Genetic Influences Affecting

Alcohol Use Among Asians

TAMARA L. WALL, PH.D., AND CINDY L. EHLERS, PH.D.

Aldehyde dehydrogenase (ALDH) is one of the two enzymes primarily involved in alcohol

metabolism. Several variants exist of the gene that produces ALDH. One of these gene variants, which generates a nonfunctional enzyme, is present in Asians but not in Caucasians and

African­Americans. People with two copies of the defective gene respond to alcohol

consumption with intense flushing and other unpleasant reactions, such as nausea.

Consequently, these people consume very little alcohol and are at a much lower risk for

alcoholism than people with functional ALDH genes. People with one copy of the defective gene

also flush after ingesting alcohol and are at relatively lower risk for alcoholism than people with

fully functional genes. In addition, these people have more intense, but not necessarily less

pleasant, reactions to alcohol as assessed by both physiological and psychological measures.

People with the defective gene variant also respond to alcohol consumption with characteristic

changes in brain activity. KEY WORDS: alcohol flush reaction; Asian; aldehyde dehydrogenase; isoenzyme;

gene; genotype; risk factors; brain; AOD use; AOD dependence; ethanol metabolism; racial differences

1 lcoholism is a complex disorder vulnerability for alcoholism, and provides moderate amount of alcohol (Chan 1986).

arising from both biological (i.e., a theoretical perspective of the results. This reaction, although documented in

genetic) and sociocultural (i.e., Chinese poetry as early as the first century environmental) factors. During the past two B.C., first was reported in the scientific lit­

Adecades, studies in humans assessing indi­ ALCOHOL­INDUCED erature in 1972 (Wolff 1972). The flushing vidual differences in the response to alcohol FLUSHING AMONG ASIANS reaction is characterized by a rapidly in­ have increased our understanding of how creased blood flow to the skin of the face, People of Asian descent consistently expe­ genetic traits may contribute to a person’s neck, and chest; other symptoms may in­ rience lower levels of alcoholism and higher predisposition to alcoholism (Schuckit 1994). clude increased heart rate (i.e., tachycardia), rates of abstinence than other ethnic groups Some studies have aimed at identifying decreased blood pressure (i.e., hypotension), (Helzer et al. 1990; Klatsky et al. 1983). factors that might increase the risk for the headache, nausea, and vomiting (Chan 1986). Researchers have offered two explanations disorder, whereas others have addressed for these observations (reviewed in Sue and The manifestations of the flushing response protective factors. Most studies have focused Nakamura 1984). An “environmental” hypo­ vary widely: Some people intensely experi­ on people who statistically are at high risk thesis suggests that cultural values among for alcoholism, such as children of alcoholic Asians emphasize drinking in moderation. Tamara L. Wall, Ph.D., is an assistant professor fathers, although some research has exam­ Conversely, the “genetic” theory proposes in the Department of Psychiatry at the Univer­ ined people with a statistically lower risk, that Asians experience a different physio­ sity of California, San Diego, California, and an such as those of Asian heritage. This article logical reaction to alcohol. Bridging this adjunct member in the Department of Neuro­ presents evidence that both alcohol use and dichotomy, Sue and Nakamura (1984) have pharmacology at the Scripps Research Institute, alcoholism among Asians are genetically attributed the low rates of alcohol consump­ La Jolla, California. influenced, reviews studies examining tion among Asians to an interaction between Cindy L. Ehlers, Ph.D., is an associate member individual differences in the response to cultural and physiological factors. in the Department of Neuropharmacology at the alcohol that are associated with the genetic One physiological factor that may protect Scripps Research Institute, La Jolla, California.

Asians from heavy drinking is the alcohol­ This work has been supported by National Insti­ 1 The terms “alcoholism” and “alcoholic” as used in induced flushing reaction that about one­ tute on Alcohol Abuse and Alcoholism grants this article are summary terms for the diagnoses of half of Chinese, Japanese, Koreans, and AA00098, AA00155, and AA06420 as well as alcohol abuse and alcohol dependence. other Asians experience after drinking a General Clinical Research Center grant RR00833.

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Alcohol Use Among Asians

ence the full range of symptoms, whereas others have significantly milder reactions after consuming the same alcohol dose. NAD+ NAD+

THE GENETIC BASIS FOR Alcohol Acetaldehyde Acetate

THE FLUSHING REACTION ADH ALDH The alcohol­induced flushing response is associated with the process by which the Figure 1 body metabolizes alcohol. Two enzymes are The pathway of alcohol metabolism. Once in the liver, alcohol is converted primarily involved in alcohol metabolism— into acetaldehyde and the acetaldehyde is converted into acetate. The alcohol dehydrogenase (ADH), which con­ enzyme alcohol dehydrogenase (ADH) catalyzes the first half of alcohol metabolism, and the enzyme aldehyde dehydrogenase (ALDH) catalyzes verts alcohol to acetaldehyde, and aldehyde the second half. NAD+ is a coenzyme that plays an accessory role in dehydrogenase (ALDH), which converts enzyme catalysis. acetaldehyde to acetate (figure 1). Re­ searchers hypothesize that an elevated level of acetaldehyde, a highly reactive and poten­ 2 1 2 ALDH2 allele (ALDH2 /2 genotype), or however, generally have no, or only a tially toxic by­product, in the blood and 2 2 2 3 two ALDH2 alleles (ALDH2 /2 genotype). mild, flushing response. tissue causes the flushing reaction (Harada A person with two identical alleles (e.g., et al. 1981). Two mechanisms could con­ 1 1 ALDH2 /2 genotype) is called homozy­ ALDH2 Genotype and Flushing as tribute to increased acetaldehyde levels: a gous for that allele; a person with two higher­than­normal acetaldehyde production a Protective Factor for Alcoholism different alleles is called heterozygous. by ADH or a slower­than­normal acetalde­ The physiological characteristics of flush­ The ALDH2 genotype determines how hyde breakdown by ALDH. ing are similar to the reactions to alcohol well the ALDH2 enzyme functions: An in people taking the medication disulfiram enzyme containing any defective subunits 2 (i.e., Antabuse™), which is used to deter Different Forms of ADH and ALDH encoded by the ALDH2 allele is less active alcoholics from drinking. Molecular stud­ Both ADH and ALDH exist in different than an enzyme containing only functional 1 ies found that disulfiram mimics ALDH2 forms (i.e., isoenzymes) in the body. Iso­ subunits encoded by the ALDH2 allele. Fur­ deficiency by inhibiting the enzyme and enzymes are groups of enzymes that per­ thermore, an enzyme consisting only of thus causing increased levels of acetalde­ form the same chemical reaction but have defective subunits (i.e., in a person homozy­ 2 hyde after alcohol consumption (Harada et a slightly different amino acid composition gous for ALDH2 ) will be less active than 2 al. 1982). The similarity between the effects and different kinetic properties. ALDH, for an enzyme consisting of both functional and of disulfiram and the flushing reaction example, has four isoenzymes: three that defective subunits (i.e., in a heterozygous suggests that the aversive effects of ac­ primarily exist in the cell’s cytoplasm and person). As a result of the reduced enzyme 2 etaldehyde may discourage drinking or one—called ALDH2—that is located in activity in people with at least one ALDH2 excessive drinking in Asians and thus serve the cell’s energy­producing structures, the allele, the conversion of acetaldehyde to ace­ as a protective factor against alcoholism. mitochondria. ALDH2 is responsible for tate is slowed, creating excess levels of blood Several studies demonstrating signifi­ most of the acetaldehyde breakdown in the acetaldehyde after alcohol consumption. cantly lower levels of alcohol use and alco­ cell. Thus, alcohol­induced flushing and 2 holism in Asians with ALDH2 alleles other symptoms related to alcohol sensi­ Racial Differences in the support this idea. For example, people tivity have been attributed primarily to an 2 Frequency of ALDH2 Alleles homozygous for the ALDH2 allele drink ALDH2 deficiency (Harada et al. 1981). very little alcohol (Takeshita et al. 1994) and Each ALDH molecule consists of four Researchers can determine a person’s are not found among alcoholics (Thomasson parts, or subunits, all of which are produced ALDH2 genotype using DNA extracted et al. 1991; Chao et al. 1994). Asians who (i.e., encoded) by the same gene. The gene from a small blood sample. Such molecular are heterozygous drink significantly less encoding the ALDH2 isoenzyme is called analyses have found that the distribution of and are much less likely to be alcoholic ALDH2. This gene exists in two variants, ALDH2 alleles varies among different ethnic 1 than Asians homozygous for the functional or alleles. One allele, ALDH2 , encodes a groups (Goedde et al. 1992): Nearly all 1 4 ALDH2 allele (Chao et al. 1994; Takeshita functional enzyme subunit; the other allele, people of Caucasian and African­American 2 et al. 1994; Thomasson et al. 1991). The ALDH2 , contains a small change in the descent are homozygous for the functional 1 heterozygous genotype does not provide full gene and thus encodes a defective subunit ALDH2 allele. Among Asians, however, that causes ALDH deficiency. Because only about 50 percent are homozygous for 3 1 The basis for this mild flushing response, which also ALDH2 , 30 to 40 percent are heterozygous, every person inherits two copies of each has been reported in some other ethnic groups (e.g., gene—one from the mother and one from and 5 to 10 percent are homozygous for the Caucasians and Native Americans), is not well under­ 2 the father—three different combinations of defective ALDH2 allele. stood but may relate to other environmental or genetic

ALDH2 alleles (i.e., three different ALDH2 As described previously, these geno­ factors, such as mutations in ADH genes. genotypes) are possible (figure 2): A person types among Asians predict their response 4 1 1 1 Some researchers have proposed that genetic can have two ALDH2 alleles (ALDH2 /2 to alcohol. People who have at least one variations in alleles of ADH also could increase the 1 2 genotype), one ALDH2 allele and one ALDH2 allele experience elevated ac­ rate of acetaldehyde formation, deterring heavy

etaldehyde levels as well as a readily ob­ drinking (Takeshita et al. 1994) and contributing to 2 For a definition of this and other technical terms used servable facial flush following alcohol decreased risk in Asians for developing alcoholism 1 in this article, see central glossary, pp. 182–183. ingestion. Asians homozygous for ALDH2 , (Thomasson et al. 1991; Chao et al. 1994).

VOL. 19, NO. 3, 1995 185 protection from alcoholism, however, because 12 to 19 percent of Chinese and 2 Japanese alcoholics have one ALDH2 allele

(Chao et al. 1994; Thomasson et al. 1991). Functional ALDH21 allele Thus, a growing body of evidence suggests that possession of at least one 2 Defective ALDH2 allele reduces a person’s alcohol 2 ALDH2 allele use and predisposition to alcoholism. The findings demonstrate that a genetic factor can influence, but not necessarily prede­ Homozygous Heterozygous Homozygous for ALDH21 for ALDH22 termine, the development of alcoholism.

Each person’s predisposition to alcoholism Mild or no flushing Flushing Severe flushing probably depends on both genetic and envi­ ronmental factors. Studies of alcoholics who Figure 2 The three possible genotypes* for the ALDH2 gene and their associated are heterozygous for the ALDH2 gene may phenotypes. Each person has a pair of chromosomes carrying the ALDH2 allow researchers to learn more about the gene, one inherited from the mother and one from the father. The two interactions among genes or between genes chromosomes can carry either the same allele (homozygous) or two and environmental factors that affect the different alleles (heterozygous). development of alcoholism. *For a definition of this term and others used in this figure, see central glossary, pp. 182–183.

Physiological and Psychological

Consequences of ALDH Genotype

Recent studies have investigated in more detail the physiological response to alcohol 30 in Asians having different ALDH2 geno­ 1 1 ALDH2 /2 (n = 15) types (Wall et al. 1992, 1993, 1994; Wall ALDH21/22 n and Ehlers 1995). In these studies, the sub­ ( = 14) jects were male, American­born university * students of Chinese, Japanese, and Korean 20 * descent whose ALDH2 genotypes were de­ termined from blood samples. Each subject was tested on two occasions after receiving either a placebo or 0.75 milliliters of alcohol Rating Units 10 per kilogram of body weight (mL/kg, equal to two to three alcoholic drinks). All subjects reacted comparably to the placebo beverage and had similar blood alcohol concentra­ tions (BAC’s) after consuming the alcoholic 0 beverage. Alcohol, however, induced very 0 different physiological reactions in subjects, 30 60 90 120 150 corresponding to the three different geno­ Time After Alcohol Dose types described earlier. For example, two Figure 3 Subjective self-assessment of the “effects of alcohol” by 15 men homo- subjects who were homozygous for the de­ 1 1 2 2 zygous** for ALDH2 (solid line) and 14 men with the ALDH2 /ALDH2 fective ALDH2 allele became ill after drink­ genotype (dotted line) at different times after a single dose of alcohol ing the alcoholic beverage, experiencing (0.75 ml/kg body weight). The intensity of reported alcohol effects is nausea, vomiting, extreme tachycardia, and presented in arbitrary rating units. Error bars indicate standard error of hypotension. These observations confirm the mean. the assumption that people who are homozy­ 2 gous for ALDH2 are most likely to experi­ *= significant difference between the groups (p < 0.05). ence severe physiological reactions; their **For further explanation, see figure 2. intolerance of alcohol may help to explain why no one with this genotype has been 1 found to be alcoholic. with two functional ALDH2 alleles, even negative effects of intoxication, such as

The ALDH2 genotype appears to affect though they had similar BAC’s and similar feeling “uncomfortable,” “nauseated,” and not only physiological reactions but also recent drinking patterns. For example, “terrible overall,” but statistically these re­ more subjective responses to alcohol. In the heterozygous subjects reported both signif­ sults were not significantly different from experiment described above, the subjects icantly stronger “effects of alcohol” than the responses of the subjects homozygous 1 1 were asked to assess the effects the alco­ subjects homozygous for ALDH2 (figure 3) for ALDH2 . holic beverage had on them. The men who and more intense attributes of intoxication, These findings contradict the hypothesis were heterozygous for ALDH2 reported such as feeling “high,” “great overall,” and that people who are heterozygous for more intense, but not necessarily more un­ “drunk.” The heterozygous subjects also ALDH2 drink less because they experience pleasant, reactions to alcohol than the men tended to more strongly experience the only aversive alcohol effects. In fact, the

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tion (less than 0.5 gram of alcohol per kilo­

Table 1 Typical Effects of Different Alcohol Doses on the Activities of Different EEG gram of body weight [g/kg], corresponding 1 Frequency Bands to fewer than two to three drinks) reduce the

amplitudes of slow­ and fast­alpha waves

Frequency Band Alcohol Dose and increase the amplitudes of the beta

waves (table 1). Moderate alcohol doses

Low Moderate High (0.5 to 1.0 g/kg) usually result in increased

(< 0.5 g/kg) (0.5–1.0 g/kg) (> 1.0 g/kg) slow­alpha and theta waves and decreased

(less than 2–3 drinks) (3–6 drinks) (more than 3–6 drinks) fast­alpha waves. Larger doses of alcohol

(more than 1.0 g/kg), which are associated delta (< 4 Hz) with sedation and drowsiness, produce theta (4.0–7.5 Hz) increased increased increases in the amplitude of the theta slow alpha (7.5–9.0 Hz) decreased increased waves (Begleiter and Platz 1972; Ehlers et fast alpha (9.0–12.0 Hz) decreased decreased al. 1989; Kalant and Woo 1981). The beta (> 12.0 Hz) increased magnitude of these alcohol effects, how­ 1 The brain waves measured with an electroencephalogram (EEG) are grouped into several “bands,” each containing ever, varies significantly among people. waves with a certain frequency range. The frequency indicates how often a wave recurs in a certain time and is

measured in hertz (Hz). 1 Hz = 1 cycle per second. The genetic vulnerability for alco­

SOURCES: Summarized from Begleiter and Platz 1972; Ehlers et al. 1989; and Kalant and Woo 1981. holism, as inferred from a family history of

the disorder, partly determines a person’s results suggest that heterozygous people states. EEG’s allow researchers to charac­ brain response to alcohol. For example, who regularly consume alcohol may have terize and quantify the brain’s spontaneous children of alcoholics, who are at elevated a more intense positive response to alco­ electrical activity and provide information risk for developing alcoholism, have a 1 hol than those homozygous for ALDH2 . about brain responses to external sensory different EEG response to alcohol from

Thus, one mechanism that may contribute stimuli. These responses also are called control subjects without alcoholic relatives to the decreased rate of alcohol use and al­ event­related potentials (ERP’s). (Cohen et al. 1993; Ehlers and Schuckit coholism among Asians with at least one To measure ERP’s, the subjects are 1991). Sons of alcoholic fathers in particu­ 2 ALDH2 allele could be heightened sensitiv­ exposed to stimuli (e.g., sounds or lights) lar may have a less intense EEG response ity to relatively low doses of alcohol (Wall while their EEG is being recorded. When to alcohol, possibly reflecting an innate et al. 1992). A person with this heightened an uncommon stimulus occurs (e.g., a red lower level of sensitivity to alcohol (Cohen sensitivity would need to drink less to ex­ light in a sequence of green and yellow et al. 1993; Ehlers and Schuckit 1991). perience the same response to alcohol as a lights), the brain produces a characteristic Not only does alcohol consumption person with lower sensitivity. Consequently, pattern of brain waves. One ERP wave that affect the spontaneous brain activity re­ 2 a person carrying the ALDH2 allele may has been studied frequently in alcohol re­ flected by the EEG patterns, it also alters avoid high intake of alcoholic beverages and search is called P300 because it can be brain responses to external stimuli (i.e., thus be less likely to develop alcoholism. detected about 300 milliseconds after the the ERP’s). Acute alcohol administration

If the ALDH2 genotype affects not only uncommon stimulus. Although scientists reduces the amplitude of P300 and/or people’s physiological responses but also believe that the P300 wave reflects specific increases the time between the stimulus their subjective feelings of intoxication, neurocognitive functions (e.g., the brain’s and the appearance of P300 (i.e., the 2 possession of an ALDH2 allele also may evaluation of the stimulus and the process of latency), suggesting reduced efficiency in influence a person’s vulnerability to alco­ selecting a response), they do not know the brain processing (Porjesz and Begleiter hol at the level of brain functioning. The physiological basis for these functions. 1985). The intensity of alcohol’s effect on following sections describe research aimed Twin and family studies indicate that P300 varies according to the dose ingested at understanding how different combina­ many EEG parameters are largely geneti­ (Rohrbaugh et al. 1987). A person’s genetic tions of ALDH2 alleles may affect the cally determined (van Beijsterveldt and vulnerability for alcoholism also appears Boomsma 1994). A smaller number of brain’s response to alcohol. to affect the P300 response. For example, studies also suggest moderate to high alcohol­induced P300 changes were smaller heritability for ERP’s (van Beijsterveldt in men at high risk for developing alco­ MEASURING THE BRAIN’S and Boomsma 1994). Both EEG parame­ holism (i.e., men having an alcoholic RESPONSE TO ALCOHOL ters and ERP’s are sensitive to the effects father) than in men at lower risk (Elmasian Electrophysiological techniques provide of acute and chronic alcohol use (Porjesz et al. 1982; Schuckit et al. 1988). noninvasive ways to assess various ele­ and Begleiter 1985). ments of brain function. One of the most Alcohol’s acute effects on EEG pat­ ALDH2 Genotype and common methods, the electroencephalo­ terns have been studied since the 1930’s. In the Electrophysiological gram (EEG), is performed by attaching general, low doses of alcohol that result in electrodes to a person’s scalp and recording mild intoxication and behavioral activa­ Response to Alcohol the spontaneous electrical brain activity, Because electrophysiological responses 5 The frequency describes how often the wave goes appear to be correlated with a person’s known as brain waves. Brain waves can be through a complete cycle during a given time period. divided into several different groups—slow genetic predisposition to alcoholism, re­ The frequency usually is measured in hertz (Hz); 1 Hz alpha, fast alpha, beta, delta, and theta— searchers have used EEG patterns and 5 according to their frequency (see table 1). = 1 cycle per second. ERP’s to evaluate alcohol’s effects on brain 6 Changes in brain waves (e.g., their ampli­ The amplitude describes the height of a wave, from functioning in college students of Asian 6 tude ) correlate with changes in the level of its lowest to its highest point. For electrical waves, origin with different ALDH2 genotypes consciousness or different psychological the amplitude usually is measured in millivolts. (Wall et al. 1993; Wall and Ehlers 1995).

VOL. 19, NO. 3, 1995 187 ALDH21/21 (n = 15) ALDH21/22 (n = 14)

-10 -10

-5 -5

0 0 Microvolts Microvolts

5 5

10 10

0 100 200 300 400 500 0 100 200 300 400 500 TONE Milliseconds TONE Milliseconds

Placebo Alcohol

Figure 4 Mean event-related potentials in 15 subjects homozygous* for ALDH21 and 14 heterozygous* subjects after drinking a placebo beverage (solid line) or a beverage containing 0.75 ml/kg alcohol (dotted line). The subjects had to press a button when they heard a rarely presented tone. In both groups, alcohol delayed the appearance of the P300 wave (the segment occurring between 300 and 450 msec) and decreased P300 amplitude, but the effects were stronger in the heterozygous subjects than in the homozygous subjects.

*For further explanation, see figure 2. SOURCE: Adapted from Wall and Ehlers 1995.

The subjects received either a placebo or a decreased the amplitude and increased the subjective feelings of intoxication and elec­ moderate dose of 0.75 mL/kg alcohol before latency of the P300 wave. In the heterozy­ trophysiological parameters. Conversely, their brain waves were recorded. Subjects gous subjects, however, alcohol’s effects on people at lower risk for alcoholism (e.g., 1 homozygous for the functional ALDH2 P300 were significantly greater than in the members of ethnic groups with a low preva­ 1 allele showed a typical EEG response, in­ subjects homozygous for ALDH2 , although lence of the disorder) would experience a cluding increased theta and slow­alpha and all subjects had equivalent BAC’s (figure 4). heightened response to alcohol. decreased fast­alpha activity. These data indicate that people heterozy­ Studies reviewed in this article that

In the heterozygous subjects with one gous for ALDH2 experience a more intense examined the acute responses to alcohol in 2 ALDH2 allele, however, the slow­alpha response to alcohol and that their brain func­ Asian men support this model. The men fell activity decreased significantly compared tioning may be more affected by alcohol into three groups with respect to their genetic with that of the subjects homozygous for than that of people homozygous for the risk for developing alcoholism: extremely 1 1 ALDH2 . This pattern of alcohol­related ALDH2 allele. low risk (homozygous for the defective 2 EEG changes in the heterozygous subjects is ALDH2 allele), moderately low risk (het­ consistent with the increased activation that erozygous for ALDH2), and relatively high 1 may be caused by elevated acetaldehyde HEORETICAL AND risk (homozygous for the functional ALDH2 T levels (Wall et al. 1993) and differs from the allele). The same groups were found to be RESEARCH IMPLICATIONS pattern seen in Caucasian sons of alcoholics highly sensitive, intermediately sensitive, and

(Ehlers and Schuckit 1991). These findings One model of genetic influences in alco­ minimally sensitive to the effects of alcohol. suggest that EEG responses may help to holism suggests that a person’s genetically Although genetic factors may contribute measure the effects of acute intoxication determined reaction to alcohol may affect to a person’s risk for or protection from alco­ on brain functioning and genetically the likelihood of both drinking alcohol holism, their interactions with environmental influenced reactions to alcohol. and developing alcoholism (Schuckit 1994). factors determine their overall vulnerability.

The response to alcohol in the same This theory predicts that compared with the For example, as described here, the ALDH2 subjects also was assessed using ERP’s general population, people at higher risk for genotype helps determine the level of alco­

(Wall and Ehlers 1995). The study found developing alcoholism (e.g., children of al­ hol consumption among Asians. The pro­ that compared with a placebo, alcohol coholic fathers) may respond less intensely posed mechanism, however, by which this consumption in all subjects significantly to alcohol, as assessed by measures such as gene influences the development of alco­

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holism (i.e., by evoking a more intense the ALDH2 genotype help determine the and Alcoholism Research Monograph No. 18. DHHS response to alcohol in brain functioning) can risk of Asians for alcoholism also may have Pub. No. (ADM)89–1435. Bethesda, MD: the Institute, only manifest itself after alcohol use and important implications for evaluating the 1989. pp. 373–382. may even require a certain level of alcohol predisposition to alcoholism of other, non­ KLATSKY, A.L.; SIEGLAUB, A.B.; LANDY, C.; AND ■ FRIEDMAN, G.D. Racial patterns of alcoholic beverage consumption. In contrast, environmental Asian populations. use. Alcoholism: Clinical and Experimental Research factors, such as cultural attitudes that em­ 7:372–377, 1983. phasize abstinence or moderate alcohol consumption, can protect against the devel­ REFERENCES PORJESZ, B., AND BEGLEITER, H. Human brain electro­

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