National Institute on Alcohol Abuse and Alcoholism No. 28 PH 356 April 1995
Alcohol and Tolerance
Alcohol consumption interferes with many bodily functions and affects behavior. However, after chronic alcohol consumption, the drinker often develops tolerance to at least some of alcohol's effects. Tolerance means that after continued drinking, consumption of a constant amount of alcohol produces a lesser effect or increasing amounts of alcohol are necessary to produce the same effect (1). Despite this uncomplicated definition, scientists distinguish between several types of tolerance that are produced by different mechanisms.
Tolerance to alcohol's effects influences drinking behavior and drinking consequences in several ways. This Alcohol Alert describes how tolerance may encourage alcohol consumption, contributing to alcohol dependence and organ damage; affect the performance of tasks, such as driving, while under the influence of alcohol; contribute to the ineffectiveness or toxicity of other drugs and medications; and may contribute to the risk for alcoholism.
Humans and animals develop tolerance when their brain functions adapt to compensate for the disruption caused by alcohol in both their behavior and their bodily functions. This adaptation is called functional tolerance (2). Chronic heavy drinkers display functional tolerance when they show few obvious signs of intoxication even at high blood alcohol concentrations (BAC's), which in others would be incapacitating or even fatal (3). Because the drinker does not experience significant behavioral impairment as a result of drinking, tolerance may facilitate the consumption of increasing amounts of alcohol. This can result in physical dependence and alcohol-related organ damage.
However, functional tolerance does not develop at the same rate for all alcohol effects (4-6). Consequently, a person may be able to perform some tasks after consuming alcohol while being impaired in performing others. In one study, young men developed tolerance more quickly when conducting a task requiring mental functions, such as taking a test, than when conducting a task requiring eye-hand coordination (4), such as driving a car. Development of tolerance to different alcohol effects at different rates also can influence how much a person drinks. Rapid development of tolerance to unpleasant, but not to pleasurable, alcohol effects could promote increased alcohol consumption (7).
Different types of functional tolerance and the factors influencing their development are described below. During repeated exposure to low levels of alcohol, environmental cues and processes related to memory and learning can facilitate tolerance development; during exposure to high levels of alcohol, tolerance may develop independently of environmental influences.
Acute tolerance. Although tolerance to most alcohol effects develops over time and over several drinking sessions, it also has been observed within a single drinking session. This phenomenon is called acute tolerance (2). It means that alcohol-induced impairment is greater when measured soon after beginning alcohol consumption than when measured later in the drinking session, even if the BAC is the same at both times (8-10).
Acute tolerance does not develop to all effects of alcohol but does develop to the feeling of intoxication experienced after alcohol consumption (4). This may prompt the drinker to consume more alcohol, which in turn can impair performance or bodily functions that do not develop acute tolerance.
Environment-dependent tolerance. The development of tolerance to alcohol's eff ects over several drinking sessions is accelerated if alcohol is always administered in the same environment or is accompanied by the same cues. This effect has been called environment-dependent tolerance. Rats that regularly received alcohol in one room and a placebo in a different room demonstrated tolerance to the sedative and temperature-lowering effects of alcohol only in the alcohol-specific environment (11). Similar results were found when an alcohol-induced increase in heart rate was studied in humans (12). When the study subjects always received alcohol in the same room, their heart rate increased to a lesser extent after drinking in that room than in a new environment.
Environment-dependent tolerance develops even in "social" drinkers in response to alcohol-associated cues. In a study analyzing alcohol's effects on the performance of an eye-hand coordination task, a group of men classified as social drinkers received alcohol either in an office or in a room resembling a bar. Most subjects performed the task better (i.e., were more tolerant) when drinking in the barlike environment (13). This suggests that for many people, a bar contains cues that are associated with alcohol consumption and promote environment-dependent tolerance.
Learned tolerance. The development of tolerance also can be accelerated by practicing a task while under the influence of alcohol. This phenomenon is called behaviorally augmented (i.e., learned) tolerance. It first was observed in rats that were trained to navigate a maze while under the influence of alcohol (14). One group of rats received alcohol before their training sessions; the other group received the same amount of alcohol after their training sessions. Rats that practiced the task while under the influence of alcohol developed tolerance more quickly than rats practicing without prior alcohol administration.
Humans also develop tolerance more rapidly and at lower alcohol doses if they practice a task while under the influence of alcohol. When being tested on a task requiring eye-hand coordination while under the influence of alcohol, people who had practiced after ingesting alcohol performed better than people who had practiced before ingesting alcohol (15). Even subjects who only mentally rehearsed the task after drinking alcohol showed the same level of tolerance as those who actually practiced the task while under the influence of alcohol (15).
The expectation of a positive outcome or reward after successful task performance is an important component of the practice effect on tolerance development. When human subjects knew they would receive money or another reward for successful task perfmance while under the influence of alcohol, they developed tolerance more quickly than if they did not expect a reward (16). The motivation to perform better contributes to the development of learned tolerance.
Learned and environment-dependent tolerance have important consequences for situations such as drinking and driving. Repeated practice of a task while under the influence of low levels of alcohol, such as driving a particular route, could lead to the development of tolerance, which in turn could reduce alcohol-induced impairment (16). However, the tolerance acquired for a specific task or in a specific environment is not readily transferable to new conditions (17,18). A driver encountering a new environment or an unexpected situation could instantly lose any previously acquired tolerance to alcohol's impairing effects on driving performance.
Environment-independent tolerance. Exposure to large quantities of alcohol can lead to the development of functional tolerance independent of environmental influences. This was demonstrated in rats that inhaled alcohol vapors (19). In another study, mice demonstrated tolerance in environments different from the one in which the alcohol was administered (20). Significantly larger alcohol doses were necessary to establish this environment-independent tolerance than to establish environment-dependent tolerance (20)
Tolerance that results from a more rapid elimination of alcohol from the body is called metabolic tolerance (2). It is associated with a specific group of liver enzymes that metabolize alcohol and that are activated after chronic drinking (21,22). Enzyme activation increases alcohol degradation and reduces the time during which alcohol is active in the body (2), thereby reducing the duration of alcohol's intoxicating effects.
However, certain of these enzymes also increase the metabolism of some other drugs and medications, causing a variety of harmful effects on the drinker. For example, rapid degradation of sedatives (e.g., barbiturates) (23) can cause tolerance to them and increase the risk for their use and abuse. Increased metabolism of some prescription medications, such as those used to prevent blood clotting and to treat diabetes, reduces their effectiveness in chronic drinkers or even in recovering alcoholics (24). Increased degradation of the common painkiller acetaminophen produces substances that are toxic to the liver (25) and that can contribute to liver damage in chronic drinkers.
Tolerance and the Predisposition to Alcoholism
Animal studies indicate that some aspects of tolerance are genetically determined. Tolerance development was analyzed in rats that were bred to prefer or not prefer alcohol over water (26,27). The alcohol-preferring rats developed acute tolerance to some alcohol effects more rapidly and/or to a greater extent than the nonpreferring rats (26). In addition, only the alcohol-preferring rats developed tolerance to alcohol's effects when tested over several drinking sessions (27). These differences suggest that the potential to develop tolerance is genetically determined and may contribute to increased alcohol consumption.
In humans, genetically determined differences in tolerance that may affect drinking behavior were investigated by comparing sons of alcoholic fathers (SOA's) with sons of nonalcoholic fathers (SONA's). Several studies found that SOA's were less impaired by alcohol than SONA's (28,29). Other studies found that, compared with SONA's, SOA's were affected more strongly by alcohol early in the drinking session but developed more tolerance later in the drinking session (30). These studies suggest that at the start of drinking, when alcohol's pleasurable effects prevail, SOA's experience these strongly; later in the drinking session, when impairing effects prevail, SOA's do not experience these as strongly because they have developed tolerance (30). This predisposition could contribute to increased drinking and the risk for alcoholism in SOA's.
Alcohol and Tolerance--A Commentary by
NIAAA Director Enoch Gordis, M.D.
Tolerance can be a useful clue for clinicians in identifying patients who may be at risk for developing alcohol-related problems. For example, younger patients who are early in their drinking histories and who report that they can "hold their liquor well" may be drinking at rates that will place them at risk for medical complications from alcohol use, including alcoholism. The fact that tolerance to all of alcohol's effects does not develop simultaneously is also important; people who are mildly tolerant may exhibit more symptoms of impairment when faced with unfamiliar activities, such as driving in an unknown area, than when they are engaged in routine actions, such as driving home from work. Lastly, although we know that initial sensitivity to alcohol may play a role in the development of alcoholism, the role of tolerance in maintaining addiction to alcohol needs further exploration.
(1) American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Washington, DC: the Association, 1994. (2) Tabakoff, B.; Cornell, N.; & Hoffman, P.L. Alcohol tolerance. Annals of Emergency Medicine 15(9):1005-1012, 1986. (3) Chesher, G., & Greeley, J. Tolerance to the effects of alcohol. Alcohol, Drugs and Driving 8(2):93-106, 1992. (4) Vogel-Sprott, M.D. Acute recovery and tolerance to low doses of alcohol: Differences in cognitive and motor skill performance. Psychopharmacology 61(3):287-291, 1979. (5) Pohorecky, L.A.; Brick, J.; & Carpenter, J.A. Assessment of the development of tolerance to ethanol using multiple measures. Alcoholism: Clinical and Experimental Research 10(6):616-622, 1986. (6) Tabakoff, B., & Kiianmaa, K. Does tolerance develop to the activating, as well as the depressant, effects of ethanol? Pharmacology Biochemistry & Behavior 17(5):1073-1076, 1982. (7) Tabakoff, B., & Hoffman, P.L. Tolerance and the etiology of alcoholism: Hypothesis and mechanism. Alcoholism: Clinical and Experimental Research 12(1):184-186, 1988. (8) Beirness, D., & Vogel-Sprott, M. The development of alcohol tolerance: Acute recovery as a predictor. Psychopharmacology 84(3):398-401, 1984. (9) Bennett, R.H.; Cherek, D.R.; & Spiga, R. Acute and chronic alcohol tolerance in humans: Effects of dose and consecutive days of exposure. Alcoholism: Clinical and Experimental Research 17(4):740-745, 1993. (10) Hiltunen, A.J., & Järbe, T.U.C. Acute tolerance to ethanol using drug discrimination and open-field procedures in rats. Psychopharmacology 102(2):207-212, 1990. (11) Mansfield, J.G., & Cunningham, C.L. Conditioning and extinction of tolerance to the hypothermic effect of ethanol in rats. Journal of Comparative and Physiological Psychology 94(5):962-969, 1980. (12) Dafters, R., & Anderson, G. Conditioned tolerance to the tachycardia effect of ethanol in humans. Psychopharmacology 78(4):365-367, 1982. (13) McCusker, C.G., & Brown, K. Alcohol-predictive cues enhance tolerance to and precipitate "craving" for alcohol in social drinkers. Journal of Studies on Alcohol 51(6):494-499, 1990. (14) LeBlanc, A.E.; Gibbins, R.J.; & Kalant, H. Behavioral augmentation of tolerance to ethanol in the rat. Psychopharmacologia 30:117-122, 1973. (15) Vogel-Sprott, M.; Rawana, E.; & Webster, R. Mental rehearsal of a task under ethanol facilitates tolerance. Pharmacology Biochemistry & Behavior 21(3):329-331, 1984. (16) Sdao-Jarvie, K., & Vogel-Sprott, M. Response expectancies affect the acquisition and display of behavioral tolerance to alcohol. Alcohol 8(6):491-498, 1991. (17) Siegel, S., & Sdao-Jarvie, K. Attenuation of ethanol tolerance by a novel stimulus. Psychopharmacology 88(2):258-261, 1986. (18) Tsibulsky, V.L., & Amit, Z. Role of environmental cues as Pavlovian-conditioned stimuli in enhancement of tolerance to ethanol effects: 1. Lethal effects in mice and rats. Pharmacology Biochemistry & Behavior 45(2):473-479, 1993. (19) Tabakoff, B., & Culp, S.G. Studies on tolerance development in inbred and heterogeneous stock National Institutes of Health rats. Alcoholism: Clinical and Experimental Research 8(5):495-499, 1984. (20) Melchior, C.L., & Tabakoff, B. Modification of environmentally cued tolerance to ethanol in mice. Journal of Pharmacology and Experimental Therapeutics 219(1):175-180, 1981. (21) Lieber, C.S. Metabolism of ethanol and associated hepatotoxicity. Drug and Alcohol Review 10(3):175-202, 1991. (22) Lieber, C.S. The microsomal ethanol oxidizing system: Its role in ethanol and xenobiotic metabolism. Biochemical Society Transactions 16(3):232-239, 1988. (23) Misra, P.S.; Lefèvre, A.; Ishii, H.; Rubin, E.; & Lieber, C. S. Increase of ethanol, meprobamate and pentobarbital metabolism after chronic ethanol administration in man and in rats. American Journal of Medicine 51(3):346-351, 1971. (24) Lieber, C.S. Interaction of ethanol with other drugs. In: Lieber, C.S., ed. Medical and Nutritional Complications of Alcoholism: Mechanisms and Management. New York: Plenum Press, 1992. pp. 165-183. (25) Sato, C.; Matsuda, Y.; and Lieber, C.S. Increased hepatotoxicity of acetaminophen after chronic ethanol consumption in the rat. Gastroenterology 80(1):140-148, 1981. (26) Waller, M.B.; McBride, W.J.; Lumeng, L.; & Li, T.-K. Initial sensitivity and acute tolerance to ethanol in the P and NP lines of rats. Pharmacology Biochemistry & Behavior 19(4):683-686, 1983. (27) Lê, A.D., & Kiianmaa, K. Characteristics of ethanol tolerance in alcohol drinking (AA) and alcohol avoiding (ANA) rats. Psychopharmacology 94(4):479-483, 1988. (28) Schuckit, M.A. Ethanol-induced changes in body sway in men at high alcoholism risk. Archives of General Psychiatry 42(4):375-379, 1985. (29) Schuckit, M.A., & Gold, E.O. A simultaneous evaluation of multiple markers of ethanol/placebo challenges in sons of alcoholics and controls. Archives of General Psychiatry 45(3):211-216, 1988. (30) Newlin, D.B., & Thomson, J.B. Alcohol challenge with sons of alcoholics: A critical review and analysis. Psychological Bulletin 108(3):383-402, 1990.
ACKNOWLEDGMENT: The National Institute on Alcohol Abuse and Alcoholism wishes to acknowledge the valuable contributions of Boris Tabakoff, Ph.D., professor and chairman of the Department of Pharmacology, University of Colorado School of Medicine, Denver, CO, to the development of this Alcohol Alert.
All material contained in the Alcohol Alert is in the public domain and may be used or reproduced without permission from NIAAA. Citation of the source is appreciated.
Copies of the Alcohol Alert are available free of charge from the Scientific Communications Branch, Office of Scientific Affairs, NIAAA, Willco Building, Suite 409, 6000 Executive Boulevard, Bethesda, MD 20892-7003. Telephone: 301-443-3860.
U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service * National Institutes of Health
Updated: October 2000