden death. It is becoming clear that alcohol ingestion can result in profoundly different actions on the cerebral circulation (e.g., vasodilation, vasoconstriction-spasm, vessel rupture), depending upon dose and physiologic state of host. Using rats, it has been demonstrated that acute, high doses of ethanol can result in stroke-like events concomitant with alterations in brain bioenergetics. We review recent in vivo findings obtained with 31P-NMR spectroscopy, optical reflectance spectroscopy, and direct in vivo microcirculatory studies on the intact brain. Alcohol-induced hemorrhagic stroke is preceded by a rapid fall in brain intracellular free magnesium ions ([Mg2+]i) followed by cerebrovasospasm and reductions in phosphocreatine (PCr)/ATP ratio, intracellular pH, and the cytosolic phosphorylation potential (CPP) with concomitant rises in deoxyhemoglobin (DH), mitochondrial reduced cytochrome oxidase aa3 (rCOaa3), blood volume, and intracellular inorganic phosphate (Pi). Using osmotic mini-pumps implanted in the third cerebral ventricle, containing 30% ethanol, it was found that brain [Mg2+]i is reduced 30% after 14 days; brain PCr fell 15%, whereas the CPP fell 40%. Such animals became susceptible to stroke from nonlethal doses of ethanol. Human subjects with mild head injury have been found to exhibit early deficits in serum ionized Mg (IMg2+); the greater the degree of early head injury (30 min-8 h), the greater and more profound the deficit in serum IMg2+ and the greater the ionized Ca (ICa2+) to IMg2+ ratio. Patients with histories of alcohol abuse or ingestion of alcohol prior to head injury exhibited greater deficits in IMg2+ (and higher ICa2+/IMg2+ ratios) and, unlike the subjects without alcohol, did not leave the hospital for at least several days. Women, for some unknown reason, exhibit a much higher incidence of morbidity and mortality from subarachnoid hemorrhage (SAH) than men. Data on 105 men and women with different types of stroke indicate that, on the average, a 20% deficit in serum IMg2+ is seen; total Mg (TMg) or blood pH is usually near normal. Women with SAH, however, exhibit much lower IMg2+ and higher ICa2+/IMg2+ ratios; the presence of ethanol in the blood is associated with even more depression in IMg2+ in SAH in women. It is possible that prior alcohol ingestion is, in large measure, responsible for a great deal of this unexplained higher incidence of SAH in women. It has recently been reported that the cyclical changes in estrogenic hormones appear to control the serum IMg2+ level in young women. A surge in estrogenic levels prior to SAH could thus precipitate, in part, the SAH. In other human studies, it has been shown that migraines and headache, dizziness, and hangover, which accompany ethanol ingestion, are associated with rapid deficits in serum IMg2+ but not in TMg. The former, and the alcohol-associated headache, can be ameliorated with IV administration of MgSO4. Premenstrual tension-headache (PTH) and its exacerbation by alcohol in women is also accompanied by deficits in IMg2+, and elevation in serum ICa2+/IMg2+; IV MgSO4 corrects the PTH and the serum deficit in IMg2+. Animal experiments show that IV Mg2+ can prevent alcohol-induced hemorrhagic stroke and the subsequent fall in brain [Mg2+]i, [PCr], pHi, and CPP. Other recent data indicate that alcohol-induced cellular loss of [Mg2+]i is associated with cellular Ca2+ overload and generation of oxygen-derived free radicals; chronic pretreatment with vitamin E prevents alcohol-induced vascular injury and pathology in the brain." [Abstract]

Mira L, Maia L, Barreira L, Manso CF.
Evidence for free radical generation due to NADH oxidation by aldehyde oxidase during ethanol metabolism.
Arch Biochem Biophys 1995 Apr 1;318(1):53-8
"Several studies associate ethanol hepatic toxicity to the generation of reactive oxygen species. Ethanol metabolism by alcohol dehydrogenase (ADH) originates acetaldehyde and NADH, with the subsequent increase of the NADH/NAD+ ratio. Some authors have suggested that the oxidation of acetaldehyde by aldehyde oxidase (AO) may be responsible for oxyradical generation during ethanol metabolism. In this study we demonstrated that AO acts not only upon acetaldehyde but also upon NADH, with superoxide anion radical (O2.-) formation. The apparent Km of NADH for AO was approximately 28 microM, a much smaller value than the one reported for acetaldehyde (1 mM). The NADH oxidation by AO promoted the O2.- generation and the ADP-Fe(3+)-dependent microsomal lipid peroxidation in a NADH and AO concentration-dependent manner. If in these experiments NADH is substituted by ethanol, NAD+, and ADH, a higher level of lipid peroxidation will be obtained. To explain this observation a vicious cycle which increases the oxyradical production is suggested: ADH reduces NAD+ to NADH, which is oxidized by AO, generating reactive oxidative species plus NAD+ available again for reduction by ADH. From the studies which were done in the presence of some antioxidants it was observed that the addition of SOD and/or catalase did not inhibit lipid peroxidation, but these results do not exclude the participation of reactive oxygen species. Our studies indicate that the NADH oxidation by AO may play a role in ethanol-induced generation of reactive oxygen species, contributing to its hepatotoxicity." [Abstract]

Aragon CM, Spivak K, Amit Z.
Effect of 3-amino-1,2,4-triazole on ethanol-induced narcosis, lethality and hypothermia in rats.
Pharmacol Biochem Behav 1991 May;39(1):55-9
"It has been proposed that ethanol can be oxidized in brain via the peroxidatic activity of catalase and that centrally formed acetaldehyde may mediate several of the psychopharmacological actions of ethanol. The present study was designed to investigate the role of brain catalase in the mediation of ethanol-induced narcosis, hypothermia and lethality in rats. Rats were pretreated with the catalase inhibitor 3-amino-1,2,4-triazole (AT) or saline. Five hours later, animals in each pretreatment group received IP injections of ethanol (3 or 4 g/kg). Ethanol-induced narcosis was significantly attenuated in AT-pretreated rats compared to the saline control group. As well, AT pretreatments reduced significantly the lethal effect of these ethanol doses. However, AT-pretreated ethanol-injected animals significantly reduce their body temperature as compared to the saline-ethanol animals. Blood ethanol determinations revealed that AT did interfere with ethanol metabolism. AT inhibits significantly brain catalase activity at all doses used in this study. The results indicate a role for brain catalase in ethanol effects. Furthermore, they suggest that catalase may be involved in the oxidation of ethanol in brain and that centrally formed acetaldehyde may play a role in ethanol-induced narcosis and lethality, but not hypothermia." [Abstract]

Morozov IuE, Salomatin EM, Okhotin VE.
[Brain acetaldehyde and ethanol: method of determination and diagnostic significance in ethanol poisoning]
Sud Med Ekspert 2002 Mar-Apr;45(2):35-40
"The content of ethanol and acetaldehyde in the limbic cortex and reticular formation of the brain was measured by gas-liquid chromatography in lethal ethanol poisoning. The content of acetaldehyde was significantly increased in the gyrus cinguli of the brain. Lethal poisonings occurred during any stage of ethanol intoxication. The data characterizing individual ethanol tolerance were obtained, which can be used for differential diagnosis of ethanol poisoning in practical forensic medicine." [Abstract]

Daniel G. Herrera, Almudena G. Yagüe, Siv Johnsen-Soriano, Francisco Bosch-Morell, Lucía Collado-Morente, Maria Muriach, Francisco J. Romero, and J. Manuel García-Verdugo
Selective impairment of hippocampal neurogenesis by chronic alcoholism: Protective effects of an antioxidant
PNAS published June 5, 2003, 10.1073/pnas.1230907100
"A major pathogenic mechanism of chronic alcoholism involves oxidative burden to liver and other cell types. We show that adult neurogenesis within the dentate gyrus of the hippocampus is selectively impaired in a rat model of alcoholism, and that it can be completely prevented by the antioxidant ebselen. Rats fed for 6 weeks with a liquid diet containing moderate doses of ethanol had a 66.3% decrease in the number of new neurons and a 227-279% increase in cell death in the dentate gyrus as compared with paired controls. Neurogenesis within the olfactory bulb was not affected by alcohol. Our studies indicate that alcohol abuse, even for a short duration, results in the death of newly formed neurons within the adult brain and that the underlying mechanism is related to oxidative or nitrosative stress. Moreover, these findings suggest that the impaired neurogenesis may be a mechanism mediating cognitive deficits observed in alcoholism." [Abstract]

Abe K, Yamaguchi S, Sugiura M, Saito H.
The ethanol metabolite acetaldehyde inhibits the induction of long-term potentiation in the rat dentate gyrus in vivo.
Br J Pharmacol 1999 Aug;127(8):1805-10
"1. Ethanol has been reported to inhibit the induction of long-term potentiation (LTP) in the hippocampus. However, the correlation between the effects of ethanol in vivo and in vitro remained unclear. In addition, previous works have little considered the possibility that the effect of ethanol is mediated by its metabolites. To solve these problems, we investigated the effects of ethanol and acetaldehyde, the first metabolite in the metabolism of ethanol, on the induction of LTP at medial perforant path-granule cell synapses in the dentate gyrus of anaesthetized rats in vivo. 2. Oral administration of 1 g kg-1 ethanol significantly inhibited the induction of LTP, confirming the effectiveness of ethanol in vivo. 3. A lower dose of ethanol (0.5 g kg-1) failed to inhibit the induction of LTP in intact rats, but significantly inhibited LTP in rats treated with disulfiram, an inhibitor of aldehyde dehydrogenase, demonstrating that LTP is inhibited by acetaldehyde accumulation following ethanol administration. 4. Intravenous injection of acetaldehyde (0.06 g kg-1) significantly inhibited the induction of LTP. 5. The inhibitory effect of acetaldehyde on LTP induction was also observed when it was injected into the cerebroventricules, suggesting that acetaldehyde has a direct effect on the brain. The intracerebroventricular dose of acetaldehyde effective in inhibiting LTP induction (0.1 - 0.15 mg brain-1) was approximately 10 fold lower than that of ethanol (1.0 - 1.5 mg brain-1). 6. It is possible that acetaldehyde is partly responsible for memory impairments induced by ethanol intoxication." [Abstract]

Verster JC, van Duin D, Volkerts ER, Schreuder AH, Verbaten MN.
Alcohol hangover effects on memory functioning and vigilance performance after an evening of binge drinking.
Neuropsychopharmacology 2003 Apr;28(4):740-6
"The impairing effects on memory functioning after acute alcohol intoxication in healthy volunteers and after chronic use in alcoholics are well established. However, research determining the next-morning effects of a single episode of binge drinking on memory functioning is scarce. A total of 48 healthy volunteers participated in a single-blind study comprising an evening (baseline) session, followed by a treatment administration (ethanol 1.4 g/kg or placebo), and a morning session. Memory was tested with a word-learning test (including immediate and delayed recall, and recognition). Further, a 45-min Mackworth clock test for measuring vigilance was included (parameters: number of hits and false alarms) and subjective alertness was assessed, to infer whether word-learning test findings reflect sedation or specific memory impairments. Delayed recall in the morning session was significantly worse in the alcohol group when compared to the placebo group (F(1,42)=6.0, p<0.02). In contrast, immediate recall and recognition were unimpaired in the alcohol group. In the morning session, relative to the placebo group, subjective alertness was significantly reduced in the alcohol group before and after the tests (F(1,44)=8.7, p<0.005; F(1,44)=13.3, p&<0.001, respectively). However, in the Mackworth clock test, the alcohol group and placebo group did not differ significantly in the morning session. The specific findings of impaired delayed recall show that memory retrieval processes are significantly impaired during alcohol hangover. Vigilance performance was not significantly affected, indicating that this memory impairment does not reflect sedation." [Abstract]

Kim DJ, Yoon SJ, Lee HP, Choi BM, Go HJ.
The effects of alcohol hangover on cognitive functions in healthy subjects.
Int J Neurosci. 2003 Apr; 113(4): 581-94.
"A hangover is characterized by the constellation of unpleasant physical and mental symptoms that occur between 8 and 16 h after drinking alcohol. We evaluated the effects of experimentally-induced alcohol hangover on cognitive functions using the Luria-Nebraska Neuropsychological Battery. A total of 13 normal adult males participated in this study. They did not have any previous histories of psychiatric or medical disorders. We defined the experimentally-induced hangover condition at 13 h after drinking a high dose of alcohol (1.5 g/kg of body weight). We evaluated the changes of cognitive functions before drinking alcohol and during experimentally-induced hangover state. The Luria-Nebraska Neu