This section has articles on some aspects of the physical and psychological complications of substance abuse. It contains an overview of Medical and Behavioral Toxicity and individual articles on the following: Cardiovascular System; Cognition; Dermatological; Endocrine and Reproductive Systems; Immunologic; Liver (Alcohol); Liver Damage (Other Drugs); Mental Disorders; Neurological; Nutritional ; and those Due to Route of Administration. Each article is extensively cross-referenced and will refer the reader to other articles throughout the Encyclopedia that will either expand or simplify concepts introduced here, and to articles on the many other behavioral and nonmedical complications that arise as a result of alcohol and drug use.
Cardiovascular System (Alcohol and Cocaine)
Since the 1960s, the effects of Alcohol (ethanol) on the heart and blood vessels have been extensively studied. Clearly, the toxic effects of both acute and chronic ingestion are independent of nutritional and cardiovascular risk factors. In 1964, a relationship was established between the duration and quantity of alcohol use and the degree of heart disease in patients without nutritional or liver disease. Alcoholism, once felt to be coincidental with heart muscle damage, is now among the most frequently identified causes, according to two recent studies that report a 32 percent and a 45 percent incidence, respectively.
Attention was also paid to Cocaine abuse as the popularity of this drug skyrocketed in the 1980s (an estimated 30 million Americans had used it and some 6 million were users in 1985). Here too came the recognition that acute and chronic-use users were associated with cardiopulmonary manifestations. A 1998 survey estimated that nearly twelve million Americans use cocaine and alcohol together, and researchers have found a unique product of the body when these two drugs are used in combination—Cocaethylene.
Effects of Acute Administration in Those With and Without Heart Disease.
Even mildly intoxicating levels of alcohol affect the cardiovascular system. The magnitude of effects may depend on the chronicity of use. When six ounces of scotch were given to both alcoholics and nonalcoholics, neither of which groups was suffering from previously recognized cardiac problems, over a two-hour period, only the nonalcoholics demonstrated evidence of diminished heart muscle contractility (pumping less blood per contraction). This depressant effect is enhanced by increasing blood levels 75 milligrams/100 milliliters, but remains for only a few hours after ingestion ceases. However, the amount of blood the heart can pump per minute may actually increase in normal subjects acutely exposed to alcohol, because of an acceleration of the heart rate (increase of contractions per minute).
During the late-intoxication/early-withdrawal stage of acute alcohol consumption, blood pressure may be affected in the noncardiac alcoholic. Blood-pressure elevation is the rule. Blood levels of certain hormones, as well as urinary levels of certain breakdown products, correlate directly with blood-pressure response, which appears to vary with the degree of alcohol intake.
Arrythmias, abnormal heart rhythms, are also commonly described in patients without cardiac problems during acute alcohol intoxication. The so-called holiday heart syndrome represents an acute transient-rhythm disturbance in persons without otherwise detectable heart disease who are examined following heavy drinking. Atrial fibrillation—a very rapid and irregular but generally not life-threatening heart rhythm—was the most common heartbeat irregularity. Normal rhythm was restored in all cases, but recurrence of the syndrome is common.
Cardiac patients who have already had at least one prior episode of heart failure, and who have not compensated by clinical means, usually with symptoms of severe fatigue and shortness of breath, may exhibit even greater sensitivity to acute alcohol consumption. Such individuals given six ounces of scotch over two hours exhibited a substantial increase in measured internal heart pressures, suggesting poor heart function and reserve.
EFFECTS OF CHRONIC ALCOHOL USE
Results of studies on alcoholic subjects without evidence of heart disease suggest that a subclinical disease state may exist. In this situation, recognition of the possibility of disease exists, but no methodology has been developed to detect one in the clinic. In one study, those with at least a ten-year history of heavy alcohol consumption were compared to controls. These patients had biopsy-proven fatty liver disease (a common sequel to chronic alcohol use) without prior history of heart disease. The response of the heart's main pumping chamber—the left ventricle—to storehouses was assessed. Alcoholic hearts were found to have abnormally high internal pressures and could not appropriately compensate by increasing forward blood flow. An index of heart contractions in response to the stimulus was correspondingly low in the alcoholics compared to control. Doppler echocardiography, an ultrasound technique for assessing heart function, has also demonstrated an inability of the heart muscle to relax and its chambers to fill properly with blood. Therefore, the pumping chamber of the heart cannot fill or expel blood in a proper manner. Not surprisingly, autopsy specimens from these patients demonstrate fibrosis, development of abnormal and often harmful tissue, and scarring of the heart muscle. Consideration must also be given to cardiac status in cirrhotics, a group once thought relatively resistant to heart muscle failure. A group of thirty-seven patients with cirrhosis of the liver but no evidence of heart disease were studied. One subset with poor heart function at rest had an abnormal response to left ventricle stressors. The other subset, which had abnormally vigorous function at rest, also failed to respond appropriately to stressors, suggesting cardiac dysfunction in this group of patients despite a lack of symptoms.
MECHANISMS OF ACTION
The exact mechanism by which alcohol exerts its effects on the heart muscle, at the cellular level, remains speculative. It is believed that altered movement of calcium ions within these cells may be of major importance.
The Picture of Clinical Heart Failure.
A full-blown cardiomyopathic picture, a complete observance of disease of the middle layer of the heart, although relatively uncommon among alcoholics, is not unlike that seen with other causes of this syndrome. Most commonly, complaints of weakness and fatigue are present before a history of exertional and nocturnal shortness of breath. Engorgement of the veins of the neck, an enlarged, tender liver, and swelling of the legs and feet are other peripheral signs of heart failure frequently seen in these patients. Heart size is variable. The most significant cardiomegaly, enlargement of the heart, is seen in those patients who develop atrioventricular valve regurgitation, a leaking of blood backward from the large to the small heart chambers, as a result of muscle weakness. This abnormal flow creates heart murmurs and may give a clue to the severity of disease. Blood clots are also a common feature of this syndrome. They often form in the vein of the leg or along the walls of the heart chambers and can travel to the lungs and brain causing near instantaneous death or stroke.
Studies performed in the 1960s clearly documented these effects of alcohol on cardiac difficulties that are left untreated. In one, a patient was fed twelve to sixteen ounces of Scotch daily. Gradually, over a four-month period, he developed the signs and symptoms of heart failure. These reversed when the alcohol was discontinued. This sensitivity to alcohol has individual variability and, unfortunately, the factors contributing to this are unknown. There may be some difference in susceptibility between the sexes. In a study of matched subjects with alcoholic cirrhosis under age forty-five, measures of heart muscle performance were significantly worse in men than in women. Experience also shows that heart failure is rare in alcoholic women prior to menopause.
In either gender, heart failure is generally found in those who continuously (chronically) ingest intoxicating amounts for a minimum of ten years. Isolated studies do, however, suggest the potential for the beneficial effects of cessation of alcohol ingestion. One study of thirty-one alcoholics matched for degree of heart size and symptoms found that all twelve abstainers survived over several years, while all nineteen who continued drinking died. A study of sixty-four patients found a 9 percent mortality rate among abstainers over four years and a 57 percent mortality rate in persistent drinkers.
Coronary Artery Disease.
Chest pain in patients with alcoholic hearts is not uncommon, although it had long been held that chronic alcoholics have less severe atherosclerotic coronary artery disease, characterized by a hardening of the arteries accompanied by cholesterol and fatty blockages, than nonalcoholics. Yet, it has been postulated that many heavy drinkers may have a higher incidence of heart attacks (myocardial infarction). Heart attacks have even been reported in a small number of patients without significant coronary disease—possibly related to the scarring of coronary arteries or the spontaneous formation of blood clots within them.
Alcohol may exert at least an indirect effect on coronary anatomy via interaction with fat metabolism. Three major components of fat metabolism, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides all impact on coronary atherosclerosis or plaquing. Levels of LDL cholesterol (the so-called bad cholesterol responsible for atherosclerosis) appear to be lowered by heavy alcohol use. Moderate use (1-3 drinks per day) does not seem to affect levels of either triglycerides or LDL cholesterol.
HDL cholesterol, the so-called good cholesterol (believed to be protective against atherosclerosis), has shown a consistent relationship with even moderate alcohol consumption. Alcohol is believed to enhance the activity of the enzymes lipoprotein lipase and hepatic triglyceride lipase—thereby favoring HDL production. Autopsy studies have shown a lower prevalence of atherosclerosis, blockages, in alcoholics and cirrhotics. Whether this is due to malnutrition or direct effects on fat metabolism remains unclear.
A reduced degree of coronary disease has also been documented in light as compared to nondrinkers. Two recent studies both support the hypothesis that light or moderate alcohol intake appears to reduce the risk of fatal and nonfatal heart attacks and the need for coronary angioplasty and bypass operations in both men and women. Neither study included many heavy drinkers, and multiple coronary-risk factors (including cigarette Smoking) were accounted for. Although these studies supported the positive association between increased HDL cholesterol levels and alcohol intake, no consensus exists to promote alcohol use for the primary prevention of coronary artery disease, owing to its ease of addiction and other multiple harmful effects.
Cocaine abuse has dramatically increased in the United States since the 1980s. One consequence has been the recognition of cocaine's unpredictable medical side effects—the most dramatic and devastating of which are cardiovascular. These include acute impairment of blood supply to the heart muscle, and heart attacks, as well as hypertension, accelerated arteriosclerosis, ruptured aorta artery, inflammation of heart muscle, cardiomyopathy (heart disease), cardiac arrythmia, and sudden death.
Cocaine has two separate primary pharmacologic effects on the heart and vascular system. First, it causes an accumulation of Catecholamines—accomplished by increasing their release (which include epinephrine [also called adrenaline], Norepinephrine, and Dopamine) from both brain and spinal cord stores and by blocking their reuptake at nerve endings. The result is a more pronounced and long lasting stimulation of the sympathetic nervous system, heart muscle, and vascular smooth muscle, represented clinically by an increase in heart rate, blood pressure, heart contractions, vasoconstriction, when blood vessels constrict, and coronary vascular resistance, a resistance of the blood vessels to blood flow. Cocaine may also induce vasoconstriction via direct stimulation of calcium into smooth muscle cells.
Cocaine's second pharmacologic property is a local anesthetic effect on cardiac tissue. Cocaine can paralyze the movement of the ions (like sodium and potassium) required for the inherent electrical stimulation of heart-muscle function. Therefore, severe toxicity may result—with acute electromechanical dysfunction manifest as an abnormally slow heart rate or acute pump failure.
Several controlled trials have assessed the acute effects of cocaine on humans. Investigators have demonstrated a dose-related increase in heart rate and blood pressure. Others have induced a significant reduction in coronary blood flow in patients receiving intranasal (inhaled through the nose), cocaine at 2 milligrams per kilogram, with coronary angiography, a test using a chemical that can be tracked and seen in the body using an x-ray, revealing a diffuse reduction in vessel caliber (width). Coronary vasospasm, a sudden constriction of the blood vessel, has also been documented with intra-nasal administration. The effects of chronic use have been studied in animal models, with two experiments demonstrating that cocaine fed to rabbits on high cholesterol diets significantly increased aortic atherosclerosis, or blockages, as compared to rabbits fed similar diets minus the cocaine.
Since all the mechanisms discussed above either increase myocardial oxygen demand or decrease myocardial oxygen supply, heart attacks are natural consequences of cocaine toxicity. Many case reports have temporarily related cocaine use to myocardial infarction, frequently in patients without coronary artery narrowing. Thrombosis, the acute formation of an occlusive clot in a blood vessel, has been documented in nearly one-third of cases. This is consistent with evidence that cocaine causes an increase in the aggregation, collection and buildup, of platelets, blood elements that cling together to initiate blood clotting. Cocaine toxicity may also cause rupture of pre-existing small lipid-containing bulges on the arterial walls, as well as coronary spasm, both of which trigger thrombus formation.
Case reports have also suggested that cocaine has a primary depressant effect on cardiac muscle. Otherwise healthy patients have developed acute cardiac dilation and pump failure associated with acute or chronic cocaine use. With abstinence, such signs and symptoms resolved over days to weeks. Animal studies have confirmed this phenomenon. Autopsy studies on patients with cocaine in the bloodstream have shown inflammation and scarring of heart muscle cells in up to 20 percent, as compared with 4 percent of controls, suggesting a pathologic link.
Ultimately, most cocaine-related deaths are caused by cardiac arrhythmias. Abnormally fast and abnormally slow heart rates have been reported with cocaine use. Low and moderate doses often trigger the fast and massive doses the slow, including the complete cessation of heart beats (termed asystole ). The combination of alcohol and cocaine may be even more dangerous than cocaine alone. In the presence of alcohol (ethanol), in humans, cocaine is metabolized to the compound Cocaethylene. This chemical renders the combination of cocaine and alcohol more lethal than either alone, and a twenty-one times greater risk of sudden death exists in people with associated coronary artery disease.
The effects of alcohol and cocaine on vascular physiology do not bypass the brain. Epidemiologic studies indicate a passive association between the amount consumed and the risk of cerebral vascular accidents, generally presenting as intracranial hemorrhage, blood vessel ruptures in the head. In one study, heavy drinkers were twice as common among men and seven times as common among women who had sustained intracranial hemorrhage than in the general population. Furthermore, heavy drinkers were more likely to have been intoxicated in the twenty-four hours prior to their event. Young adults and women, generally unlikely candidates for intracranial hemorrhage, are not immune when subjected to acute, or heavy intoxication.
The mechanism for this remains unclear. Hypertension is a known risk factor for stroke in general and alcohol-induced hypertension may be a causative factor. The same may be postulated with cocaine use. As with alcohol-induced cardiomyopathy, individuals who reduce their alcohol intake have a significantly lower risk of developing hemorrhagic stroke than those who continue its use.
(See also: Alcohol ; Complications )
Ahmed, S. S., & Regan, T. J. (1992). Cardiotoxicity of acute and chronic ingestion of various alcohols in cardiovascular toxicology. In D. Acosta, Jr. (Ed.), Cardiovascular Toxicology (2nd. ed.). New York: Raven Press.
Regan, T. J. (1991). Alcohol and the heart. In K. Chatterjie & W. Parmley (Eds.), Cardiology. New York: Gower Medical Publishing.
Thomas, B. A., & Regan, T. J. (1990). Interactions between alcohol and cardiovascular medication. Alcohol, Health, and Resort World, 14, 333-339.
Revised by Andrew J. Homburg
Psychoactive Drugs of abuse, used for their perceived mind-altering effects, often have additional cognitive effects of which the drug user may not be aware. A cognitive effect is an impact on mental functions—including processes of learning, perceiving, imagining, remembering, feeling, thinking, reasoning, knowing, and judging.
Psychoactive drugs produce cognitive effects by causing chemical changes in the brain. These effects are mostly short-lived and correspond to the duration and intensity of the chemical changes in the brain. However, cognitive effects can persist after the drug has been eliminated from the body, and some can be irreversible. The common cognitive effects of some psychoactive drugs of abuse are summarized below.
Ethanol (also called ethyl alcohol) is the drinking Alcohol of Beers and Brews, wine, distilled spirits, or medicinal compounds; it acts by depressing or reducing cognitions. Initially, alcohol reduces inhibitions, and this results in more spontaneity or impulsivity and a feeling of relaxation. As the amount of alcohol acting on the brain increases, the ability to perceive, remember, reason, and judge is progressively impaired. Further increases in the amount of alcohol can depress the brain and cognitions to the point of loss of consciousness. Due to cognitive impairment, the person may not perceive the impairment (e.g., "I'm not drunk") and take undue risks (e.g., Drunk Driving, indiscretions).
Alcoholic blackouts are impairments of memory for events that occurred while one was conscious but under the influence of alcohol. Such black-outs are not limited to chronic alcoholics. Long-term use of alcohol can lead to subtle impairment of perceiving, responding, and remembering that may not be detectable without special psychometric tests. A particular form of impairment of memory, called the amnestic syndrome, has been seen in alcoholics; they are unable to remember recent events although memories from long ago remain reasonably intact. By contrast, in alcoholic dementia, deficits in all cognitive functions are seen. Some deficits may persist for life even if the person stops drinking.
Paranoid states of unfounded suspicion or jealousy may manifest or be aggravated under the influence of alcohol. In alcoholic, Hallucinations people can have vivid but unreal perceptions while awake; these typically occur as a result of neurochemical changes in the brain when alcohol use is abruptly discontinued after periods of excessive drinking. Even after months have elapsed since their last drink, alcoholics can have cognitive deficits, especially in visual-spatial abilities, hand-eye coordination, abstract reasoning, and new learning.
TRANQUILIZERS, SEDATIVES, AND HYPNOTICS
These drugs are often collectively referred to as "downers." Persons taking them are at risk for the cognitive impairments discussed above, under "Alcohol." The Elderly are particularly at risk for confusion.
Stimulant drugs have effects that are the reverse of depressant drugs—they arouse the nervous system. They include such drugs as Cocaine, Amphetamines (speed), and Caffeine. In low doses, perception is heightened, attention is increased, and thought processes are speeded up, resulting in a feeling of greater alertness. Memory, however, may be affected, resulting in impaired recall of material learned while under the influence of stimulants. Higher doses intensify the above effects, leading to restlessness and rapidity of thoughts, which reduce attention. Vulnerable persons may become paranoid or even psychotic. Higher effective doses of stimulants may occur via intravenous administration or smoking of cocaine, affecting the brain rapidly and resulting in an abrupt "rush" or "high." These effects are typically short-lived but are so intense (pleasurable) that individuals may repeat doses. Discontinuation of stimulants after a long period of use often leads to a temporary period of Depression. There is evidence that long-term and repeated doses of stimulants can severely damage the brain and affect concentration, mood, and reasoning
Cannabis sativa is often used for the subjective effects of relaxation and a decreased awareness of conflicts. It is also known to distort perception of time and to reduce responsiveness. Long-term use of Cannabis has been associated with apathy, under-achievement, and lack of motivation.
Hallucinogenic drugs distort perceptions and cause hallucinations. They include Lysergic Acid Diethylamide (LSD), Phencyclidine (PCP), Mescaline, Psilocybin mushrooms, and several newer drugs with hallucinatory and stimulant effects (called "designer drugs," e.g. ecstasy. Apart from profound effects on perceptions, responsiveness, learning, and judgment are affected. Some users experience flashbacks—spontaneous vivid recollections of experiences that occurred while under the influence of hallucinogens.
USE DURING PREGNANCY
Psychoactive drugs used during Pregnancy affect the developing fetus. Prenatal exposure, particularly to alcohol but possibly to Cannabis, or stimulants has been associated with cognitive impairments detectable early in the child's life and eventually resulting in developmental problems and school, social, and occupational difficulties.
(See also: Imaging Techniques )
Martin, P. R., & Hubbard, J. R. (2000). Substance abuse and related disorders. Current Diagnosis and Treatment in Psychiatry. Ebert, M. H., Loosen, P. T., Nurcombe, B., eds., McGraw-Hill, 233-259
Martin, P. R., Lovinger, D. M., Breese, G. R. (1995). Alcohol and other abused substances. Principles of Pharmacology: Basic Concepts and Clinical Applications. Munson, P., and Mueller, R. A., eds. New York: Chapman & Hall, 417-452.
With the exceptions of rashes and other skin conditions resulting from idiosyncratic or allergic reactions to drugs, most drug use complications involving skin damage result from the use of hypodermic needles or other means of drug injection that involve breaking the skin surface. There are three primary types of injection: (1) subcutaneous, also known as "skin-popping," wherein the needle is injected into or directly under the skin surface; (2) intramuscular (IM), wherein the needle is injected into muscle mass, often in the shoulder or buttock; and (3) intravenous (IV), direct injection into a blood vessel. Skin damage can result from repeated injection in the same area, failure to clean the injection site, nonsterile needles, and/or impurities or insoluble materials in the substance injected. Adulterants in the drugs, liquids used to dilute the drugs and contaminated injection paraphernalia, and the surface of the injection site all provide sources of viruses, bacteria, and fungi.
The most common skin damage from repeated injection is needle-track scars. These are usually caused by unsterile injection techniques or by the injection of fibrogenic particulate matter—material often used by dealers to add bulk and weight to the drug or buffers in tablets that have been ground up and liquified for injection. Carbon deposited on needles by users who try to sterilize by heating the needle tip with a match may produce a "tattoo" discoloration, accompanied by a mild inflammatory reaction under the skin at the point of entry. Such scars are found mostly on the arms, but they can occur anywhere on the user's body that has been used as an injection site, including thighs, ankles, neck, and penile veins.
Needle abscesses, characterized by redness; a stinging, itching sensation; and swelling at the site, often result from repeated injection without cleaning the injection site. Such skin flora as staphylococci and streptococci are driven beneath the skin surface to infect the site, often with pus formation. Forms of contact dermatitis can also result from allergic reactions, especially to fluids used to sterilize the skin at injection sites. Infections and allergic reactions increase as an individual's resistance decreases with a drug-compromised immune system.
Subcutaneous injection of Sedative-Hypnotic drugs, such as Barbiturates, can cause cellulitis—where the tissue becomes reddened, hot, painful, and swollen at the injection site. If not treated, the cellulitis may last for a long time. In extreme cases, the cellulitis may eventually cover most of the user's body as new needle sites are used to avoid painful areas. Superficial cellulitis, septic thrombophlebitis, and simple needle abscesses can usually be treated with local heat, incision, and drainage, followed by culture and sensitivity testing and appropriate antimicrobial therapy.
Repeated intravenous injection may produce anaerobic infections or abscesses that produce a foul-smelling discharge, sometimes gas formation, and a cellulitis that is characterized by a rapidly progressing stony or wooden-hard tenseness, often some distance from the original needle site. Although the mechanism of these infections is unclear, it is thought to involve a disruption of blood supply to the area from edema (fluid collection) resulting from the cellulitis. Treatment involves wide incision and pressure reduction in the affected area. Kaposi's Sarcoma. Kaposi's Sarcoma is a malignancy arising in the skin usually in the cells lining the blood vessels (endothelium). The lesions have a nodular or plaquelike appearance, may be localized and indolent or disseminated, and involve aggressive spreading to mucous membranes and visceral organs, especially the gastrointestinal tract.
Prior to 1980 and the advent of the human immunodeficiency virus (HIV) and AIDS, Kaposi's sarcoma was considered a rare disease and primarily limited to elderly males of Mediterranean ethnic origin. Since that time, widespread dissemination of HIV and the epidemic of AIDS accompanying it has made Kaposi's sarcoma much more common. Substance abusers who administer their drugs parenterally (subcutaneously, intramuscularly, intravenously) are a higher risk group for Kaposi's sarcoma since many of these individuals inject drugs with unsterile needles that frequently are used in common with others. They therefore have an excellent opportunity of acquiring HIV from infected blood.
The aggressive form of Kaposi's sarcoma has occurred in at least one-third of patients with AIDS and has reached epidemic proportions in the United States and many African countries. In many AIDS patients, Kaposi sarcoma lesions may actually be the first notable manifestation of the disease. The lesions usually first appear on the upper part of the body, but rapidly spread to lymph nodes, the mucosa of the mouth and the gastrointestinal tract and other visceral organs.
Chemotherapy is the treatment of choice, either a single agent or a combination of agents. Interferon-a effectively slows the progression of lesions and cures others. The injection of vincristine into the lesions is also useful. The course of the disease is dictated by the level of immunosuppression that is present.
(See also: Allergies to Alcohol and Drugs ; Complications: Route of Administration )
Cohen, S., & Gallant, D. M. (1981). Diagnosis of drug and alcohol abuse. Brooklyn: Career Teacher Center, State University of New York.
Senay, E. C., & Raynes, A. E. (1977). Treatment of the drug abusing patient for treatment staff physicians. Arlington, TX: National Drug Abuse Center.
Seymour, R. B., & Smith, D. E. (1987). The physician's guide to psychoactive drugs. New York: Hayworth Press.
David E. Smith
Richard B. Seymour
Revised by Ralph Myerson
Endocrine and Reproductive Systems
Many fundamental challenges remain in understanding the impact of Alcohol and drugs on endocrine and reproductive function. This article presents what is currently known; before beginning, a few caveats deserve attention.
Many factors may influence the degree to which illegal drug or alcohol abuse may cause an abnormality of endocrine or reproductive function. These factors include (1) the amount and duration of consumption; (2) the route of illegal drug administration; (3) whether there is preexisting or concurrent damage to an endocrine/reproductive organ; (4) concurrent use of another drug; and (5) the genetic predilection for an endocrine disorder. Often, our knowledge about these factors and how they interact with one another is more limited than what is known about the range of endocrine and reproductive dysfunction associated with the chronic consumption of alcohol and the abuse of illicit drugs.
Knowledge is also limited because some endocrine or reproductive consequences may be manifested only by an abnormal result from a laboratory (biochemical) test. The absence of a physical sign or a clinical symptom may lead to the false impression that there is no endocrine/reproductive consequence. In addition, there are challenges in ascertaining whether the alcohol- or drug-abuse related endocrine/reproductive dysfunction is due to the drug itself or to the social context in which the drug is used. Finally, endocrine or reproductive disturbances may also occur from the consequences of Withdrawal syndromes when the drugs or alcohol ingestion is stopped or reduced. To the extent to which these issues have been clarified, we will note them here.
Most endocrine and reproductive function is influenced directly or indirectly by the Brain—specifically by the functional interactions of the brain's hypothalamus and pituitary with the target endocrine organs. The hypothalamus produces pituitary-regulating hormones; all are peptides except one (Dopamine). In response to each of these hypothalamic hormones, the pituitary releases a hormone, which influences the function of an endocrine or reproductive organ.
The anecdotal reports of changes in sexual function following alcohol consumption was the stimulus for much of the research targeting hypothalamic-pituitary relationships, since impairments here may often result in sexual dysfunction. Although acute alcohol use has been reported in public surveys to be associated with increased sexual drive and functioning, clinical and animal research have revealed major hormonal dysfunctions in chronic or heavy alcohol users.
Prolactin (PRL)—the pituitary hormone associated with preparation during pregnancy for breastmilk secretion—is increased with heavy alcohol use; however, chronic alcohol use inhibits the pituitary release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Both LH and FSH are important in regulating the sex hormones produced by the testes in males and the ovaries in females. Yet, when alcohol is administered acutely, there are no significant changes in PRL, LH, or FSH serum levels.
Heavy alcohol consumption is associated with an increase in pituitary-secreted adrenocorticotropic hormone (ACTH), partly explaining the "pseudo-"Cushing's syndrome (moon faced appearance, central obesity, muscle weakness) and the increased melanocyte-stimulating hormone (MSH), which possibly leads to darkening skin pigmentation. Although there is no consistent effect of heavy alcohol use on the pituitary's release of thyroid-stimulating hormone (TSH) or growth hormone (GH), a rise in the blood alcohol level is associated with the inhibition of antidiuretic hormone (ADH) release from the posterior pituitary, resulting in increased urination.
Complaints of derangements of libido (sex drive) and sexual functioning in Opioid addicts (Heroin) were among the first lines of clinical evidence to suggest the possible role of such narcotics in altering hypothalamic-pituitary functioning. Although most of what is known about drug-abuse related hypothalamic-pituitary abnormalities focuses on heroin use, the epidemic proportions of Cocaine abuse and dependency in the 1980s have brought renewed scientific interest to this area.
Studies have shown that opioid use has been associated with increased serum PRL without disturbances in serum GH or TSH levels; and cocaine use has been associated with both high and low PRL levels. The contradictory findings in the case of cocaine use might be attributable to the variations in patterns of cocaine use. Animal studies have shown that gonadotropin-releasing hormone (GnRH), released from the hypothalamus, did not stimulate PRL following acute cocaine administration, and it did not prevent acute cocaine-associated PRL suppression. Elevated levels of dopamine have been observed during acute cocaine administration, but chronic cocaine use may deplete dopamine.
In patients receiving Methadone therapy for opioid addiction, some investigators have reported a normal rise in TSH released by the pituitary, in response to stimulation by the hypothalamic hormone called thyrotropin-releasing hormone (TRH). Others have observed a blunted TSH and PRL response following TRH administration in active heroin users.
Although normal basal LH secretion has been observed in cocaine abuse, opiate use is associated with decreased basal FSH and LH levels in males. In female heroin addicts, these low levels of the pituitary gonadotropins have clinical relevance, resulting in a consistently normal FSH response and a variable LH response following a GnRH challenge.
Some researchers have demonstrated normal functioning of the hypothalamic-pituitary-adrenal (HPA) axis in former heroin addicts who were maintained on methadone both long-term and only for a number of months. However, there is also evidence suggesting alteration of the normal biological rhythm of hormonal secretion.
Diminished sexual drive and performance in opioid users have raised questions about the relationship between such narcotic drug use and disturbances in the levels of sex hormones. Although some reports show no significant differences in serum-testosterone levels between heroin addicts, Methadone-Maintained patients, and normal controls, other studies have not confirmed these results. Some researchers have reported plasma levels of testosterone to be consistently lower in active heroin addicts, in addicts who self-administer heroin in controlled research settings, and to be within normal range in long-term methadone-maintained patients. Additionally, some evidence shows that plasma testosterone levels that are depressed under circumstances of heroin administration followed by methadone maintenance and then withdrawal gradually returned to preheroin-use levels.
Opioid effects on the estrogens of both males and females may be responsible for the clinical observations of sexual dysfunction. In the male heroin addicts studied, the plasma estradiol concentrations were either low or within normal ranges; in the females, the plasma estrogens are low. A clear explanation of these observed derangements in plasma testosterone and estrogens is unknown. Female heroin addicts frequently experience cessation of or irregular menses. However, most regain normal menstrual function when stabilized on methadone and under these circumstances fertility seems unaffected. The anecdotal reports and, in limited cases, experimental evidence of the influence of Marijuana on sexual function and sex-hormone levels are also inconsistent and confusing.
The illicit drug-related disturbances discussed above suggests that the narcotic-related depressions in sex-hormone production of the ovaries and testes may occur because they reduce the pituitary's stimulation of these sex organs. Still, this has not been a consistent finding.
REPRODUCTION AND PREGNANCY
Impotence, atrophy of the testes, infertility, and decreased libido are not uncommon complaints in male alcoholics. These observations are thought to be secondary to the direct effects of alcohol on testicular tissue, to an alcohol-associated decrease in sperm motility, and to an alcohol-related decrease in Vitamin A and zinc. Both Vitamin A and zinc are important in maintaining testicular tissue growth. In young females, alcohol abuse is associated with amenorrhea and anovulation; in chronic users, with early menopause. There is evidence that vaginal blood flow decreases as the alcohol serum level increases.
Despite these clinical observations, when rigorously investigated, there were no consistent changes in estradiol, progesterone, or testosterone. Consequently, it is difficult to determine whether these observations were due to alcohol-related liver disease, malnutrition, or the direct toxic effects of chronic alcohol use.
During Pregnancy, alcoholism is associated with increased risk of spontaneous abortion and the development of Fetal Alcohol Syndrome (FAS). FAS is comprised of a characteristic pattern of skin/facial abnormalities with growth and development impairments, which are believed to be related to alcohol's suppression of the sex hormone progesterone. While the features of FAS may vary, fetal abnormalities associated with alcohol can be divided into the following four categories: (1) growth deficiency; (2) central nervous system dysfunction; (3) head and facial abnormalities, and (4) other major and minor malformations.
Our understanding of the relationship between opioid drug use and the functioning of the adrenal gland is based on incomplete and often contradicting information. Some scientists have published reports of normal plasma cortisol levels (from the adrenals) during heroin use and withdrawal, under research conditions of heroin self-administration, and during methadone-maintenance treatment. In methadonetreated patients, ACTH produced by the pituitary stimulates the adrenal gland to produce cortisol. In another study, there was a decreased plasma-cortisol response to intravenous cosyntropin (an ACTH-like substance) stimulation in methadone-treated patients. There are also reports of low normal or subnormal plasma-cortisol levels in heroin users and disturbances in the daytime cortisol secretion from the adrenal gland in methadone-maintained patients.
The variable findings from the several studies may be attributed to differences in the types of drugs used, in the state of stress-associated drug withdrawal, in patterns of drug use, in study design, or to a combination of these and other as yet unknown factors. There is also the well-known problem of ACTH measurement, often resulting in falsely low values.
The opioids are virtually the only class of illegal drugs for which there is information about the pharmacologic effects on serum-glucose levels. We have long-standing reports of opiate-associated hyperglycemia, but the mechanisms explaining these empirical observations are incompletely understood. In association with chronic opioid use, there are reports of both low levels of serum glucose and high levels of insulin. The conflicting results of some investigations may be due, in part, to differences in study design (e.g., nutritional state of the research subjects, amount of the glucose used in clinical studies, or the time(s) administered).
To briefly review the regulation of glucose control: The pancreas, an endocrine organ located in the upper abdomen, plays a central role by secreting glucagon to raise serum-glucose levels and by secreting insulin to lower serum-glucose levels. After the discovery of endogenous opioid peptides in the human pancreas, subsequent research provided information that one such endogenous opioid, beta-endorphin, stimulates the secretion of glucagon and a biphasic rise of insulin. This may, in part, explain the observations of both elevated and reduced serum-glucose levels in heroin users. Whatever the nature of the exact mechanism, glucose metabolism is deranged in both heroin and methadone use by some direct or indirect parameter of serum-glucose regulation.
The alcohol-related aberrations of carbohydrate metabolism are also quite complex. Some investigators have demonstrated that acutely administered alcohol may result in a reversible and mild resistance to the glucose-lowering effects of insulin, perhaps explaining the observations of a rise in glucose following alcohol use. In fasting individuals, alcohol administration can lead to severe depressions of serum glucose, primarily by reducing the liver's production of glucose. Serum-glucose levels are also lower in chronic alcohol users with concurrent alcohol-related liver disease. Nevertheless, serum levels are elevated in alcoholics with concurrent alcohol-related destruction of the pancreas. Even without other concurrent diseases, alcohol consumption may result in either no changes or in minimal to mild elevations or reductions in serum glucose.
Located in the anterior aspect of the neck, the thyroid gland secretes thyroxine (T4) and other hormones whose principal purpose is to regulate the metabolism of other tissues in the body. The production of T4 by the thyroid is under the control of the TSH produced by the pituitary. Therefore alterations in thyroid function can be the result of problems directly involving the gland or disruptions in the TSH-mediated control of the thyroid gland.
Despite the frequency, duration, or amount of use, it appears that there are no clinical signs or symptoms of thyroid dysfunction in chronic heroin or alcohol users. Disturbances in biochemical indices (laboratory tests) of thyroid function are, however, not uncommon in opiate or alcohol use. The total T4 is decreased while the amount of biologically available T4 (free T4) and other indices of thyroid function are normal in heavy alcohol users.
In active heroin users or during heroin withdrawal, total T4 levels are increased in association with normal, subnormal, or high levels of other parameters of thyroid function. In methadone-maintained persons, there are reports of normal and slight-to-significant increases in total T4 in conjunction with increased levels of thyroxine-binding globulin (TBG), a protein that binds thyroid hormones in blood. Interestingly, successful methadone maintenance is associated with a correction of these biochemical disturbances.
There are a number of possible explanations for the biochemical derangements observed during opiate use. To maintain an adequate range of biologically active T4, the total T4 is increased whenever there is an increase in TBG. Perhaps the increase in total T4 is the result of a direct opiate-induced elevation of TBG. It is also possible that the altered liver function seen in chronic heroin and alcohol users may be responsible TBG abnormalities, leading to disturbances in T4 levels. Finally, it is possible that opiate-related or alcohol-related disturbances may be due to a combination of the above mechanisms as well as to some other still undefined processes.
The observations of increased fractures sustained by alcoholics has prompted investigations about the role alcohol may play in disturbances of the structure and mechanical properties of bone. Some studies have shown reduced bone mass in alcoholics, while others have reported decreases in compact and trabecular bone mass—a condition called osteoporosis. Some of these disturbances in new bone formation may be mediated by alcohol's impairment of calcium and Vitamin D metabolism, both of which are crucial to bone metabolism. Nevertheless, there does remain considerable doubt as to whether the bone complications are due to alcohol itself or due to alcohol-related liver disease, to malnutrition, or to a potential host of other factors. Chronic liver disease unrelated to alcohol has also been a cause of osteoporosis and other bone diseases.
The endocrine and reproductive consequences of illicit drug and alcohol abuse are extensive and profound. Both drug and alcohol abuse result in clinically significant multiglandular derangements. Although knowledge about the dimensions of such disturbances to endocrine and reproductive function slowly increases, explanations of the scientific mechanisms accounting for these observations remain to be elucidated. Given the role of alcohol and illicit drugs in society, however, the spectrum of related endocrine and reproductive complications can be expected to expand and, thereby, increase in public-health significance.
(See also: Complications: Liver Damage )
Felig, P., et al. (1987). Endocrinology and metabolism, 2nd ed. New York: McGraw-Hill.
Hamid, A., et al. (1987). Alcohol and reproductive function: A review. Obstetrical and Gynecological Survey, 42 (2), 69-74.
Lalor, B. C., et al. (1986). Bone and mineral metabolism and chronic alcohol abuse. Quarterly Journal of Medicine, 59, 497-511.
Smith, C.G., & Asch, R. H. (1987). Drug abuse and reproduction: Fertility and sterility. The American Fertility Society, 48 (3), 355-373.
Lawrence S. Brown, Jr.
Revised by Ralph Myerson
This article describes the basic and clinical immunologic aspects of alcohol and drug abuse.
The physiological characteristics of Alcohol (ethanol) allow it to interfere intensively with the functions of immune cells. Alcohol is completely miscible with water and, to some degree, is fat-soluble. It crosses membranes by diffusion across a concentration gradient. Historically, alcohol has been associated with lower host resistance and increased infectious disease. For example, Alcoholism has been closely associated with lung abscesses, bacteremia, peritonitis, and tuberculosis. Although these infections might be a result of malnutrition or poor living conditions, prolonged consumption of alcohol also results in alterations of immune responses, ultimately manifested by increasing susceptibility to infectious agents. Overwhelming evidence shows that alcohol abuse broadly suppresses the various immune responses, seriously impairing the body's normal host defense not only to invading microbes but also to its defenses against Cancer cells.
These disruptions are the combined result of direct toxic effects on the immune system and indirect effects such as malnutrition, oxidative stress, endocrine changes, and the complications of liver disease. The alcoholic's predisposition to extracellular and intracellular infection indicates the effects of alcohol consumption at the local, humoral, and cellular levels, inhibiting immune response and host defense. Recent evidence suggests that aberrant regulation of the neuroimmune-endocrine networks may be a major risk factor for the development of alcohol-induced immunosuppression, leading to the collapse of host defense. Bidirectional communication can occur between the immune and neuroendocrine systems. Accordingly, stimulated lymphoid cells send signals mediated by cytokines and other immune products to inform the central nervous system about the activity of the immune system. Neuroendocrine molecules, in turn, may complete a feedback loop by modulating the immune response via the pituitary-endocrine axis as well as the autonomic neural output. Thus, effective feedback communications between the endocrine and the immune system may be crucial to the host's defense responses.
Clinical and experimental studies indicate a relationship between excessive alcohol use and compromised immune responses. Human studies have shown that chronic alcohol ingestion is associated with abnormalities of both humoral and cellular immunity. These abnormalities include a depression of serum bacteriocidal activity, alterations of immunoglobulin production, leukopenia, defects in chemotaxis, decreased antigen trapping and processing, and decreased T-cell mitogenesis. The clear association between alcoholism and infections such as tuberculosis and listeriosis indicates defective functioning of cell-mediated immunity. A study has linked alcohol abuse and deficient T-cell responsiveness. Skin-test reactivity using purified protein derivative and dinitrochlorobenzene has also demonstrated poor responses in alcoholics with liver disease. Natural killer (or NK) cell activity is impaired in acute alcohol intoxication and in chronic alcoholic liver disease; NK cells are programmed to recognize and destroy abnormal cells, such as virus-infected or tumor cells. Some researchers have speculated that decreased NK cell activity may be intimately involved in the increased incidence of tumors in alcoholics.
Giving alcohol to animals also has a profound effect on decreasing the weight of their peripheral lymphoid organs as measured by a decreased number of thymocytes and splenocytes. In mice, alcohol use produces thymic and splenic atrophy and alterations in the circulating lymphocytes and lymphocyte subpopulations, as well as alterations in cellular and humoral immunity and impaired cytokine production. Also impaired by dietary alcohol are antibody-dependent cellular cytotoxicity, lymphocyte proliferation, B-lymphocyte functions, and cytokine production by lymphoid cells (the lymph and lymph nodes). Thus, alcohol-induced immunosuppression may render alcoholics more susceptible to tumorigenesis and infection.
Alcoholics are susceptible to infections by bacteria such as Listeria monocytogenes, Vibrio vulnificus, Pasteurella multocida, and Aeromonas hydrophilia. The severity of these infections has raised the possibility of a neutrophil (white blood cell) abnormality in these patients. The proper functioning of neutrophils is critical for host defense against microorganisms. Neutrophils are the chief phagocytic leukocyte of the blood; they are short-lived cells having a life span of approximately four days. Their production is a tightly regulated process centered in the bone marrow. Chronic alcoholics have often been noted to be leukopenic (abnormally low in leukocytes). The toxic effect of alcohol is now believed to be caused by the depression of the T-cell-derived colony-stimulating factor rather than to direct suppression of myeloid (bone marrow) precursors secondary to bone marrow toxicity.
Neutrophils must recognize the invading pathogens, engulf them, and destroy them using a number of killing mechanisms, which include adherence, chemotaxis, locomotion, phagocytosis, and intracellular killing. Several functions of neutrophils are affected by alcohol in vitro, including impairment of chemotaxis, decreased migration of neutrophils within vessels, altered adherence to nylon fibers in vitro, impaired phagocytosis, and decreased intracellular killing of bacteria. In human with advanced cirrhosis from chronic (prolonged and excessive) ingestion of ethanol and impaired phagocytic capacity, decreased metabolic activity was observed in the liver's reticuloendothelial system; there also were impairments of neutrophil chemotaxis, bacterial phagocytosis and killing, and alterations of neutrophil-antigen expression. Neutrophil dysfunction is therefore responsible for aggravating the susceptibility to secondary infections seen in alcoholics.
The balance of cellular and humoral immune response to antigens is controlled by communication between immunocompetent cells. They are regulated to a great extent by soluble mediators (termed cytokines ) produced mostly by T-helper cells and macrophages. Cytokines are biologically active polypeptide intercellular messengers that regulate growth, mobility, and differentiation of leukocytes. Thus, cytokines have extremely important roles in the communicating network that links inducer and effector cells to immune and inflammatory cells.
Since any perturbation in the tightly controlled cytokine regulatory system can result in immune alterations modifying host resistance to infectious disease and cancer, the influence of alcohol consumption on cytokine secretion has been investigated considerably. Several studies have indicated a correlation between circulating levels of macrophage-derived cytokines and disease progression during chronic alcohol consumption. Increased plasma concentrations of tumor necrosis factor have been observed in cases of alcoholic liver disease and, interestingly, relate significantly to decreased long-term survival; plasma Interleukin-1 is also significantly increased in these patients (relative to healthy controls) but does not correlate with increased mortality.
In a model of alcohol-fed mice, we found that, compared to controls, production of all cytokines was suppressed by chronic alcohol consumption, suggesting general immunosuppression. The elevated levels of cytokines in some animals with murine (mice and rats) AIDS were, however, increased further by alcohol ingestion as compared to controls that indicated alcohol-induced aggravation of some AIDS symptoms. Similarly, those cytokines suppressed by murine AIDS were further suppressed by alcohol. Thus, alcohol exacerbated their immune dysfunction. Several pathways may be involved in mediating the interaction between the endocrine system and the immune system. Recent findings indicate that pituitary peptide hormones can directly influence immune response. In addition, when a neurotransmitter is released in lymphoid tissues, it may locally modify the functional properties of lymphocytes and release of cytokines.
In human studies regarding alcohol, all parameters, such as hormone levels and immune responses to monitor changes of immune response and neurotransmitter, are usually detected in serum. Since the serum levels of these parameters cannot accurately reflect the real situation in the lymphoid organs or tissues, some results from them, therefore, could be misleading. No animal model for alcohol studies can mimic the complications of alcoholic liver disease often observed in human alcoholics. Furthermore, the facts that different hormonal status in individual animals, even within same strain of animal, and difficulty in defining hormonal status in animals indicate that some results from animal studies could also be misleading. Therefore, the research on the mechanism of alcohol's effects on the neurological system at cellular and systemic levels and the interaction between endocrine and immune system should continue if we are to understand the complex changes caused by the direct and indirect effects of alcohol consumption.
Cocaine acts directly on lymphoid cells (the lymph and lymph nodes) and indirectly modulates the immune response by affecting the level of neuroendocrine hormones. The first studies about the impact of cocaine use on the immune response were initiated because epidemiological data demonstrated a high prevalence of Acquired Immunodeficiency Syndrome (AIDS) in polydrug users. Depending on the different administration routes, the plasma levels of cocaine in humans appear to be in the range of 0.1 to 1 micrograms per milliliter (μg/ml). Such concentrations last only for thirty to sixty minutes at these levels and then decline because of cocaine's short biological half-life of about 1 hour. The direct effects of cocaine and its metabolites on immune cells should occur only during a short time, except in heavy cocaine users who use the drug several times a day every day. Besides the direct effects on immune cells, cocaine could indirectly affect the immune response via its impact on the neuroendocrine system—and both have been shown.
Short-term exposure of mice to cocaine by daily intraperitoneal injection for fourteen days reduced body, spleen, and thymus weight in the animal. Cocaine increased the responsiveness of lymphocytes to mitogens (cell proliferation initiators) and the delayed hypersensitivity responsiveness, but it suppressed the antibody response. All the animal studies, however, suggest that the immune system requires continuous exposure to cocaine to demonstrates its suppressing or stimulating effects. After a single dose of cocaine (0.6 mg/kg), nonhabitual cocaine users showed a significant stimulation of natural killer cell activity, which is vital to defend against cancers. The levels of natural killer cells were also increased, but the levels of T-helper and suppressor cytotoxic cells, B cells, and monocytes were not elevated.
Cocaine causes neuroendocrine-mediated effects on the immune response. It stimulates the brain's hypothalamus to increase secretion, producing potentiated secretion of beta-endorphin. As a result of cocaine administration, beta-endorphin binds to opioid receptors on monocytes and lymphocytes and exerts multiple stimulating and suppressing effects on these cells, including secretion of immunoregulatory cytokines. The net outcome of the reactions related to the immune response of the host is difficult to assess because other determinants of these interactions (such as the psychological and social situation of the cocaine user) are also possible.
There are other mechanisms that might be operating to mediate cocaine-induced immunomodulation, including nutritional deficiencies and their impact on lymphoid cells. As early as 1870, the French physician Charles Gazeau suggested that coca leaves might be used to suppress the appetite. With food deprivation, which is common under conditions of habitual drug use, the self-administration of cocaine by rats increased. Although data indicate a poor nutritional status for cocaine users, no study has yet assessed the nutritional status of drug users as it contributes to a compromised immune competence. Cocaine clearly modifies hormones with immunoregulatory properties via neurological effects. In addition, malnutrition could be a factor on cocaine use, resulting in altered disease and tumor resistance. Intravenous use of drugs, including cocaine, is associated with the transmission of Human Immunodeficiency Vi-Rus (HIV), and ultimately the development of AIDS. Immunomodulation by cocaine after HIV infection could accelerate disease development as well as overall resistance to a variety of pathogens found frequently in intravenous drug users.
Although it is now well known that the use of Tobacco is a major health hazard, millions of Americans still continue to smoke and the popularity of smokeless tobacco is on the rise. Tobacco use is the chief cause of lung cancer in smokers and is strongly linked with the oral cancers of those who use chewing tobacco or Snuff.
The pulmonary alveolar macrophage (PAM) is the cellular component of the immune system comprising the first line defense of the lung, offering protection against inhaled particles, including irritants and microbial invaders. Because PAM has exposure to both the bloodstream and the atmosphere, it is uniquely suited to perform its protective functions, which include clearance, immune modulation, and modulation of surrounding tissue. There is general agreement that the number of PAMs in smokers' lungs is increased two to twenty times above that found in the lungs of non-smokers. It also appears that there is a difference in the morphology and certain aspects of the function of alveolar macrophages between the two groups. In general, PAMs from smokers are larger, contain more lysosomes and lysosomal enzymes, and are more metabolically active than those nonsmokers, suggesting that they may be in a chronically stimulated, more active state. This might lead to the inference that there would be greater phagocytic capacity in the lungs of smokers, resulting in increased clearance of foreign matter. However, the responsiveness of smokers' macrophages to foreign bodies or bacteria was equal to or less than that of nonsmokers, leading researchers to conclude that chronic stimulation of PAMs by cigarette smoke may be harmful rather than beneficial to the immuno-competence of the lung.
There is some disagreement as to whether smoking affects the phagocytic and bactericidal activity of PAMs. The question of whether tobacco smoke alters the tumoricidal ability of PAMs has not yet been answered. Thus, the relationship between cigarette smoking, neutrophil accumulation in the lung, and lung destruction continues to be researched. It is known that particles from cigarette smoke are present in the PAMs of smokers, and researchers have found that the PAMs of cigarette smokers released a potent chemotactic factor for neutrophils, whereas those of nonsmokers did not. Therefore, cigarette smokers had an increased number of neutrophils in the lavage fluid and in lung biopsy tissue as compared to nonsmokers. Neutrophils store and release elastase, a substance implicated in the development of certain lung diseases. Smokers' lungs are exposed to a large chronic burden of elastase from neutrophils, which may predispose them to lung destruction.
A number of animal and human studies comparing peripheral blood samples of smokers and non-smokers have indicated that smokers have altered immunoglobulin levels. Elevated levels of immunoglobulin E (IgE) were present in a high proportion of the smoke-exposed animals but in none of the controls. Studies on human subjects have also revealed that IgE levels were higher in smokers than in nonsmokers. A study of coal workers indicated that both mining and nonmining smokers had depressed serum IgA and IgM levels as compared with similar groups of nonsmokers. A disturbing finding in relationship to increased immunoglobulin levels in smokers is the effect that maternal smoking may have on the fetus. In newborn infants of mothers who smoked during pregnancy, IgE was elevated three-fold. Tobacco smoke affects fetal immunoglobulin synthesis, stresses the fetal immune system, and can predispose the infant to subsequent sensitization. Thus, 34 percent of the reported asthma in childhood may be caused by maternal smoking.
Natural killer cells, thought to serve important antitumor and antiviral functions in the body, have been found to be decreased in smokers. Studies of the white blood cells called basophils in the peripheral blood indicated that there are alterations linked to tobacco smoking as well.
When considering the effect that tobacco use has on immunocompetence, other confounding variables must also be accounted for, including genetic factors, preexisting disease, and nutritional status. Smoking has been observed to cause deficiencies of vitamin C, beta-carotene (vitamin A), and other nutrients that have important functions in protecting immunity.
Tobacco smoking causes deleterious effects on the pulmonary and systemic immune systems of experimental animals and in humans. Aspects of both cell-mediated and humoral immunity are affected. It is often difficult to compare studies directly because of the variability in smoking behaviors and the differences among tobacco products. Although it is expected that heavy smoking causes the most amount of immune system damage, that does not mean light to moderate smoking is safe. Thus, if some alterations due to smoking are reversible, it is not yet known whether long-term smoking may cause the impairment of the immune system to become permanent. Further, simultaneous exposure to other air contaminants or air pollution may exert damaging synergistic effects on local or systemic immune defenses.
MORPHINE AND OTHER OPIOIDS
Several studies have drawn a parallelism between Morphine abuse and immune inhibition. In vitro studies have shown that polymorphonuclear cells and monocytes form in patients subjected to morphine treatment but that they were severely depressed in their phagocytic and killing properties as well as in their ability to generate superoxide. Opioid addiction also caused alterations in the frequencies of T-cells and null lymphocytes in human peripheral blood.
There is convincing evidence of the presence of opioid receptors on various types of human immune cells. The presence of opioid receptors on immune cells may allow for modulation of specific immune functions in the presence of exogenous opiates. Various administration schedules for opioids were shown to potentiate infections by Klebsiella pneumoniae and Candida albicans. The increased susceptibility was partly due to a decrease in reticuloendothelial-system activity as well as a reduction in the number of phagocytes, not by a direct cytotoxic effect of the opioid.
Chronic administration of morphine has also inhibited a primary antibody response of mice. These effects were worsened by naloxone (a nonaddictive analog of morphine), indicating that morphine inhibits the immune system in a specific manner—via its interaction with opioid receptors. Other studies in animals have shown that morphine can affect NK cell activity, perhaps yielding reduced resistance to tumors.
Such changes, which can also include morphine suppression of spleen and body weight, show evidence of significant changes in immune functions.
Several approaches have been used to study the effects of Marijuana or its active component, Tetrahydrocannabinol (THC), on human immune systems. These include using cells isolated from chronic marijuana smokers, from volunteers who have been only exposed to marijuana smoke, or from nonexposed donors but exposing their cells to THC in the laboratory. A survey of chronic marijuana smokers showed that the response of their cells was depressed to stimulation with mitogens (substances that cause cell division).
Several studies have shown that neither marijuana smoking nor THC is immunosuppressive. Nevertheless, other immune alterations have been associated with marijuana or THC, including significantly reduced serum IgG levels in chronic smokers; inhibition of natural killer cell activity; inhibition of phagocytic activity; elevation of serum IgD levels; and reduced T-cell numbers. THC also inhibited DNA-, RNA-, and protein synthesis in stimulated human lymphocytes.
Studies performed in animals have produced more consistent findings than those in humans. In most cases, THC is associated with immunosuppression of various immune parameters. The greater consistency observed in animal studies probably reflects the influence of genetic factors, consistent dosage levels, and controlled diets and other conditions.
Animal studies have thus provided strong evidence of the immunosuppressive effects of THC. Such effects were clearly demonstrated when animals exposed to THC were more susceptible to infections than were others. THC has also exacerbated viral infection, as has been shown in mice and guinea pigs, and it has reduced resistance to bacterial pathogens.
Obvious differences in the susceptibility of humans versus animals to the effects of marijuana and THC will be resolved when other, more regulated research studies are carried out in immunosuppression and decreased disease resistance.
MacGregor, R. R. (1986). Alcohol and immune defense. Journal of the American Medical Association, 256, 1474-1479.
Wallace, C.L., & Watson, R. R. (1990). Immunomodulation by tobacco. In Drugs of Abuse and Immune Function. Boca Raton, FL: CRC Press.
Watzl, B., & Watson, R. R. (1990). Immunomodulation by cocaine—A neuroendocrine mediated response. Life Sciences, 46, 1319-1329.
Yahya, M.D., & Watson, R. R. (1987). Minireview: Immunomodulation by morphine and marijuana. Life Sciences, 41, 2503-2510.
Ronald R. Watson
For all the attention being directed toward Heroin and Cocaine, the favorite mood-altering drug in most human societies is Alcohol. Alcohol, in different quantities for different people, is also a toxic drug—its over-consumption taxes the body's economy, produces pathological changes in liver and other tissues, and can cause disease and death. In urban areas of the United States, just one of the complications—namely scarring or cirrhosis of the liver—is the fourth to fifth most frequent cause of death for people between the ages of twenty-five and sixty-five. In recent years, changes in liver and other tissues have been directly associated with specific steps in the metabolism of alcohol (also called ethanol or ethyl alcohol), giving some hope that rational methods can be developed for prevention and treatment.
PATHOLOGY OF ALCOHOL ABUSE
Alcohol abuse affects all organs of the body (Lieber, 1992a). It atrophies many tissues, including the brain and the endocrine glands. Indeed, altered hepatic (liver) metabolism plays a key role in a variety of endocrinological imbalances (such as gonadal dysfunctions and reproductive problems). Alcohol also exerts toxic effects on the bone marrow and alters hematological status (e.g., macrocytic anemias), and it scars the heart and other muscles. This article focuses mainly on the liver and gastrointestinal tract, since this is where alcohol penetrates into the body and has its most vicious effects; this focus will also allow exemplification of the insights and possible benefits that can be derived from the application of newly acquired knowledge in biochemistry, pathology, and molecular biology.
Liver disease, one of the most devastating complications of alcoholism, was formerly attributed exclusively to the malnutrition associated with Alcoholism. Indeed, nutritional deficiencies are common in the alcoholic for various reasons, some socioeconomic, but also because alcohol is a unique compound. Alcohol is a drug, a psychoactive drug, but unlike other drugs, which have negligible energy value, alcohol has a high energy content—each gram of alcohol contributes 7.1 kilocalories, which means that a cocktail or a glass of wine will provide 100 to 150 kilocalories. Thus, alcoholic beverages are similar to food in energy terms, but, unlike food, they are virtually devoid of vitamins, proteins, and other nutrients; they act as a provider of empty calories.
As shown in Figure 1, because of its large energy load, alcohol decreases the appetite for food and displaces other nutrients in the diet, thereby promoting primary malnutrition (Lieber, 1991a). Nutrition is also impaired because alcohol affects the gastrointestinal tract. Alcohol-induced intestinal lesions, including pancreatitis, are associated with maldigestion and malabsorption, causing secondary malnutrition. Moreover, malnutrition itself will create functional impairment of the gut. Finally, alcohol (ethanol or its metabolite acetaldehyde) also adversely affects nutritional status by altering the hepatic activation or degradation of essential nutrients.
Indeed, in experimental animals, malnutrition may produce a variety of liver alterations, including fatty liver and fibrosis; however, the extent to which malnutrition contributes to the development of liver disease in the alcoholic remains unclear. Furthermore, studies conducted in the past three decades have shown that either the initial liver lesion—the fatty liver—or the ultimate stage of cirrhosis can be produced by excess alcohol, even in the absence of dietary deficiencies (Lieber & DeCarli, 1991), because ethanol (via its metabolism and/or its metabolite acetaldehyde) exerts direct hepatotoxic effects. Thus, malnutrition plays a permissive, but not an obligatory, role in alcohol-related somatic pathology.
METABOLISM OF ETHANOL AND SOME INTERACTIONS
Ethanol is readily absorbed from the gastrointestinal tract. Only 2 percent to 10 percent of that absorbed is eliminated through the kidneys and lungs; the rest is oxidized in the body, principally in the liver. Except for the stomach, extrahepatic (outside the liver) metabolism of ethanol is small. This relative organ specificity probably explains why, despite the existence of intracellular mechanisms to maintain homeostasis (equilibrium), ethanol disposal produces striking metabolic imbalances in the liver (Lieber, 1991b). These effects are aggravated by the lack of a feedback mechanism to adjust the rate of ethanol oxidation to the metabolic state of the hepatocyte (liver cell) and the inability of ethanol, unlike other major sources of calories, to be stored in the liver or to be metabolized or stored to a significant degree in peripheral tissues. As summarized here, the displacement by ethanol of the liver's normal substrates and the metabolic disturbance produced by the oxidation of ethanol and its products explain many of the hepatic and metabolic complications of alcoholism.
A major pathway for ethanol disposition involves alcohol dehydrogenase (ADH), an enzyme of the cell sap (cytosol) that catalyzes the conversion of ethanol to acetaldehyde. Liver ADH exists in multiple molecular forms that arise from the association in various permutations of different types of subunits. Extrahepatic tissues contain isozymes of ADH with a much lower affinity for ethanol than the hepatic isozymes; as a consequence, at the levels of ethanol achieved in the blood, these extrahepatic enzymes are inactive, and therefore, extrahepatic metabolism of ethanol is negligible, with the exception of gastric metabolism. Because of the extraordinary high gastric ethanol concentration after alcohol consumption, even the gastric ADH with low affinity for ethanol becomes active, and significant gastric ethanol metabolism ensues. This decreases the bioavailability of ethanol and represents a kind of protective barrier against systemic effects, at least when ethanol is consumed in small social-drinking amounts. This gastric barrier disappears after gastrectomy (Caballeria et al., 1989) and may be lost, in part, in the alcoholic, because of a decrease in gastric ADH (Di Padova el al., 1987).
Similar effects may also result from gastric ADH inhibition by some commonly used drugs. For example, aspirin, or some H2-blockers such as those used in treatment of ulcers (Di Padova et al., 1992) were found to inhibit gastric ADH activity and to result in increased blood levels of ethanol when alcohol was consumed in amounts equivalent to social drinking. Women also have a lower gastric ADH activity than do men (Frezza et al., 1990); as a consequence, for a given intake, women's blood ethanol levels are higher, an increase that is compounded by their body composition (more fat, less water than men) and, on average, a lower body weight. Their higher blood ethanol levels, in turn, may therefore contribute to women's greater susceptibility to alcohol.
Alcohol dehydrogenase converts ethanol to acetaldehyde and hydrogen. Hydrogen is a form of fuel that can be burned (oxidized). Normally, the liver burns fat to produce the energy required for its own functioning but, when alcohol is present, its hydrogen displaces fat as the preferred fuel. When the liver stops burning fat and instead burns the hydrogen from the ethanol, however, fat accumulates, and a fatty liver develops, which is the first stage of alcoholic liver disease (Lieber, 1992a). Once a fatty liver has developed, fat accumulation does not increase indefinitely, even though alcohol consumption may be continued (Salaspuro et al., 1981). Fat deposition is offset, at least in part, by lipoprotein secretion, resulting in hyperlipemia—elevated amounts of fat in blood. Hyperlipemia of a moderate degree is commonly associated with early stages of alcoholic liver injury, but it wanes with the progression of liver disease (Lieber & Pignon, 1989). In some individuals, marked hyperlipemia may develop, sometimes associated with Zieve's syndrome—hemolytic anemia, fatty liver, and jaundice. This represents the potentiation, by alcohol, of an underlying abnormality in the metabolism of either lipids (essential hyperlipemia) or carbohydrates (prediabetes, pancreatitis). In addition, the degree of hyperlipemia is also influenced by the duration of alcohol intake. The capacity for a hyperlipemic response develops progressively and is accompanied by an increased activity of enzymes of the endoplasmic reticulum (within the living cells) engaged in lipoprotein production. This hyperlipemia involves all lipoprotein classes, including high-density lipoproteins (HDL), which have been said to be involved in the protection against atherosclerosis and in the lesser incidence of coronary complications in moderate drinkers (compared to total abstainers). However, factors other than alcohol may also contribute to this apparent protection. The ability of the liver to respond with hyperlipemia reflects the integrity of the hepatocytes; its capacity decreases with the development of more severe liver injury.
Elucidation of the hepatic redox (contraction of oxidation reduction) associated with ethanol oxidation via the alcohol dehydrogenase pathway has also furthered our understanding of associated disorders in carbohydrate, purine, and protein metabolism—including hypoglycemia (low blood sugar), hyperlactacidemia (excessive levels of lactic acid in the blood) and acidosis, as well as hyperuricemia (elevated uric acid levels in blood) (Lieber, 1992a).
In addition to the enzyme ADH, alcohol is also oxidized in the liver by the enzyme system referred to as the microsomal ethanol-oxidizing system (MEOS), which involves a specific cytochrome P-450 (P450IIE1) (Lieber, 1987). Contrary to ADH, this pathway is inducible by chronic alcohol consumption. In rat livers (Lieber et al., 1988) and in human liver biopsies of heavy drinkers (Tsutsumi et al., 1989), a five to tenfold increase of this alcohol-inducible form was found. This induction represents one of the most striking biochemical differences between heavy drinkers and normals and provides an explanation for the metabolic tolerance to ethanol—a more rapid metabolism—that develops after alcohol abuse. The induction spills over to microsomal systems that metabolize other substrates, resulting in cross-tolerance to other drugs—not only sedatives and tranquilizers but also many commonly used medications such as anticoagulants and hypoglycemic agents. Thus, heavy drinkers require an increased dosage of many commonly used medications, at least at the initial stage, prior to the development of severe liver disease, which, when it develops, it will offset the enzyme induction, at which time drug dosage may have to be decreased. What complicates treatment of heavy drinkers even further is the fact that the microsomal enzymes (especially P450IIE1) also activate many xenobiotic agents (substances from outside the body) to highly toxic compounds. This explains the increased vulnerability of heavy drinkers to the hepatotoxicity of industrial solvents, anesthetics, analgesics (painkillers), and chemical carcinogens. The latter contribute to the increased incidence of various cancers in the alcoholic.
Alcohol has a major impact on gastrointestinal cancers, with a significant increase in the incidence of neoplasms of the oropharynx, the esophagus, the stomach, the liver, and the colon (Garro & Lieber, 1990). There is also activation to toxic metabolites of commonly used drugs and even over-the-counter analgesics (acetaminophen or paracetomal) (Sato et al., 1981) and vitamins, such as Vitamin A. In the heavy drinker, there are both increased breakdown and hepatic depletion of Vitamin A (Leo & Lieber, 1982), with adverse consequences. In addition, alcohol potentiates the toxicity of Vitamin A (Leo et al., 1982), which complicates supplementation with the vitamin in the presence of alcohol abuse. Alcohol abuse also promotes the microsomal breakdown of testosterone and its conversion to estrogens, which, together with testicular toxicity and decreased testosterone production, results in hypoandrogenism—the loss of masculinity (Lieber, 1992a).
In addition to environmental factors, there are individual differences in rates of ethanol metabolism that appear to be genetically controlled, and the possible role of heredity in the development of alcoholism in humans has been emphasized. The induction of the MEOS pathway also leads to increased conversion of alcohol to acetaldehyde, a highly reactive and thus potentially toxic compound.
TOXICITY OF ACETALDEHYDE
Acetaldehyde causes injury through the formation of adducts with proteins, resulting in antibody formation, inactivation of many key enzymes, decreased deoxyribonucleic acid (DNA) repair, and alterations in cell structures such as microtubules, mitochondria, and plasma membranes (Lieber, 1988, 1992a). Acetaldehyde also promotes synthesis of hepatic collagen—the key protein of scar tissue; furthermore, it causes glutathione depletion, thereby exacerbating the toxicity mediated by free radicals, which results in lipid peroxidation and other tissue damage (Lieber, 1991b). Because of the far-reaching toxicity of this metabolite of ethanol, some of the liver cells die; this attracts inflammatory cells, which results in the more severe stage of alcoholic hepatitis, one of the precursors to the ultimate scarring or cirrhosis.
Once there is cirrhosis, a number of complications ensue, including obstruction of blood flow—with portal hypertension (elevated pressure in the veins leading from the intestine to the liver) and internal, life-threatening bleeding of distended veins, so-called varices. There is also a buildup of water in the abdominal cavity, so-called ascites (Lieber, 1992a).
Acetaldehyde is particularly elevated if drinking occurs in pregnancy; it crosses the placenta (Karl et al., 1988) and has been incriminated in the pathogenesis of the Fetal Alcohol Syndrome (FAS), the most common preventable cause of cogenital abnormalities.
The bulk of acetaldehyde is oxidized to acetate by an acetaldehyde dehydrogenase of the liver mitochondria. Lack of the active form of the enzyme in some Asians explains their high blood acetaldehyde and flushing reaction after alcohol. Di-Sulfiram (Antabuse—a drug used in recovering alcoholics) is an inhibitor of acetaldehyde dehydrogenase. It raises the acetaldehyde levels after drinking and thereby causes flushing and several adverse effects that can be utilized to sustain abstinence in patients motivated to take the compound.
TREATMENT AND CONCLUSION
Alcoholics suffer commonly from malnutrition. Therefore, nutritional deficiencies, when present, should be corrected—although such efforts were found to be ineffective in fully preventing liver disease in view of the intrinsic toxicity of ethanol (Lieber, 1991b; Lieber & DeCarli, 1991).
Although progress is being made at offsetting the direct toxicity of ethanol through chemical means (Lieber, 1992b), at present, the single fully effective way of preventing somatic alcoholic injury remains control of the toxic agent—ethanol—through control of consumption. Full abstinence is required in those who are genetically (or otherwise) prone to develop craving or to exhibit dependence, or those who are predisposed to develop the major somatic complication with chronic use of alcohol.
For the others, moderation is recommended. What is considered "moderate" or "excessive" has been the subject of debate. One view is that on the average, moderate drinking represents no more than one drink a day in women and no more than two drinks a day in men—with a drink being 12 ounces of regular beer, 5 ounces of wine, or 1.5 ounces of distilled spirits (80 proof) (Dietary Guidelines, 1990). It is important, however, that "excess" be defined individually, taking into account not only gender, but also heredity and personal idiosyncrasies.
Caballeria.J. et al. (1989). The gastric origin of the first pass metabolism of ethanol in man: Effect of gastrectomy. Gastroenterology, 97, 1205-1209. Dietary Guidelines. (1990). Nutrition and your health: Dietary guidelines for Americans (3rd ed.). Washington, DC: U.S. Department of Agriculture.
Di Padova, C. et al. (1987). Effects of fasting and chronic alcohol consumption on the first pass metabolism of ethanol. Gastroenterology, 92, 1169-1173.
Di Padova, C. et al. (1992). Effects of ranitidine on blood alcohol levels after ethanol ingestion: Comparison with other H2-receptor antagonists. Journal of the American Medical Association, 267, 83-86.
Frezza, M. et al. (1990). High blood alcohol levels in women: Role of decreased gastric alcohol dehydrogenase activity and first pass metabolism. New England Journal of Medicine, 322, 95-99.
Garro, A. J., & Lieber. C. S. (1990). Alcohol and cancer. Annual Review of Pharmacology and Toxicology, 30, 219-249.
Karl, P.I. et al. (1988). Acetaldehyde production and transfer by the perfused human placental cotyledon. Science, 242, 273-275.
Leo, M. A., & Lieber, C. S. (1982). Hepatic vitamin A depletion in alcoholic liver injury. New England Journal of Medicine, 307, 597-601.
Leo, M. A., Arai, M., Sato, M., & Lieber, C. S. (1982). Hepatotoxicity of vitamin A and ethanol in the rat. Gastroenterology, 82, 194-205.
Lieber, C. S. (1987). Microsomal ethanol oxidizing system (MEOS). Enzyme, 37, 45-56.
Lieber, C. S. (1988). Metabolic effects of acetaldehyde, Biochemical Society Transactions, 16, 241-247.
Lieber, C. S. (1991a). Alcohol, liver and nutrition. Journal of the American College of Nutrition, 10, 602-632.
Lieber, C. S. (1991b). Hepatic, metabolic and toxic effects of ethanol: 1991 update. Alcoholism: Clinical and Experimental Research, 15, 573-592.
Lieber, C.S. (ed.). (1992a). Medical and nutritional complications of alcoholism: Mechanisms and management. New York: Plenum Press.
Lieber, C. S. (1992b). Hepatotoxicity of alcohol and implications for the therapy of alcoholic liver disease. In J. Rodes & V. Arroyo (Eds.), Therapy in liver disease (pp. 348-367). Barcelona: Ediciones Doyma.
Lieber, C. S., & De Carll L. M. (1991). Hepatotoxicity of ethanol. Journal of Hepatology, 12, 394-401.
Lieber, C. S., & Pignon, J-P. (1989). Ethanol and lipids. In J. C. Fruchart & J. Shepherd (Eds.), Human plasma lipoproteins: Chemistry, physiology and pathology (pp. 245-280). New York: Walter De Gruyter.
Lieber, C.S. et al. (1988). Role of acetone, dietary fat and total energy intake in induction of hepatic microsomal ethanol oxidizing system. Journal of Pharmacology and Experiment Therapeutics, 247, 791-795.
Salaspuro M. P. et al. (1981). Attenuation of the ethanol induced hepatic redox change after chronic alcohol consumption in baboons: Metabolic consequences in vivo and in vitro. Hepatology, 1, 33-38.
Sato, C., Matsuda, Y., & Lieber, C. S. (1981). Increased hepatotoxicity of acetaminophen after chronic ethanol consumption in the rat. Gastroenterology, 80, 140-148.
Tsutsumi, R. et al. (1989). The intralobular distribution of ethanol-inducible P450IIE1 in rat and human liver. Hepatology, 10, 437-446.
Charles S. Lieber
Revised by Ralph Myerson
Liver Damage (Other Drugs)
The liver is the largest organ of the human body, normally weighing about 3.3 pounds (1.5 kg). It occupies the right upper quadrant of the abdominal cavity just below the diaphragm. As befitting its anatomical prominence, its function is essential to maintain life. If we surgically removed the entire liver from any animal (including humans), it will fall into a coma shortly and die. The absence of a certain critical mass of functioning liver tissue is incompatible with life. While the human liver has a remarkable resilience and regenerative capacity after injury or illness, this is true only up to a certain point. If illness pushes the liver beyond the "point of no return," the person dies.
The liver has a multitude of complex functions and is justly called the "laboratory" of the human body. It secretes a digestive juice into the intestine, called bile; it produces a number of essential proteins, clotting factors, and fatty substances; it stores and conserves energy-producing sugars; it detoxifies both internally produced and external toxins and drugs that would otherwise be poisonous to the human organism—just to name some of its important functions.
What can seriously jeopardize this very important organ and consequently the well-being and survival of the individual? For one, there are diseases—both congenital and acquired—over which we have little or no control, such as some genetically determined and developmental abnormalities, circulatory liver problems, certain tumors, and infections.
A very large part of hepatology (the technical term to describe the study and treatment of liver diseases) is, however, devoted to liver problems created by a peculiar human behavior—the abuse of Alcohol and drugs. Whereas discussions as to whether Alcoholism and Drug Abuse are truly self-inflicted problems elicit a variety of opinions, the liver disease that results from substance abuse in a given individual could have been avoided if the substance-abusing behavior had not occurred. Beyond the psychosocial consequences of substance abuse, diseases of the liver (and brain) represent the major Complications of alcohol and drugs.
The morbidity (disease incidence) and mortality (death incidence) from alcoholic and drug-induced liver injury are very high. In the scientific literature, it is well established that the mortality from alcoholic liver disease is correlated with the per capita alcohol consumption; in fact, the prevalence of alcoholism in a given society has been calculated from liver mortality statistics. While alcohol is a direct liver toxin, most of the other commonly abused psychoactive substances are generally not known to affect the liver directly to a great extent; their major contribution to liver morbidity and mortality is via exposing people to viral hepatitis—a potentially fatal disease.
ALCOHOLIC LIVER DISEASES
Another article in this encyclopedia discusses the relationship between alcohol and the liver in great detail. In any article dealing with the effects of drugs on the liver, however, alcohol must be addressed.
The gamut of alcoholic liver diseases and their interrelationship is illustrated in Figure 1.
Alcoholic Fatty Liver.
Fat accumulation in the liver is an almost universal response to excessive alcohol consumption. It occurs in the majority of heavy drinkers. How and why fat accumulates in liver cells is complicated and not completely understood; but we know for sure that it happens. If you examine a piece of biopsied liver tissue from an alcoholic under the microscope, you see that many liver cells are loaded with big bubbles consisting of fat, almost totally occupying the cell. In most cases, this fatty change does not matter too much as far as the patient's health is concerned. It is an almost invariable response to too much alcohol consumption and an early warning. The person who has nothing worse than an alcoholic fatty liver may not feel sick at all, and only if a biopsy is done can the fatty liver be diagnosed. The doctor may feel an enlarged liver by palpation, which may be a bit tender. The laboratory test may show a slight elevation in the blood of some liver enzymes, best known by their initials: SGOT (or AST) and SGPT (or ALT). These enzymes are elevated because some of them tend to leak out of the fatty liver cells into the blood.
If a person stops drinking, the fat disappears from the liver cells, the swelling subsides and the AST and ALT levels become normal. The two-way arrow in the diagram of Figure 1 indicates that fatty liver is reversible with abstinence, and the condition may fluctuate back and forth between normal and fatty liver with abstinence and drinking, respectively. Thus, this, per se is not likely a serious situation; it is an early warning that "your liver does not like alcohol" and that possibly worse things might yet come. There was a time when fatty liver was regarded as the precursor of the end-stage liver disease called cirrhosis (indicated by the broken arrow and question mark on Figure 1), but in the 1990s, most physicians do not believe that this direct connection exists.
This is a potentially more serious form of alcoholic liver disease. A certain proportion of alcoholics, in addition to accumulating fats in their livers when drinking, will develop inflammation (hepatitis means liver inflammation)-consisting of an accumulation of white blood cells, the death (necrosis) of some of the liver cells, and the presence of some very characteristic material (called Mallory bodies). Again, all this can be seen under the microscope in a biopsied piece of tissue.
The clinical picture of alcoholic hepatitis can be very variable. At one extreme is the person who feels perfectly well and only the biopsy could tell that something is wrong. At the other extreme is the patient with a swollen and painful liver, yellow jaundice (a yellowing of the entire body from bile pigment leaking into the blood), fever, and disturbed consciousness—who dies. Between these extremes are people with varying degrees of seriousness of the illness; for example, with or without some jaundice, with or without pain and fever, etc. The blood's white cell count is usually elevated. The bilirubin (bile pigment) level may be elevated in patients who are yellow (a pale to deep mustard). The liver enzymes are higher than normal in the blood, because they leak out of the inflamed liver cells. However, these values are not as high as in viral hepatitis and, characteristically, in alcoholic hepatitis AST (SGOT) is higher than ALT (SGPT), which helps to distinguish alcoholic hepatitis from viral hepatitis (difficult to do at times). In viral hepatitis not only are the absolute enzyme values higher, but the ratio is reversed: ALT is higher than AST.
Thus, the outcome of alcoholic hepatitis can be death (worst scenario) or recovery (best scenario)-as shown on Figure 1. Repeated episodes of drinking and alcoholic hepatitis, however, even if the patient does not die in a given episode, can lead to the endstage of alcoholic liver disease: cirrhosis.
In terms of histology (tissue damage) this indeed is an end-stage disease: a cirrhotic liver cannot become normal; in Figure 1, there is no arrow between cirrhosis and normal liver. Clinically, cirrhosis is a serious disease, potentially fatal, but not inevitably so. Alcoholism is not its only cause, but it is by far the most common.
Under the microscope a cirrhotic liver shows a disorganized architecture: the dead (necrotic) liver cells have been replaced by scar tissue. The liver tries to repair itself: In a somewhat haphazard fashion it attempts to produce new liver tissue in the form of nodules, which are separated from each other by scar. These newly formed liver nodules may indeed sustain liver function and thus life for a time, but at a price: the liver's blood circulation is mechanically compressed. Thus, the pressure increases in the blood vessels leading to the liver. Some of these overloaded blood vessels, especially those on the border of the stomach and esophagus (called esophageal varices), can rupture any time, causing a major hemorrhage.
Those who develop the cirrhotic stage of alcoholic liver disease present their symptoms in various ways. Some of them look quite normal and only the biopsy will reveal the presence of cirrhosis. Others are jaundiced, the yellow color coming from bile pigment leaking out of the damaged liver into the blood, thus staining the skin and the whites of the eyes. Still others have large fluid accumulations in their extremities (edema) or in their abdominal cavity (ascites); the latter may make these patients—men or women—look like they are nine months pregnant. Some may vomit blood, because of the hemorrhaging. In most advanced cases, there is just not enough functioning liver tissue left; the liver no longer can perform its "laboratory" function, and the person slips into a coma and may die.
When cirrhotic patients are examined by doctors, their livers do not feel smooth on palpation, but bumpy from all those nodules that formed. At first the liver may be swollen and enlarged, but at the later stages it shrinks. The ultrasound picture suggests a patchy, disorganized architecture of the liver. The spleen may enlarge from the increased pressure in the blood vessels. The liver enzymes (AST and ALT) may be moderately elevated as in other forms of alcoholic liver disease, but this has no prognostic importance. More ominous signs pointing toward severely compromised liver functions are the following: a decrease in blood level of albumin (an important protein manufactured by the liver), deficiency in blood-clotting factors that are also made in the liver, and the presence of anaemia (low hemoglobin and red blood cell count).
What Can Kill a Cirrhotic Patient? Ascites (fluid accumulation in the abdomen) is very uncomfortable and unsightly but, by itself, usually does not kill—unless it gets spontaneously infected, which is always a threat. Generally, cirrhosis compromises the immune system, rendering cirrhotic alcoholics susceptible to all sorts of potentially overwhelming infections. Portal hypertension is a serious complication of the cirrhotic fibrosis. The obstruction to portal vein flow through the liver results in the development of other vein channels to accommodate the return of blood from the abdominal organs which comprise the blood in the portal vein. The result is the development of varices (enlarged, engorged veins) in the stomach and esophagus. These enlarged, thin-walled veins are prone to rupture leading to one of the most serious complications of cirrhosis of the liver—bleeding varices. This constitutes an emergency and calls for immediate intervention in the form of measures to control the bleeding. A variety of therapies are available, all of which have all been employed with a varying degree of success that depends on the severity of the hemorrhage and the skill and experience of the physician. Once the bleeding has been controlled, the patient should be considered for an appropriate permanent venous shunt procedure whereby venous blood bypasses the liver. Finally, total decompensation of liver-cell function may cause coma and death.
The good news is that even when there is irreversible cirrhosis at the tissue level, death may not be inevitable. Survival depends mainly on two factors: luck and alcohol abstinence. Abstaining alcoholics with cirrhosis can stabilize and survive on what's left of their liver tissue without necessarily and relentlessly progressing to one of the fatal outcomes. A famous Yale University study many years ago showed clearly the correlation between abstinence and survival in cirrhosis.
Who Gets Which Alcoholic Liver Disease?
There are still no certain answers to this question. Fatty liver is an almost universally predictable response to heavy alcohol consumption, but this by itself is seldom a serious problem. A smaller number of people develop alcoholic hepatitis and still fewer (variously estimated in different populations between 5 to 25% of alcoholics) end up with cirrhosis. Considering the large number of alcoholics in our society, the minority who develop cirrhosis still represents huge numbers; cirrhosis is one of the leading causes of all deaths.
Still, why do some alcoholics develop alcoholic hepatitis and cirrhosis, while others who drink equally heavily do not? The amount of alcohol consumption and the length of time of heavy drinking is certainly one risk factor. Gender may be another: Women's livers generally are more vulnerable to the effects of alcohol than those of men, given equal alcohol exposures. Finally, there may be a genetically determined (but still unclarified) individual susceptibility, which may explain why some people never get cirrhosis, why some do after many years of alcoholism, and why still others get cirrhosis at a young age or after a relatively short drinking career.
Prognosis and Treatment.
The issues of prognosis and treatment cannot be separated from each other. The cornerstone of treatment is complete abstinence from alcohol; achieving abstinence can arrest the progression of liver disease, even in established cirrhosis. Continued drinking leads to deterioration and death.
One therapeutic issue relating to alcoholism itself, should be addressed here because it is relevant to liver disease. The drug Disulfiram (Antabuse) is sometimes prescribed to reinforce abstinence: its unpleasant, sometimes severe interaction with alcohol is used as a deterrent against drinking. Since disulfiram (as so many other drugs) has been occasionally reported to produce liver toxicity of its own, the presence of alcoholic liver disease is sometimes regarded as a relative contraindication against the prescription of disulfiram. The liver toxicity caused by alcohol far outweighs any risk that may be caused by disulfiram.
Are there any other treatment techniques available beyond abstinence that can help the recovery from alcoholic liver damage? In the late 1980s, a Toronto research group reported the beneficial effect of propylthiouracil (PTU). This is a drug normally used for the treatment of thyroid disease, but by reducing oxygen demand in the body (including in the liver), it might help to repair the damage caused by alcohol. The early results were promising but it is still not a widely accepted treatment. Other drugs, such as corticosteroids (to decrease inflammation) or colchicine (to decrease scar formation) have dubious value.
There are relatively effective treatments available for some of the complications of alcoholic liver disease so that the patient may survive and thus begin his or her abstinence program. The fluid accumulation in the extremities (edema) or in the abdomen (ascites) can he helped by diet modifications (salt restriction), water removing drugs (diuretics), albumin infusion, or tapping the abdomen. Infections can be treated with antibiotics. The brain syndrome of liver failure (so-called hepatic encephalopathy or, in severe cases, hepatic coma) can improve with dietary means (protein restriction) or some drugs (e.g., neomycin, lactulose). The potentially or actually bleeding esophageal varicose veins can be obliterated by certain injections through a gastroscope (so-called sclerotherapy), and the bleeding risk can be lessened by beta-blocking drugs or some surgical procedures to decrease pressure.
Finally, in the 1990s we have the possibility of liver transplantation. If all else fails, a successful liver transplant cures alcoholic liver disease. Apart from the general problems of donor matching and supply, some people have raised objections on ethical grounds to offering transplantation for alcoholic (i.e., "self-inflicted") liver disease. This is not an acceptable objection and goes against medical ethics. Well-motivated recovering alcoholics are entitled, as much as anybody else, to a life-saying procedure. In fact, studies have shown that the very dramatic and heroic nature of this operation may be an extremely powerful motivator for future abstinence by liver recipients. Numerous successful transplants have been carried out on alcoholics.
DRUGS AND THE LIVER
There are many drugs in medicinal use that can have direct liver toxicity. Peculiarly, most of the psychoactive drugs that people tend to abuse are not known to be particularly harmful to the liver. Occasional liver damage has been reported with Solvent sniffing and Cocaine use, but this is not a common problem. Narcotics (opioids), anti-anxiety, and other sedative drugs (such as Barbiturates), Marijuana, and Hallucinogens do not usually cause liver injury.
There are, however, several relevant secondary issues concerning drug abuse and the liver. For one, a damaged liver (for example from alcohol or hepatitis) results in poor tolerance of Sedatives, because good liver function is necessary to eliminate sedatives properly; impaired liver function can therefore result in exaggerated sedative effect. Conversely, some sedatives, notably Barbiturates (which were often abused in the past and sometimes still are), actually stimulate ("induce") certain liver enzymes, which can result in increased elimination (i.e., decreased effect) of another therapeutically necessary drug. For example, a barbiturate user (or abuser) may have poor effect from a clotting preventative (anti-coagulant) drug that is necessary in heart disease or after a stroke. Some drugs do the opposite—they inhibit liver enzymes. For example, the anti-ulcer drug cimetidine (Tagamet), which per se has no Psychoactive effect, can cause such enzyme inhibition; if a person at the same time also happens to use or abuse a sedative, the sedative can have an exaggerated effect.
Generally speaking, the normal liver transforms or inactivates drugs (detoxification) to less active or harmless forms. A notable and important exception is acetaminophen, one of the most commonly used medications against Pain and fever (e.g., the various Tylenol preparations). The liver can transform acetaminophen into a toxic metabolic derivative that might cause a potentially lethal, acute liver injury. Generally, this does not happen at ordinary therapeutic acetaminophen dose levels. In the case of an acetaminophen overdose, however, such severe liver toxicity can occur that a person will die within days. Most of such overdoses are, of course, suicidal attempts.
Acetaminophen itself does not have any psycho-active (mind-altering) properties; thus people do not abuse it for such reasons. Many marketed acetaminophen preparations, however, are combined with Codeine (a Narcotic). People seeking narcotic "highs" from such preparations might ingest them in large enough quantities to subject themselves to potentially severe liver injury. It is the codeine they are after, but it is the bystander acetaminophen that may kill them. There is an antidote against acetaminophen poisoning (called acetylcysteine), but it is effective only if it is given within a few hours (less than a day) after the ingestion of the drug. The person who is overdosing with a suicidal intent is more likely to be discovered and brought to quickmedical attention than an unintentionally overdosing drug abuser. An additional issue in the acetaminophen story is that there is strong evidence of increased risk when alcohol and acetaminophen are combined. In alcoholics, relatively low, even therapeutic, doses of acetaminophen can cause severe and potentially fatal liver damage.
Apart from acetaminophen, direct liver toxicity is not a major feature of substance abuse except in the case of alcohol. The liver disease that is very commonly associated with drug use is viral hepatitis (liver inflammation) which is not caused by the drugs themselves but by infection with a virus. It is then transmitted from person to person through contaminated needles and syringes. The problem of viral hepatitis, then, is largely that of injecting drug users (IDUs).
VIRAL HEPATITIS IN DRUG ABUSERS
In the mid-1990s, at least five types of disease-causing hepatitis viruses have been identified, and they are designated by the letters of the alphabet, A-E. Table I summarizes some of their important characteristics. Of the five, hepatitis A and E are not particularly associated with injecting drug abuse; but the other three very much are and they will be discussed in some detail in that context.
This virus (which used to be called "serum hepatitis") is endemic to some parts of the world, such as Southeast Asia, where as much as 10 percent of the population may be infected. In the Western world, IDUs represent the greatest reservoir for hepatitis B virus. It is transmitted through a direct blood-borne route, such as (1) contaminated needles and syringes (which drug addicts notoriously did not sterilize in the past); (2) from an infected mother across the placenta and through the umbilical cord of a developing Fetus; (3) from blood contaminating accidental needle-stick injuries in health-care workers; and (4) from any blood to blood contact occurring during sexual intercourse. At one time blood transfusions were a common source of infection, but since the 1970s we have had a reliable test to screen out infected donors.
The symptoms of hepatitis B infection vary. In its severest form, it can cause general unwellness, fever, jaundice, coma, and death. The majority of patients, even with marked jaundice and fever, do not die. Many infected people do not even have an overt illness; they may not feel sick at all or may just have transient "flu-like" symptoms. There may be a tender enlargement of the liver. If such people are tested in the laboratory, they have elevated enzymes, such as AST (also known as SGOT) and ALT (also known as SGPT), which are usually much higher than the values found in alcoholic liver disease (in contrast to alcohol, viral hepatitis tends to cause more elevation in ALT than in AST). The bilirubin (bile pigment) level will be high if the person has yellow jaundice.
There are now quite good serological tests for hepatitis B. A virus particle (hepatitis B's antigen) can be identified in infected people. Those who recover from the illness and clear the virus out of their body will develop a protective antibody that will prevent their reinfection. The antibody can be detected in a laboratory test.
The majority of people who get infected with hepatitis B do recover and acquire protective antibodies. A sizable minority of those who survive, however, perhaps 10 percent, will continue to carry the virus (remain "antigen positive"); and some of these will have a chronic liver inflammation that can end up in cirrhosis. The cirrhosis caused by hepatitis B is essentially similar to alcoholic cirrhosis, with the same consequences and potential complications described above. Moreover, hepatitis B has the potential to cause liver cancer in some of those who develop cirrhosis. Not only is hepatitis B in such chronically infected individuals a threat to their own survival, but it is also a source of infection to others, particularly to their needle-sharing partners, to their sexual partners, and to their developing fetuses and newborn babies.
Until about 1990, this was called "non-A-non-B hepatitis," because we knew that there were viral hepatitis cases that were caused by neither of the two identifiable viruses, A or B. An antibody test can now identify this virus, which is called hepatitis C. The antibody detected is not a protective antibody, but it is similar to the AIDS (HIV) antibody in that it indicates the presence of the virus. A lot of the viral hepatitis caused by blood transfusions in the past was due to hepatitis C infection; the antibody test can eliminate this source of transmission, since it is used to screen the donor blood supply.
Injecting drug users, however, remain a major reservoir and source for the spread of this virus. Hepatitis C is transmitted similarly to hepatitis B—and, for that matter, to HIV—primarily through direct blood to blood contact (by contaminated injection Paraphernalia) and to a lesser extent, but still possibly, via sex and from mother to fetus. The primary infection goes very often unnoticed. The laboratory tests, in addition to hepatitis C antibodies, will show elevated ALT and AST levels. Since this is a newly identified virus, the natural history of hepatitis C is not yet clear. A fair amount of evidence suggests that chronic hepatitis, eventual cirrhosis, and liver cancer may be an even greater risk with hepatitis C than it is with hepatitis B. Some studies in the current medical literature indicate that 50 to 80 percent of intravenous drug addicts may be positive for hepatitis C, so we are not talking about a trivial problem here.
This is a very peculiar virus, which was originally called "delta agent" and later renamed hepatitis D. It is an incomplete virus that can exist only in the presence of hepatitis B. When the two organisms combine, the outcome is a particularly nasty, potentially lethal hepatitis, both in terms of acute mortality and chronic consequences. Discovered in Italy about 1990, in North America hepatitis D is known to be primarily harbored by the injection drug-using population.
Prevention and Treatment of Viral Hepatitis.
Obviously the best prevention for injection drug users would be to stop injecting drugs. Other, often more realistic prophylactic measures—which are now all familiar from the HIV scene—are the use of sterile (or at least bleached) needles and syringes, needle-exchange programs, and condoms for sexual activities.
Immediately after a known or suspected exposure to hepatitis B, the injection of an antibody preparation (known as "hepatitis B immune globulin") can prevent illness. A more permanent prophylaxis in high-risk populations is provided by the hepatitis B vaccine, which gives long-term immunity in previously uninfected individuals. IDUs certainly represent one of these high risk populations, although the widespread use of the hepatitis B vaccine in this group raises some obvious ethical and logistic dilemmas. At the present time, there is no passive or active immunization available for hepatitis C.
The acute phase of any form of viral hepatitis cannot be treated effectively. Chronic hepatitis B and C infection may respond, to a certain extent, to some antiviral drugs known as interferons, which are currently widely studied. Finally, as mentioned under alcoholic liver disease, the most radical form of therapy in the end-stages is liver transplantation.
Gold, M. S. (1991). The Good News about Drugs and Alcohol. New York: Villard.
Lieber, C. S. (1992). Medical disorders of alcoholism. New York: Plenum.
Mezey, E. (1982). Alcoholic liver disease. In H. Popper & F. Shaffner (Eds.), Progress in liver diseases. New York: Grune & Stratton.
Shapiro, C. N. (1994). Transmission of hepatitis viruses. Annals of Internal Medicine, 120, 82.
Woolf, G. M., & Levy, G. A. (1988). Chronic viral hepatitis. Medicine in North America, 21, 3379.
Revised by Ralph Myerson
Medical and Behavioral Toxicity Overview
Alcohol and other drugs of abuse have caused and continue to cause considerable adverse health effects to both the individual and to society. Both legal and illegal drugs (substances) of abuse are taken to modify mood, feeling, thinking, and perception. As with most drugs (medications), both acute and chronic toxicities occur. In general, the term acute refers to the short period of time when the drug is present in the body, exerting its main effects. The term chronic refers to a longer term, usually years.
Acute toxicity results in the impairment of behavior leading to other complications (e.g., trauma) and, in the case of some drugs, high doses can decrease breathing (respiratory depression) or change the rhythm of the heart, leading to accidental or intentional death. Chronic use can result in organ damage, which may lead to chronic illness or death (as with alcoholic cirrhosis of the liver). Persistent use of many classes of drugs also leads to Tolerance (an increased amount is required to produce the same effects) and physiologic (physical) dependence, so that a Withdrawal syndrome is associated with sudden cessation of drug use. Drug users who employ hypodermic needles and syringes (injecting drug users [IDUs]) are at risk for blood-borne diseases associated with the use of unsterile equipment, such as hepatitis and human immunodeficiency virus (HIV 1 and 2—the viruses responsible for AIDS; see Acquired Immunodeficiency Syndrome).
This article focuses on Alcohol as the representative drug, but other drugs of abuse will be referred to where appropriate. In North America, diagnosis of alcohol and other psychoactive substance abuse/dependence is usually made according to the Diagnostic and Statistical Manual (DSM) of the American Psychiatric Association (APA). The fourth edition, called DSM-IV, defines psychoactive substance dependence as at least three of the following (occurring in the same 12-month period):
- tolerance, as defined by either of the following:
- need for markedly increased amounts of the substance to achieve intoxication or desired effect
- markedly diminished effect with continued use of the same amount of the substance
- withdrawal, as manifested by either of the following:
- the characteristic withdrawal syndrome for the substance
- the same (or closely related) substance is taken to relieve or avoid withdrawal symptoms
- the substance is often taken in larger amounts or over a longer period than was intended
- a persistent desire for or unsuccessful efforts in cutting down or controlling substance use
- a great deal of time is spent in activities necessary in obtaining the substance (e.g., visiting multiple doctors or driving long distances), using the substance (e.g., chain-smoking), or recovering from its effects
- important social, occupational, or recreational activities are given up or reduced because of substance use
- continued substance use despite knowledge of having had a persistent or recurrent physical or psychological problem that was likely to have been caused or exacerbated by the substance (e.g., recurrent cocaine use despite recognition of cocaine-induced depression; continued drinking despite recognition that an ulcer was made worse by alcohol consumption)
The diagnosis of alcohol and other substance abuse (as opposed to dependence) relies on:
- A maladaptive pattern of substance use leading to clinically significant impairment or distress as manifested by one or more of the following occurring at any time during the same twelve-month period:
- recurrent substance use resulting in a failure to fulfill major obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substance-related absences, suspensions, or expulsions from school; neglect of children or household)
- recurrent use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by substance use)
- recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct)
- continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with family members about consequences of intoxication; physical fights)
- Has never met criteria for Substance Dependence for this class of substance.
These criteria continue to evolve and are likely to be somewhat changed in the future. Clearly the lack of one of the above diagnoses does not preclude a given person from being at risk for complications of alcohol or drug use (e.g., trauma as a result of intoxication).
THE ACUTE EFFECTS OF ALCOHOL
At the level of the cell, very high doses of alcohol (ethanol) seem to act by disrupting fat (lipid) structure in the central nervous system (anesthetic effect). Lower doses are thought to interact with various proteins and Neurotransmitters (which act as Receptors), such as Glutamate, GABA (Gamma-Amino Butyric Acid), cyclic AMP (adenosine mono-phosphate), and G proteins. Other actions may involve ion (calcium) channels. The reinforcing (rewarding) effects of alcohol may be mediated via Dopamine (a neurotransmitter) in specific brain regions; dopamine acts as an intermediary compound in the reinforcement process. The reinforcement of responses to other drugs of abuse, such as Cocaine, are also thought to be mediated via dopamine.
For most persons at least some of the acute effects of alcohol are well known on the basis of personal experience. Low doses cause blood vessels to dilate. The skin becomes flushed and warm. There is relaxation and mild sedation. Persons become talkative with loss of inhibitory control of emotions. Small doses (one to two drinks) do not impair complex intellectual ability; however, as the dose increases (two or more drinks or as the blood alcohol concentration approaches and exceeds the legal limit) impairment at multiple levels of the nervous system occurs. All types of motor performance are eventually affected, including maintenance of posture, control of speech, and eye movements. These movements become slower and more inaccurate. There is a decrease in mental functioning, such that there is impairment in attention and concentration, and a diminishing ability to make mental associations. There is a decreased ability to attend to incoming sensory information. Night and color vision are impaired. Judgment and discrimination and the ability to think and reason clearly are adversely affected. Even higher doses result in a stuporous condition associated with sleeping, vomiting, and little appreciation of surroundings. This is followed by coma and sometimes death from decreases in the functioning of the brain centers that control respiration.
DOES ALCOHOL IN MODERATION HAVE A BENEFICIAL EFFECT?
The impact of alcohol has been further enhanced recently by an impressive amount of evidence from epidemiological and clinical case-control and cohort studies over the last two decades demonstrating an inverse relationship between moderate alcohol consumption and coronary heart disease. Individuals find themselves caught in a dilemma between the oft-preached dangers of drinking and its recently acclaimed benefits.
Early investigators, impressed by France's relatively low incidence of coronary heart disease despite an intake of saturated fats at least three times that of the United States (the so-called "French paradox"), focused their studies on the potential cardioprotective properties of red wine. Based on other studies, however, the present consensus is that all alcoholic beverages—wine, beer, and liquor, in moderation, are associated with a lower coronary artery disease risk (Rimm et al., 1996). In dose-range studies, a J or U shaped curve has been demonstrated whereby the equivalent of two alcoholic drinks per day is associated with a decreased incidence of coronary heart disease compared with no drinks, while higher doses result in an increased risk of infarction as well as the well-known problems produced by alcohol excess.
Inasmuch as most American households already are exposed to alcohol (Thun et al., 1997). advice as to the benefits of moderation may be offered without reserve. In the case of abstainers, however, the risks of initiating alcohol appear to outweigh its potential benefits. This is especially applicable in families that include adolescents.
ACUTE EFFECTS OF OTHER DRUGS OF ABUSE
Other drugs of abuse can be classified into stimulants, depressants, Opioids, and drugs that alter perception (including Hallucinogens). The effects of any drug depends on the dose taken at any one time, the previous drug experience of the user, the circumstances in which the drug is taken, and the manner (route of administration) in which the drug is taken.
Stimulants such as cocaine and Amphetamine produce euphoria, increased confidence, increased sensory awareness, increased Anxiety and suspiciousness, decreased appetite, and a decreased need for sleep. Physiological effects include increases in heart rate, blood pressure, and pupil size, and decreases in skin temperature.
Depressants such as the minor tranquillizers (including the Benzodiazepines, Barbiturates, and other Sedative-Hypnotics) produce acute effects of a similar nature to alcohol—also a depressant. Actual effects vary according to drug, so that benzodiazepines (such as diazepam/Valium) produce less drunkenness compared to alcohol or barbiturates.
The term opioid refers to both drugs derived from Opium (opiates) and other synthetic drugs with similar actions—those acting on the same receptor system. The term NARCOTIC is usually synonymous with opioid, but it can technically also include other drugs included in the Harrison Narcotic Act (e.g., cocaine). Opioids produce euphoria, sedation (to which rapid tolerance develops), itching, increased talkativeness, increased or decreased activity, a sensation of stomach turning, nausea, and vomiting. There are minor changes in blood pressure and the pupils become constricted (made smaller).
Drugs that alter perception include those above as well as Marijuana, Phencyclidine (PCP), and Lysergic Acid Diethylamide (LSD). In general, most drugs of abuse can cause hallucinations under some circumstances. The drugs which more specifically affect perception (hallucinogens) produce a combination of depersonalization, altered time perception, body-image distortion, perceptual distortions (usually visual), and sometimes feelings of insight. Physiological effects such as changes in heart rate and blood pressure may also occur.
Alcohol is a significant factor in accident-related deaths. The main causes are motor-vehicle Accidents, falls, drownings, and fires and burns. Approximately 50 percent of motor-vehicle fatalities (driver, pedestrian, or cyclist) in the United States are alcohol-related, with the incidence having fallen a little in recent years. These alcohol-related accidents are more common at nights and on weekends. Falls are the most frequent cause of nonfatal accidents and the second most frequent cause of fatal accidents. According to various surveys of fatal falls, those that are alcohol-related range from 17 to 53 percent; for nonfatal falls, from 21 to 77 percent (Hingson & Howland, 1987). The higher the blood alcohol content (BAC), the higher is the risk for falls. The third leading cause of accidental death in the United States is drowning. About half (47-65%) of adult deaths by drowning are alcohol-related (Eighth Special Report to U.S. Congress, 1993). Fires and burns are the fourth leading cause of accidental death in the United States. Studies on burn victims show that alcohol intoxication is common. Cigarette smoking while drinking is an additional cause of fires and burn injuries. Estimates of the rates of intoxication range from 37 to 64 percent.
Users of other drugs of abuse (e.g., cocaine and opioids) also have higher rates of accidents in comparison to the nondrug-abusing population. The combination of cocaine and alcohol has been reported to be commonly associated with motor-vehicle deaths. Between 1984 and 1987 in New York City, 18 percent of motor-vehicle deaths showed evidence of cocaine use at autopsy. Cigarette smokers have higher rates of accidents than do non-smokers. Drugs that alter perception, such as PCP, are also associated with accidents mostly related to an impaired sense of judgment.
Associations between criminal activity and alcohol use have been established; however, methodological inadequacies of studies in this area preclude a clear causal relationship between alcohol use and crime. The strongest association between crime and alcohol use occurs in young males. Other forms of drug abuse (e.g., Heroin and cocaine) have much higher associations with criminality. For example the majority of persons enrolled in Methadone programs have extensive criminal careers. Those involved in drug dealing are at a high risk of being both a perpetrator or a victim of homicide.
Several studies indicate an association between alcohol use/abuse and spousal abuse; however, the nature of this interaction is not well understood. Intoxication is associated with an increase in negative behavior for episodic drinkers while less negative behavior is seen in steady drinkers, suggesting that drinking may be a short-term solution to problems for regular drinkers. Clearly, alcohol use is associated with physical Violence in some families, and there also appears to be a link between alcohol and child abuse. Female caregivers with a diagnosis of alcohol abuse, alcohol dependence, recurrent depression, or Antisocial Personality are more likely to report physical abuse of their children than those without these diagnoses (Bland & Orn, 1986).
From 20 to 36 percent of Suicide victims have a history of alcohol abuse or had been drinking prior to death. Alcohol use is linked more to impulsive than to premeditated suicides, and to the use of firearms, rather than to other modes of killing. Death from Overdose of illicit drugs is common; most of these are thought to be accidental but some are intentional.
Trauma or Severe Injuries.
A history of trauma has been found to be a marker for (sign of) alcohol abuse. Emergency room trauma victims often have high rates of intoxication. Furthermore, heavy alcohol use both interferes with recovery from serious injuries and increases rates of mortality for a given injury. Users of illicit drugs have a higher age-adjusted rate of mortality than do non-users. Many of these deaths result from trauma.
Fetal Alcohol Syndrome (FAS).
Since the 1970s, alcohol has become firmly established as a teratogen (an agent that produces defects in the developing fetus). It is considered the most common known cause of mental retardation. FAS defects range from specific structural bodily changes to growth retardation and subtle cognitive-behavioral abnormalities. The diagnostic criteria for Fetal Alcohol Syndrome are the following: prenatal (before birth) and postnatal (after birth) growth retardation; characteristic craniofacial defects; central nervous system dysfunction; organ system malformations. When only some of these criteria are met, the diagnosis is termed fetal alcohol effects (Eighth Special Report to U.S. Congress, 1993). The abnormalities in physical appearance seem to decrease with age whereas the cognitive deficiencies tend to persist. There is no clear dose-response relationship between alcohol use and abnormalities. The safe amount of drinking during pregnancy (if it exists at all) is unknown. The peak level of blood (or brain) alcohol attained and the timing in relation to gestation (and particular organ development) are probably more important than the total amount of alcohol consumed during pregnancy. Genetic and maternal variables also seem to be important. Native-American and African-American children seem to be at high risk. While the public is generally aware of the relationship between alcohol consumption and fetal abnormality, surveys reveal that there is a need for greater public education in this area.
Smoking is associated with low birthweight. Cocaine use in Pregnancy has been associated with complications (e.g., placental separation and in utero bleeding), and it appears to be associated with congenital abnormalities. Heroin use in pregnancy is associated with premature delivery and low birthweight; often there is a withdrawal syndrome in the baby at birth. Methadone (a long-acting opioid) usually reduces rates of prematurity and low birthweight but still causes as much or more opioid withdrawal in the newborn.
There is clear epidemiologic evidence for an increased risk of certain types of Cancer in association with alcohol consumption. These include cancer of the esophagus, oropharynx, and liver. Other cancers possibly associated with alcohol consumption include cancer of the breast, stomach, prostate, and colon (Geokas, 1986). Alcohol plays a synergistic (additive) role with smoking Tobacco in the development of cancer, particularly with respect to the head, neck and esophagus. There are several possible mechanisms through which alcohol enhances the onset of cancer. Alcohol appears to modify the immune response to cancers, facilitate delivery of carcinogens (substances which enhance cancer onset), and impair protective responses. Overall, alcohol is considered to act as a co-carcinogen; for example, it increases the likelihood of certain smoking-induced cancers.
Smoking is, of course, well established as a cause of lung as well as other cancers. Smoking is responsible for 85 percent of lung cancers and has been associated with cancers of the mouth, pharynx, larynx, esophagus, stomach, pancreas, uterine cervix, kidney, ureter, and bladder (Bartecchi et al., 1994). Chewing tobacco (Smokeless Tobacco) is associated with mouth cancer. The chewing of Be-Tel Nuts with lime is common in Asia and results in absorption of arecoline (a mild stimulant). This practice also causes cancer of the mouth. It has been suggested that Marijuana smoking also causes lung cancer, since high tar levels are present in the smoked products.
ALCOHOL USE AND ABUSE AMONG ADOLESCENTS
Alcohol use among adolescents is a serious world-wide problem. Surveys indicate that up to 54 percent of eighth graders, and up to 84 percent of twelfth graders report having consumed alcohol (O'Malley et al, 1998). There is little doubt that parents' attitudes and habits concerning drinking are important influences on adolescent drinking (Ary et al, 1993). However, there is also evidence that adolescents who abuse alcohol often have coexisting psychopathology such as sociopathy, and bouts of depression and anxiety (Clark and Bukstein, 1998).
Another significant reason for concern about alcohol ingestion by adolescents is the close association of alcohol abuse with the use of other drugs. There is considerable evidence that alcohol use tends to precede use of illicit drugs, and some researchers argue that, based on long-term studies, alcohol serves as a "gate-way" to the use of illicit substances. As early as the eighth grade, alcohol users were found to have a significantly higher prevalence of cigarette smoking, and use of marijuana and cocaine than non-users of alcohol. This difference persists through grade 12 and thereafter (Kandel and Yamaguchi, 1993).
THE EFFECTS OF ALCOHOL ON BODILY SYSTEMS
Acute alcohol consumption causes impairment as described above. Alcohol potentiates the action of many drugs that produce acute effects on the brain. High blood-alcohol levels can result in "blackouts." This condition is due to acute loss of memory associated with intoxication, although the person usually behaves in apparently normal fashion during this period. Blackouts are also seen with the taking of other central nervous system depressants, such as the barbiturates and the benzodiazepines.
The main adverse consequences of chronic alcohol consumption with respect to the nervous system are the following: brain damage (manifested by dementia and alcohol amnestic syndrome); complications of the withdrawal syndrome (seizures, Hallucinations); and peripheral neuropathy. Chronic alcohol consumption results in tolerance, followed by an increased long-term consumption that likely leads to tissue damage. Physical Dependence may also develop (i.e., a withdrawal syndrome occurs on sudden cessation of drinking). The brain damage, when severe, is usually classified as one of two main disorders. The first is a type of global (general) dementia. It is estimated that 20 percent of admissions to state mental hospitals suffer from alcohol-induced dementia (Freund & Ballinger, 1988). The second is an alcohol-induced amnestic (memory-loss) syndrome, more commonly known as Wernicke-Korsakoff syndrome. This is related to thiamine (Vitamin B1) deficiency. The Wernicke component refers to the acute neurologic signs, which consist of ocular (eye) problems such as a sixth cranial nerve palsy (disturbed lateral gaze), and ataxia (impaired balance); the Korsakoff component refers to the memory impairment, which tends to be selective for short-term memory and is usually not as amenable to treatment once it has become manifest.
Milder forms of these disorders are also detectable with neuropsychologic testing or brain Imaging Techniques (CAT scans; MRI). Studies of detoxified alcoholics (without other evidence of organic brain damage) reveal that 50 to 70 percent have impairments in neuropsychologic assessment (Eckardt & Martin, 1986). In most of these cases there is reversibility with abstinence from alcohol. Severe liver disease (e.g., advanced cirrhosis or acute hepatitis) may also contribute to this neurologic impairment. Computerized tomography (CT) scans reveal that many alcoholics have cerebral atrophy—this consists of decreased brain weight, an increase in spaces (sulci) between various regions of the brain, and an increase in size of ventricles (spaces filled with cerebrospinal fluid). In a minority of cases, these structural changes are reversible with abstinence. Seizures are associated with heavy alcohol consumption and usually occur in association with alcohol withdrawal. Abstinence from alcohol is usually the only treatment needed for this type of seizure. The hallucinations that are mostly associated with alcohol withdrawal are usually treated with drugs—benzodiazepines and phenothiazines.
Peripheral neuropathy is seen in association with chronic alcoholism. Peripheral neuropathy usually refers to toxic damage to peripheral nerves. Concurrent nutritional deficiencies often contribute to this damage. This neuropathy results in changes in sensation and occasionally motor function, usually in the legs. Sometimes this can occur acutely with intoxication. For example, the abnormal posture in association with a drunken stupor can result in radial nerve ("Saturday night") palsy. Alcoholics are also at increased risk of subdural hematomas (blood clots due to ruptured intracranial veins secondary to trauma) and of stroke.
The neurologic complications associated with the acute use of other drugs of abuse include seizures (convulsions) and strokes in association with cocaine. High doses of some opioids, such as propoxyphene (Darvon) or Meperidine (Demerol) can also cause seizures. Substances which can cause delirium (reversible disorientation) include Cannabis (Marijuana), phencyclidine (PCP), lysergic acid diethylamide (LSD), and atropine. Sudden cessation of use of central nervous system depressants (benzodiazepines, barbiturates, and alcohol) can result in seizures and hallucinations. Chronic use of other substances of abuse can also result in neurologic complications. Tobacco use is associated with increased rates of stroke (but it appears to be associated with lower rates of Parkinson's disease—a progressive disorder affecting control of movement). Solvent abuse (inhaling) can cause damage to the cerebellum (the part of the brain controlling movement) and to peripheral nerves. A form of "synthetic heroin," MPTP (1-methyl-4-phenyl-1, 2, 5, 6-tetrahydropyridine), an analogue of meperidine (Demerol), has been demonstrated to cause a severe form of Parkinson's disease.
Alcohol-related diagnoses are common among psychiatric patients. For example, a recent study (Moore et al., 1989) showed that 30 percent of those admitted to a psychiatric unit had a concurrent alcohol-related diagnosis. Alcohol alone may produce symptoms and signs that mimic psychiatric disorders. Examples include depression, anxiety disorder, psychosis, and antisocial personality disorder. Alternatively, an alcohol-related disorder may co-exist with one of these or may aggravate the psychiatric disorder.
Alcohol as a central nervous system (CNS) depressant tends to cause low mood states (hypophoria) with chronic use. It does not commonly cause long-lasting significant clinical depression, but it may aggravate it. If alcohol is the primary cause of a low mood state, then abstinenee from alcohol, as the sole treatment, rapidly improves the disorder. Hallucinations may occur during alcohol withdrawal, mimicking a psychotic disorder. Similarly, the anxiety associated with alcohol withdrawal may mimic an anxiety disorder. Anxiety and hallucinations may also be seen during withdrawal from sedative-hypnotics. Behavior associated with alcoholism may lead to an erroneous diagnosis of antisocial personality disorder.
When alcohol is used for self-medication in some psychiatric conditions, such as anxiety disorders, it tends only to be of short-term help and leads to more long-term problems. Other drugs of abuse, such as the stimulants cocaine and amphetamine, also produce anxiety and occasionally may produce a psychotic state associated with acute intoxication. This usually disappears rapidly as the drug effects wear off. Withdrawal following chronic use of stimulants may be associated with depression, excessive fatigue, and somnolence (a "crash"). Tobacco smoking also appears to be somewhat associated with depression. (Individuals with a history of depression are more likely to smoke, and may develop depression when they try to stop.) The nature of this relationship is unclear, but patients with psychiatric diagnoses have higher rates of smoking than the general population. Hallucinogens (such as LSD and PCP) may also cause an acute psychotic disorder which typically disappears as drug effects wear off; however, in some cases there may be longer lasting effects. Antisocial personality disorder is a common diagnosis in those who abuse drugs.
Endocrine and Reproductive.
Alcohol produces both acute and chronic effects on virtually all endocrine organs (glands). Acutely, alcohol raises plasma catecholamines, which are chemicals released from nerve endings that are responsible for certain emotional reactions—"fear, flight, and fight". Epinephrine (adrenaline) is released from the inside of the adrenal gland (medulla) and norepinephrine (noradrenaline) from sympathetic Neurons (nerve cells) and the adrenal glands. Alcohol also causes release of cortisol from the outside (cortex) of the adrenal gland both acutely and chronically. Cortisol is a hormone (chemical messenger) responsible for multiple effects on the body, including changes in the immune response, glucose regulation, fat breakdown, blood pressure, and mood. Alcohol-induced cortisol excess can mimic Cushing's disease (a condition associated with excess cortisol production, often caused by a tumor on the adrenals) and is known as pseudo-Cushing's disease. Alcohol affects the hypothalamus (an area of the brain), where it modifies chemical-releasing factors, which in turn control release of hormones from the pituitary (a gland in the brain linked to the hypothalamus by a special blood supply), which in turn affect endocrine organs throughout the body. Acutely, alcohol also inhibits the release antidiuretic hormone (ADH) from the posterior pituitary, which results in an increase in urine production.
The best documented chronic endocrine effect of alcohol is male hypogonadism. This is a condition resulting from low sex-hormone function. Signs of this are small testes and decreased body hair. Symptoms include loss of libido and impotence. Hypogonadism can occur as a result of alcohol lowering testosterone levels. Alcohol acts both directly on the testes and indirectly via the hypothalamus. Alcoholic liver disease may also produce feminization in men, as a result of impaired metabolism (breakdown) of female sex hormones such as estrogen. Signs of such feminization in men include gynecomastia (enlarged breasts) and female fat distribution. In women who drink alcohol excessively, there is a high prevalence of gynecologic disorders (missed periods and problems in functioning of ovaries) and a possibly earlier onset of menopause than in nondrinkers. In women, also, alcohol is metabolized at different rates according to the particular phase of the menstrual cycle.
Abnormalities of both growth hormone (impaired release) and prolactin (increased release) have been described in association with acute alcohol ingestion. Thyroid function (which controls rate of body metabolism) can be indirectly affected as a result of alcoholic liver disease. This results in impaired conversion of T4 (one version of thyroid hormone) to T3 (a more active form of thyroid hormone). Furthermore, in alcoholism there are abnormalities in the proteins to which thyroid hormone binds. This results in making thyroid function tests difficult to interpret. Overall thyroid function is usually normal despite mild abnormalities in the tests.
Other drugs, particularly the opioids, also have multiple effects on the endocrine system. Opioids produce a degree of hypogonadism as a result of lowered testosterone in males and disturbed menstrual function in females. This results from opioid inhibition of gonadotropin releasing hormone (GRH) in the hypothalamus, which in turn inhibits release of LH (lutenizing hormone) and FSH (follicle stimulating hormone) from the pituitary. Opioids also inhibit corticotropin releasing factor (CRF), which results in decreased adrenocorticotrophic hormone (ACTH) and decreased cortisol. Nicotine causes release of epinephrine and norepinephrine, which in turn increase blood pressure and heart rate. Nicotine also enhances the release of ADH from the hypothalamus, which decreases urine output (i.e., counteracts alcohol's effects).
Alcohol has direct effects on both cardiac muscle and cardiac electrophysiology (electrical functioning). These effects are also dependent on prior history of alcohol use (i.e., whether there have been underlying changes due to chronic use) and whether there is any evidence of underlying heart disease. Acutely, alcohol is a myocardial depressant (decreases muscle function) and, chronically, it may cause a degeneration of cardiac muscle (known as cardiomyopathy), which can lead to heart failure (condition due to excess body fluids because of inadequate pumping function of the heart). Abstinence from alcohol leads to improvement in function in some cases.
Both acute alcohol intoxication and acute withdrawal can lead to cardiac arrhythmias (abnormal heart beats). The most frequent association is with atrial fibrillation (frequent uneven and uncoordinated contraction of the atria). This is usually not life-threatening and mostly disappears without specific treatment. High levels of alcohol consumption are associated with increased rates of coronary (blood vessels which supply heart muscle) heart disease, while low levels of consumption (in comparison to complete abstinence) may be associated with a mild protective effect (the so-called U-curve relationship). However, low levels of consumption are not recommended as a preventive measure against coronary heart disease. Cigarette smoking is a much greater risk factor for coronary heart disease than is alcoholism. It should be noted however, that 80 to 90 percent of alcoholics are also cigarette smokers.
Multiple epidemiologic studies have established a relationship between alcohol and high blood pressure (hypertension). Somewhere between 5 and 24 percent of hypertension is considered to be alcohol related (Klatsky, 1987). The relationship seems to hold most strongly for white males over the age of 55 consuming at least 3 standard drinks per day on a chronic basis. Many cases resolve with abstinence. Acute alcohol withdrawal has also been associated with hypertension, but this usually lasts for only a few days.
The acute use of cocaine (a stimulant) results in increases in heart rate and blood pressure and causes narrowing of peripheral and coronary artery blood vessels. Repeated use of cocaine has been associated with abnormal heart beats, myocardial infarction (heart attack), and possibly myocardial fibrosis (an increase of scar tissue within the heart).
Acute tobacco use also results in constriction (narrowing) of blood vessels and an increase in heart rate because of the nicotine. Chronic tobacco use is the most important of the preventable causes of coronary heart disease. The coronary arteries supply the heart muscle. Long-term tobacco use results in an increase in atherosclerosis (build up of fat and other products inside the walls of blood vessels) in most of the arteries throughout the body and increases coagulation (clotting). This has important effects on the following blood vessels: the coronary (causes angina [chest pain] and infarction [heart attack]; the aorta (causes aneurysms, the ballooning effect on the arterial wall, which can be fatal); the carotid (cause of strokes); the femoral (causes intermittent claudication, pain on walking); and the kidney (cause of kidney failure and some hypertension). Acute use of opioids have minor effects on blood pressure. There are not thought to be important chronic adverse effects of opioids on the cardiovascular system. Marijuana acutely causes increases in heart rate and blood flow.
Acutely, alcohol does not usually interfere with lung function; however a decrease in cough reflexes, a predisposition to reflux of stomach fluids, and the impairment of bacterial clearance in the respiratory tract occur after intoxication. For some persons with asthma, alcoholic beverages can induce bronchospasm (airway narrowing). This is thought to be related to nonalcoholic components in the beverage. Acute alcohol consumption also has a direct depressant effect on the respiratory center located in the brainstem. Accordingly, an overdose (intentional or unintentional) can result in death from respiratory failure (decreased ability to breathe). Alcohol also contributes to respiratory depression when taken with other central nervous system depressants such as barbiturates and benzodiazepines (minor tranquillizers). Acute alcohol intake increases sleep apnea (period of time not breathing) in those who suffer from this disorder.
Chronic alcohol consumption is associated with several pulmonary infectious diseases (in addition to risks associated with tobacco smoking). These include pneumonia, lung abscess, and tuberculosis. Aspiration pneumonia occurs in association with high levels of alcohol intoxication; it is thought to be caused by the inhalation of bacteria caused by the impairment of the usual reflexes, such as coughing. Pancreatitis and alcoholic cirrhosis are associated with pulmonary effusions (build-up of fluid on the lung).
Among the other drugs, cigarette smoking causes emphysema, chronic bronchitis, and lung cancer. The smoking of marijuana on a frequent long-term basis may also increase the likelihood of these disorders. Acute use of opiate drugs intravenously may cause pulmonary edema (accumulation of fluid in the lungs). which can be life-threatening. Chronic use of intravenous drugs may cause pulmonary fibrosis (increased scar tissue). This is probably related to impurities, such as talc, associated with the cutting of the drug (diluting the dose with fillers) prior to its sale and eventual injection.
Gastrointestinal Tract and Pancreas.
Acutely, alcohol alters motor function of the esophagus. Chronic use of alcohol increases gastroesophageal reflux. Alcohol alone does not appear to cause peptic ulcers (cigarettes do), but alcohol interferes with healing. Alcohol disrupts the mucosal barrier in the stomach and causes gastritis (inflammation of the stomach) which can lead to hemorrhage, especially when combined with aspirin. Alcohol also interferes with the cellular junctions within the small intestine, which can result in the disturbance of fluid and nutrient absorption, producing, diarrhea and malabsorption. Any resulting nutritional deficiencies can further aggravate this process.
Heavy alcohol use interferes significantly with pancreatic structure and function. Alcohol abuse and gallstone disease are the major causes of pancreatitis, and alcoholism alone is responsible for most cases of chronic pancreatitis. Alcohol changes cellular membranes, resulting in changes in transport mechanisms and the permeability of vital ions and nutrients essential for normal cellular function. Acetaldehyde, which is a breakdown product of alcohol (and also present in cigarette smoke), is toxic to cells and has been proposed as a causative agent in the development of this disorder (Geokas, 1984). Acute pancreatitis is life-threatening; patients have abdominal pain, nausea, and vomiting. Increased levels of pancreatic enzymes, such as amylase and lipase, accompany this disorder. Treatment is usually by conservative measures, such as replacement of fluids and pain relief. Chronic pancreatitis can be without symptoms; can become evident with chronic abdominal pain and evidence of malabsorption (weight loss, fatty stools, nutritional deficiencies); or, uncommonly, with diabetes mellitus as a result of the destruction of the endocrine as well as the exocrine function of the pancreas.
Alcoholic liver disease is a major cause of morbidity and mortality in the United States; in 1986, cirrhosis of the liver was the ninth leading cause of death. Alcohol causes three progressive pathological (abnormal) changes in the liver—fatty liver, alcoholic hepatitis, and cirrhosis. These changes are useful in a prognostic sense but can only be diagnosed with a liver biopsy, which is not always feasible or practical. More than one pathological condition may exist at any one time in a given patient. Fatty liver is the most benign of the three conditions, and is usually completely reversible with abstinence from alcohol; it occurs at a lower threshold of drinking compared to alcoholic hepatitis and cirrhosis. Alcoholic hepatitis ranges in severity from no symptoms at all to severe liver failure with a fatal outcome; it can be followed by complete recovery, chronic hepatitis, or cirrhosis. Treatment is primarily supportive. Similarly, the symptoms and signs of cirrhosis range from none at all to coma and death. Cirrhosis consists of irreversible changes in liver structure resulting from an increase in scar tissue. A consequence of this is an abnormal flow of blood through the liver (shunts), which can result in the adverse health consequences of bleeding and presentation of toxic substances to the brain. This, in turn, may result in effects ranging from impaired thinking to coma and death. Abstinence from alcohol can prevent progression of cirrhosis and reduces mortality and morbidity (illness) from this condition. Medications may also help to reduce mortality from alcoholic liver disease. These include propothiouracil (an antithyroid drug) and prednisone (a steroid). The former reduces the oxygen requirements for areas of the liver that are poorly perfused. The latter reduces inflammation. Women appear to be at higher risk for liver damage than are men.
Opioid use alone has not been associated with liver disease, but some opioids such as morphine can cause spasm of the bile duct, which results in acute abdominal pain. Tobacco use is associated with a more rapid metabolism (breakdown) of certain drugs in the liver. This means that sometimes higher or more frequent dosing of medicatons is required for smokers. This effect is thought to relate to the tars in tobacco rather than to the nicotine. High doses of cocaine have been associated with acute liver failure.
Acute and chronic hepatitis (types B, C, and D) is common in users of intravenous drugs. It is not usually the drug itself that causes hepatitis (inflammation of the liver) but rather the introduction of disease-producing organisms associated with the sharing of needles. Viruses and bacteria introduced by injecting drugs cause other problems, such as HIV infection and AIDS, endocarditis (infection of heart valves), cellulitis (skin infection), and abscesses.
Alcohol affects the immune system both directly and indirectly. It is often difficult to discern the direct effects of alcohol from concurrent conditions, such as malnutrition and liver disease. Alcohol affects host defense factors in a general way; it also seems to predispose those who drink heavily to specific types of infection. With respect to host factors, alcohol alone can reduce both the number and function of white blood cells (both polymorphonuclear leucocytes and lymphocytes). This both predisposes toward infection while it interferes with the ability to counteract infection. Mechanical factors are also of importance. For example intoxication with alcohol and a depressed level of consciousness (and depressed cough reflex) predisposes toward aspiration pneumonia. Specific infections that alcoholics are at higher risk for, compared to the population at large, include pneumococcal pneumonia (the most common form of pneumonia), other lung infections (Hemophilus influenzae, Klebsiella), abscesses (an-aerobic infections, ), and pulmonary tuberculosis.
Alcoholics with liver disease are at increased risk of spontaneous bacterial peritonitis (inflammation of the lining of the abdominal cavity). Other infections possibly associated with alcoholism include bacterial endocarditis (infection of the heart valves), bacterial meningitis, pancreatitic abscess, and diphtheria. HIV infected drug abusers are at increased risk of tuberculosis as well as a multitude of other infections. As mentioned above, injecting drug users are also susceptible to a variety of infections associated with use of unsterile equipment.
Changes in immune function have been reported to occur in users of other drugs of abuse, including heroin, cocaine, and marijuana. The precise relationship of the immune function change to the drug of abuse is not yet understood. Lifestyle factors such as poor nutrition are also likely to contribute to this.
In heavy alcohol consumers, malnutrition as a result of poor dietary habits is common. In women, heavy alcohol consumption is associated with lower than usual body weight to a degree similar to that also associated with tobacco smoking. There is less of a weight-lowering effect in men. Specific nutritional disorders associated with alcoholism include anemia (due to iron or folate deficiency); thiamine (Vitamin B1) deficiency—causing beri-beri or Wernicke's encephalopathy or neuropathy; malabsorption; and defective immune and hormonal responses. Alcohol also interferes with the absorption of vitamins (such as pyridoxine and Vitamin A), minerals (such as zinc), and other nutrients (such as glucose and amino acids) (Mezey, 1985).
Alcohol is metabolized (broken down) in the liver to acetaldehyde and hydrogen, and then to carbon dioxide and water. Acetaldehyde is toxic to many different cellular functions. Alcohol affects carbohydrate, lipid (fat), and protein metabolism. Alcohol can cause low blood glucose (hypoglycemia) due to inhibition of glycogen (liver stores of carbohydrate) metabolism. Alcohol also raises blood sugar and acids (alcoholic ketacidosis). By interfering with the elimination of uric acid, alcohol may precipitate acute attacks of gout. Increased urinary excretion of magnesium can result in muscle weakness. Alcohol causes disturbances in blood lipids, with mostly an increase in triglycerides and high density lipoprotein (HDL) cholesterol.
Acute alcohol consumption can decrease, whereas chronic consumption can increase, the metabolism of certain drugs. Tobacco smoking also increases the metabolism of some drugs, such as theophylline and caffeine. This results from the increased activity of various liver enzymes as discussed above.
Hematologic (Blood) System.
The effects of alcohol on the hematologic system can either be direct, or it can be indirect (as a result of liver disease or nutritional deficiencies). Uncommonly acute alcohol consumption (a very large dose in a short span of time) has direct effects on the bone marrow, resulting in decreased production of red cells, white cells, and platelets.
The most frequent effect seen in alcoholics following chronic consumption is an increase in the size of the red blood cells (macrocytosis). This is mainly due to direct toxic effects on the red cell membrane rather than to folate (a vitamin found in green vegetables) deficiency, which also causes macrocytosis. A folate deficiency, however, is sometimes seen in alcoholics caused mainly by impaired intake and absorption of folate. Iron deficiency anemia is also seen because of impaired intake of iron and because of frequent bleeding (due to a variety of factors, such as coagulation defects, gastritis, and the impaired healing of peptic ulcer). Iron-overload syndromes are also diagnosed in alcoholics and are due to a multiplicity of causes. Chronic alcohol consumption can also lead to hemolytic (excess breakdown of red blood cells) anemia, which is mainly seen in association with liver disease. Platelet production and function can be suppressed by alcohol, resulting in prolonged bleeding times.
Other drugs also exert hematologic effects. Experimental addiction to opioids results in a reversible anemia and a reversible increase in erythrocyte sedimentation rate (a nonspecific indicator of disease process). Smoking allows carbon monoxide to enter the body and bind to hemoglobin (carboxyhemoglobinemia), which consequently causes an increase in red cell production (erythrocytosis). The hematocrit value and the plasma fibronogen (a clotting factor) rise and increase blood viscosity; platelets (sticky constituents of blood important in wound healing) aggregate more in smokers. These thickening factors, together with damage to the insides of blood vessels, increase the probability of both stroke and heart attack (myocardial infarction) in smokers. White cells are also at increased levels in smokers (leucocytosis).
Chronic alcohol consumption can result in muscle cell necrosis (death). Two main patterns are seen: (1) An acute alcoholic myopathy (disturbance of muscle function) occurs in the setting of binge drinking, sometimes associated with stupor and immobilization. This results in severe muscle pain, swelling elevated creatine kinase (a muscle enzyme), and myoglobinuria (muscle protein in the urine which can cause kidney failure). (2) This pattern consists of a more slowly evolving syndrome of proximal muscle (those closest to the trunk) weakness and atrophy (decreased size). Milder degrees of muscle injury are quite common and consist of elevated levels of the muscle enzyme creatine kinase.
Cocaine use can also cause muscle damage (rhabdomyolysis), resulting in abnormalities of creatine kinase. Most drugs of abuse (especially depressants) may indirectly cause muscle damage as a result of prolonged abnormal posture, for example, sleeping in an intoxicated state on a hard surface.
Alcohol abuse causes a variety of electrolyte and acid-base (blood chemistry) disorders, which include decreases in the levels of phosphate, magnesium, calcium, and potassium. These abnormalities relate to disorders within the functioning kidney tubules (involved in secretion and reabsorption of minerals). The abnormalities usually disappear with abstinence from alcohol.
Chronic use of other abused substances is also associated with kidney (renal) damage and failure. Long-term consumption of pain-relieving medicines (daily use over many years) has been associated with kidney failure (analgesic nephropathy). This is especially associated with the combination products—those that include two or more of Codeine, Caffeine, aspirin, and phenacetin. The rewarding effects that perpetuate this form of drug use most probably relate to the codeine (an opioid) and the caffeine (a stimulant). Heroin use has been associated with a form of kidney failure known as heroin nephropathy. Its precise relationship to heroin use is unclear. Secondary effects on the kidneys from drug and alcohol abuse also occur (for example, from effects of trauma or muscle damage as described above).
American Psychiatric Association (1994). Diagnostic and statistical manual of mental disorders-fourth edition. Washington, DC: Author.
Ary D. V., et al. (1993). The influence of parent, sibling, and peer modeling and attitudes on adolescent use of alcohol. International Journal of Addiction 28 :859-80.
Bartecchi, C. E., Mac Kenzie, T.D., & Schrier, R.W.1994. The human costs of tobacco use. New England Journal of Medicine, 330, 907-912.
Bland, R., & Orn, H. (1986). Family violence and psychiatric disorder. Canadian Journal of Psychiatry, 31, 129-137.
Clark D. B., & Bukstein O. G. (1998). Psychopathology in adolescent alcohol abuse and dependence. Alcohol Health & Research World 22, 117-126.
Eckardt, M. J., & Martin, P. R. (1986). Clinical assessment of cognition in alcoholism. Alcoholism (NY) 10 (2), 123-127.
Freund, G., & Ballinger, W. E. (1988). Loss of cholinergic muscarinic receptors in the frontal cortex of alcohol abusers. Alcoholism (NY), 12 (5), 630-638.
Geokas, M.C. (Ed.). (1984). Ethyl alcohol and disease. Medical Clinics of North America, 68 (1), 1-246.
Hingson, R., & Howland, J. (1987). Alcohol as a risk factor for injury or death resulting from accidental falls: A review of the literature. Journal of Studies in Alcohol, 48, 212-219.
Kandel D. B., & Yamaguchi K. (1993). From beer to crack: developmental patterns of drug involvement. American Journal of Public Health 83, 851-5
Klatsky, A. L. (1987). The cardiovascular effects of alcohol. Alcohol and Alcoholism, 22 (suppl. 1), 117-124.
Mezey, E. (1985). Effect of ethanol on intestinal morphology, metabolism, and function. In H. K. Seitz &B. Kommerell (Eds.), Alcohol related diseases in gastroenterology. Berlin: Springer-Verlag.
Moore, R. D., et al. (1989). Prevalence, detection, and treatment of alcoholism in hospitalized patients. Journal of the American Medical Association, 261, 403-407.
O' Malley P. M., Johnston L. D., & Bachman J. G. (1998). Alcohol use among adolescents. Alcohol Health & Research World 22, 85-93
Rimm, E. B., Klatsky A., Grobbee D., et al. (1996). Review of moderate alcohol consumption and reduced risk of coronary heart disease: Is the effect due to beer, wine, or spirits? British Medical Journal, 312, 731-6.
Thun M. J., Peto R., Lopez A. D., et al. (1997). Alcohol consumption and mortality among middle-aged and elderly U.S. adults. New England Journal of Medicine 337, 1705-14.
U.S. Department of Health and Human Services. (1993). Eighth special report to the U.S. Congress on alcohol and health. Washington, DC: U.S. Government Printing Office.
John T. Sullivan
Revised by Ralph Myerson
Psychiatric disorders have long been recognized as being associated with psychoactive-substance-use disorders (commonly referred to as drug or alcohol abuse). The term dual diagnosis is frequently used to describe people with substance-use disorders combined with other psychiatric disorders. The term Comorbidity is also used to describe the situation in which an individual has two or more distinct disorders. Anxiety disorders and mood disorders are generally the disorders thought to occur in individuals with substance abuse, but other psychiatric disorders also demonstrate high rates of psychoactive-substance use also, including eating disorders (particularly Bulimia), posttraumatic stress disorder (PTSD), personality disorders, somatization disorder, and Schizophrenia. Children with Attention Deficit hyperactivity disorder (ADHD) may also be at increased risk of substance abuse as adults. Various relationships may exist between drug and alcohol use and the development of these psychiatric disturbances. In understanding the relationships between substance abuse and psychiatric disorders, the concepts of primary and secondary are of critical importance. The primary-secondary dichotomy is based on the time sequence in which each disorder developed. When a disorder is referred to as primary, this would indicate that it presented first. The rationale for using the primary-secondary concept involves improved prediction of familial clustering of the psychiatric disorder, implications for treatment, and improved outcome prediction.
In addition to the primary-secondary distinction, the approach to the individual with both a substance use and a nonsubstance use psychiatric disorder should incorporate a similar but slightly more encompassing approach. The drug or alcohol use in such individuals may be involved as a form of self-medication for the psychiatric disturbance; it may itself induce psychiatric symptoms in an otherwise unaffected individual; or the individual may be affected by both disorders (substance abuse and other psychiatric disorders) through separate routes of Vulnerability.
As can be anticipated from this introduction to dual diagnosis issues, the relationship of psychiatric disorders and substance abuse is complex. Despite this complexity, the extent of such problems underscores the need for attention to this area. Studies have shown higher prevalence rates of substance abuse in individuals with psychiatric disorders than in the general population, and conversely patients seeking care for substance abuse have shown high rates of other psychiatric disorders. Large epidemiologic studies of community samples in the United States reveal that greater than 50 percent of substance abusers have at least one other mental illness (Regier, 1990). Data from this same study indicate that approximately one third of those identified as having a mental disorder also have a substance-abuse disorder.
ALCOHOLISM AND MOOD DISORDERS
Depression and Alcoholism.
The rate of depression in individuals with alcoholism and rate of alcoholism in individuals affected with mood disorders (depression and mania) varies greatly according to different studies. The reason for the lack of agreement regarding such rates involves problems shared by all combinations of dual diagnosis. Two such problems include the means of assessment (both of substance abuse and psychiatric symptoms), and the timing of the assessment of psychiatric symptoms (i.e., in relationship to the last occurrence of substance use).
The effect that the means of assessment has upon psychiatric comorbidity is well illustrated by depression. Different rates of depression in alcoholics are seen if one uses standard clinical interviews, structured research interviews or self-report measures. Such methodological differences have led to widely differing conclusions regarding both comorbidity rates and comorbid influence. However, recent estimates from a number of sources suggests that 40 percent of all alcoholics in the U.S. are also battling depression (Larson, 1998).
The critical importance of the timing of the psychiatric assessment and its relationship to comorbidity is demonstrated by studies from the Alcohol Research Center in San Diego (Brown, 1988; Schuckit, 1990). Symptoms of depression in 191 alcoholics were recorded within 48 hours of admission for alcohol detoxification and again after 4 weeks of abstinence (Brown, 1988). Significant levels of depression were noted in 42 percent of alcoholics in the first assessment, but in only 6 percent in the follow-up evaluation irrespective of any specific antidepressant therapy.
These studies demonstrate that for a number of alcoholics, psychiatric symptoms are directly induced by the intake of alcohol, and that these symptoms should be regarded as secondary to the alcoholism. This is important for two reasons. First, if the psychiatric symptoms are secondary to the alcoholism, treatment of the psychiatric symptoms alone will not treat the main disorder (alcoholism). Second, risk for relapse of the alcoholism is high.
Another complication of alcoholism in regard to depression is poor treatment response to standard Antidepressant therapy, both pharmacologic and nonpharmacologic in type. The reason for this is unknown, but may be related to adverse social complications of the alcoholic behavior (e.g., legal problems, job difficulties, marital separation, and divorce) (Cook, 1991).
Mania and Alcoholism.
Individuals with bipolar affective disorder (manic-depressive disorder) have been noted to have increased use of alcohol during their manic episodes. Two studies have suggested that alcoholic bipolar patients have high rates of alcoholism in their families as compared to nonalcoholic bipolar patients (Morrison, 1974; Dunner, 1979). This fact suggests that the risk for alcoholism in bipolar disorder may occur due to a familial predisposition (e.g., genetic predisposition, behavior modeling, etc.), and not necessarily from a complication of the manic episode itself. Regardless, impulsive behavior during manic episodes clearly includes risk for excessive alcohol use.
SUBSTANCE ABUSE AND MOOD DISORDERS
Nearly all substances of abuse have the potential to alter mood symptoms. Classically, Psychostimulants, such as Amphetamines and Cocaine, may induce an appearance of elevated mood, racing thoughts, increased energy, and sense of well-being. Individuals who have developed tolerance to stimulants will experience, upon their discontinuation, withdrawal. These withdrawal symptoms will overlap characteristic depressive symptoms, including severe dysphoria, insomnia followed by hypersomnia, irritability, and fatigue. Opiates induce a sense of elevated mood, and increased self-esteem. A sense of decreased anxiety is also frequently reported. Upon withdrawal, depressive symptoms are accompanied by characteristic physical symptoms such as muscle aches, drug Craving, lacrimation (secretion of tears), and piloerection (goose flesh).
SUBSTANCE ABUSE AND PERSONALITY DISORDERS
Personality disorders by definition involve mal-adaptive patterns of relating to one's environment and self that lead to conflict. To meet the definition of a disorder, these patterns should be enduring qualities, and the onset of such disorders is late adolescence. Behavior induced by substance abuse should be carefully separated from behavior demonstrated during periods of abstinence. This is important, since maladaptive behavior associated with personality disorders will persist through adulthood, while maladaptive behavior that is induced by substance abuse should subside during abstinence from the substance. Two personality disorders that are closely associated with substance abuse are Antisocial Personality Disorder and borderline personality disorder.
Antisocial Personality and Alcoholism.
A great deal is known regarding the relationship of antisocial personality disorder and alcoholism. This diagnostic combination is estimated to involve as many as 2 percent of the male population of the United States. Most studies of this combination of illnesses indicate that the antisocial alcoholic has an earlier onset of drinking difficulties, more family history of alcoholism, more social complications of alcoholism, and a greater number of symptoms of other psychiatric disturbances, e.g., drug abuse, depression, mania, schizophrenia, and psychotic symptoms. Antisocial alcoholics have also been reported to attempt suicide more frequently. In addition to these more severe symptoms at the time of initial evaluation, antisocial personality disorder influences the natural history of the substance use disorders and alcoholism. This change in course is demonstrated by the following studies.
Schuckit (1985) utilized standardized research criteria to divide a group of 541 alcoholics into those who were primary alcoholics, primary drug abusers, primary antisocials, and primary affective disorders. Intake and one-year outcome were then evaluated. The primary antisocial, along with the primary drug abusers, had a poorer one-year outcome in terms of drug use, police and social problems, and higher scores (worse outcome) on a clinical-outcome scale. Schuckit concluded from this study that antisocial personality predicted a poor prognosis in terms of continued alcohol problems.
In a carefully designed study, Rounsaville and coworkers (1987) evaluated 266 alcoholics one year after treatment. Multiple-outcome measures were utilized in this study and over 84 percent of the original cohort were reevaluated. In this study, it was found that in males, an additional diagnosis of major depression, antisocial personality disorder, or drug abuse were associated with poor prognosis at one year. Further analysis in this study also supported the conclusion that the diagnosis was the factor that conveyed the poor prognosis, not general severity of psychopathology or degree of alcohol dependence.
Another study that looked at outcome of alcohol problems in subtypes of antisocials was conducted by Liskow (1991). In this study, antisocial alcoholics were subtyped as to presence of additional diagnoses of drug abuse and depression. An alcoholism-only group was included as a control group. In this study, the alcoholism-only group had the best outcome on a number of measures, while the antisocial alcoholic with drug abuse had the worst outcome. The antisocial alcoholic with no other diagnosis and the antisocial alcoholic with depression were similar in outcome—and intermediate in outcome. Overall, the differences in the alcoholism-only compared to the antisocial-only and the antisocial depressed alcoholics were small compared to the differences between the antisocial plus drug group and all other groups. This study suggests that the poor prognosis in antisocial alcoholics may depend in part on other additional psychopathology (i.e., drug abuse).
Antisocial Personality Disorder and Substance Abuse.
Individuals with antisocial personality disorder have high rates of drug use. Conversely, the dysfunctional lifestyle of an individual actively involved with substance abuse frequently involves lying, joblessness, and the inability to comply with social norms concerning issues such as child care, finances, and the legal system. This makes disentangling these disorders difficult. If one looks for evidence of conduct disturbance, particularly during the late adolescence that predates the substance abuse, then the diagnosis of antisocial personality disorder is much more reliable. The implication for this distinction involves improved ability to predict changes in the individual should long-term abstinence be achieved. The abstinent antisocial will likely continue to demonstrate behavior problems in a variety of areas, whereas someone with an intact personality would be expected to have a better prognosis.
Borderline Personality Disorder.
Less is known about borderline personality disorder and substance abuse or alcoholism. Individuals with borderline personality disorder clearly have high rates of substance abuse, and the criteria published in the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition, revised (DSMIII-R) (American Psychiatric Association, 1987) for this personality disorder include self-damaging behavior—such as substance abuse—as one of the five symptoms required to make the diagnosis. Dulit (1990) has suggested that drug abuse may be an important factor in the development of this disorder.
POSTTRAUMATIC STRESS DISORDER (PTSD) AND SUBSTANCE ABUSE
Following extreme stresses beyond the realm of normal human experience, symptoms of anxiety including intrusive recollections of the trauma, autonomic hyperactivity, and nightmares have long been observed, but PTSD as a psychiatric diagnosis is much newer. Following recognition of this disorder, the link with substance abuse has been the subject of a number of studies. Rates of alcoholism in PTSD range from 40 to 80 percent, while other forms of substance abuse may range from 20 to 50 percent. This high rate of substance abuse has led to the hypothesis that the drug use may be explained by a self-medication theory. Jelinek (1984) has proposed that in the treatment of PTSD, those with substance abuse be divided into groups with abuse that preceded the trauma and those whose abuse followed the trauma. This latter group is considered as a "self-medication group," and in this group treatment of the PTSD is felt to be the primary goal. Following treatment for the PTSD, it is believed that the substance abuse in this group will then decrease or end. In the former group, detoxification from the substance abuse and abstinence is felt to be the primary goal, and that following this the PTSD symptoms will improve.
SUBSTANCE ABUSE AND OTHER ANXIETY DISORDERS
Alcohol and Anxiety.
Individuals with anxiety disorders (e.g., generalized anxiety disorder, panic disorder, phobic disorders, obsessive-compulsive disorder) find that alcohol provides temporary relief from some of their anxiety symptoms. Large community studies of individuals with phobias suggest over a twofold increase in alcoholism risk. Panic disorder patients have rates of alcoholism approaching 20 percent, and male relatives of individuals with panic disorder have a two to three times increased rate of alcoholism when compared to controls, further suggesting a relationship between alcoholism and anxiety disorders. Another known fact is that anxiety symptoms are experienced during withdrawal. Schuckit (1990), in a study of anxiety symptoms during withdrawal, evaluated 171 alcoholics for anxiety and panic symptoms. Nearly all subjects had at least one anxiety symptom during heavy drinking, or upon abrupt discontinuation of drinking, but only 4 percent fulfilled DSM-III-R criteria for generalized anxiety disorder when three or more months of abstinence were achieved.
Anxiety and Substance Abuse.
Panic attacks have been shown to be induced by psychostimulants, particularly Cocaine. The rate of panic attacks among users of cocaine has been reported to be as high as 64 percent. Anxiety symptoms during the withdrawal phase from cocaine also increases the risk for alcohol abuse and/or benzodiazepine abuse. These substances are frequently used to ease the "crash" phase.
SUBSTANCE ABUSE AND SCHIZOPHRENIA
Only recently has the high prevalence of alcoholism in schizophrenia been noted. Likewise, the recognition of high rates of other substance abuse in the schizophrenic population was not appreciated until the 1980s. A review of published estimates of the prevalence of alcohol abuse in schizophrenia reported a range of 8.4 to 47 percent (Mueser, 1990). Stimulant abuse in this review was reported between 4 and 15 percent. The question of whether substance abuse induces a chronic schizophrenic-like psychosis even after the drugs are stopped is still open to debate. It is generally held, however, that individuals who develop schizophrenia coupled with drug abuse would most likely have developed schizophrenia regardless, but the abuse may have caused an earlier onset. The early drug use may represent efforts at self-treatment. Treatment of the schizophrenic with drug abuse presents a major clinical challenge. Such patients tend to be disruptive, prone to frequent relapse of psychosis and drug use, and do not easily fit into conventional treatment settings. Optimal care is thus difficult, and improved strategies for treatment are needed.
SUBSTANCE ABUSE AND EATING DISORDERS
Individuals with eating disorders (Anorexia and Bulimia) abuse a number of drugs and alcohol. During the course of their lives, they often use agents to reduce weight, such as laxatives, emetics, diet pills, and diuretics. Of those individuals with eating disorders who seek psychiatric treatment, as many as 35 percent have a significant substance-abuse history. Alcoholism, particularly in bulimia and bulimic anorectic patients, appears to be common. Substance abuse in eating disorders is generally thought to convey a poor prognosis for recovery.
SUBSTANCE ABUSE AND ATTENTION DEFICIT DISORDER
Children with attention deficit hyperactivity disorder (ADHD) have been noted to be at risk for development of alcoholism and cocaine abuse as they grow into adolescence and adulthood. Family studies of children with ADHD and alcoholism have demonstrated higher rates of alcoholism in family members than that seen in the general population. Goodwin (1975) compared previously hyperactive adult adoptees with and without alcoholism. As children, these alcoholics were hyperactive, truant, shy, aggressive, disobedient, and friendless. In these adoptees, those with alcoholism clearly had an excess of alcoholism in their biological parents. No alcoholism was found among the biological parents of the nonalcoholic hyperactive adoptees. These findings suggest that in the case of alcoholism and hyperactivity, the risk for alcoholism comes from a genetic basis and not necessarily from just having ADHD.
It has been estimated that 15 to 20 percent of cocaine users might also be afflicted with ADHD. Studies have been conducted using Ritalin to treat cocaine users suffering ADHD—indeed, one such study by the New York State Psychiatric Institute showed a 66 percent drop of ADHD symptoms and a decline of 75 percent in the craving of cocaine (New York State Psychiatric Institute (1996). Despite those encouraging statistics, counseling and other treatment methods are obviously still very much in need.
SUBSTANCE ABUSE AND OTHER COMPLICATIONS
Alcoholics have a 15 percent lifetime risk of Suicide. Alcohol is involved in at least 50 percent of successful suicides. Substance abusers are also recognized to have an elevated risk of suicide, and it has been reported that 70 percent of suicides in young people are associated with substance abuse. Studies of successful suicides demonstrate the ambivalent nature of this act. Alcohol or substance abuse may act as the weight that tips the scale toward suicide, or may induce the psychiatric symptoms that elicit the suicidal urge. Regardless, substance abuse is among the strongest risk factors for suicide.
Organic Brain Syndromes.
A variety of organic brain syndromes, including Delirium and dementia are associated with acute and chronic use of drugs and alcohol. Abrupt Withdrawal from alcohol or sedative-hypnotic drugs can cause withdrawal delirium (DTs). These organic effects from drug use must be carefully separated from the psychiatric conditions discussed earlier, and from neurologic conditions which can overlap their symptoms. The impact of chronic drug use and personality is an area in need of further study.
Acquired Immunodeficiency Syndrome (AIDS).
Intravenous drug use, needle sharing, and high-risk sexual practices among drug users are major risk factors for AIDS. Psychiatric manifestations of AIDS may present in a number of ways, including mood disorders, dementia, psychosis, and behavioral impairment. Suicide risk among AIDS victims is high. In evaluating the substance abuser with neuropsychiatric changes, HIV testing should be completed and treatment for AIDS should incorporate educating the patient about these risks.
Substance abuse of all kinds and many psychiatric disorders have been shown very conclusively to be associated one with the other. The combination of these disorders, as generally agreed, make such individuals more difficult to treat from the standpoint of both their psychiatric and their substance-abuse problems. Research is being conducted to determine better ways of understanding the origins of these associations.
American Psychiatric Association. (1987). Diagnostic and Statistical Manual of Mental Disorders-3rd ed.-rev. Washington, DC: Author.
Brown, S. A., & Schuckit, M. A. (1988). Changes in depression among abstinent alcoholics. Journal of the Study of Alcohol, 49, 412-417.
Cook, B. L., et al. (1991). Depression and previous alcoholism in the elderly. British Journal of Psychiatry, 158, 72-75.
Dulit, R. A., et al. (1990). Substance abuse in borderline personality disorder. Psychiatry, 147, 1002-1004.
Dunner, D. L., Hensel, B. M., & Fieve, R. R. (1979). Bipolar illness: Factors in drinking behavior. American Journal of Psychiatry, 136, 583-585.
Gold, M. S., & Slaby, A. E. (1991). Dual diagnosis in substance abuse. New York: Marcel Dekker.
Goodwin, D., et al. (1975). Alcoholism and the hyper-active child syndrome. Journal of Nervous and Mental Disorders, 160, 349-353.
Jelinek, J. M., & Williams, T. (1984). Post-traumatic stress disorder and substance abuse in Vietnam combat veterans: Treatment problems, strategies and recommendations. Journal of Substance Abuse Treatment, 1, 87-97.
Keeler, M. H., Taylor, C. I., & Miller, W. C. (1979). Are all recently detoxified alcoholics depressed? American Journal of Psychiatry, 136, 586-588.
Larson, J. (1998). Alcoholism: The Biochemical Connection. Women in Engineering and Science News.
Liskow, B., Powell, B. J., & Nickel, E. (1991). Diagnostic subgroups of antisocial alcoholics: Outcome at 1 year. Comparative Psychiatry, 31, 549-556.
Lowinson, J. H., et al. (1992). Substance abuse: A comprehensive textbook, 2nd ed. Baltimore, MD: Williams & Wilkins.
Morrison, J. R. (1974). Bipolar affective disorder and alcoholism. American Journal of Psychiatry, 131, 1130-1133.
Mueser, K. T., Yarnold, P. R., & Levinson, D.F. (1990). Prevalence of substance abuse in schizophrenia: Demographic and clinical correlates. Schizophrenia Bulletin, 16, 31-56.
New York State Psychiatric Institute. (1996). Who Gets Addicted to Cocaine and Why? New York Psychiatric Institute Newsletter, 15.
Regier, D. A., et al. (1990). Comorbidity of mental disorders and other drug abuse: Results from the epidemiology catchment area (ECA) study. Journal of the American Medical Association, 264 (19), 2511-2518.
Rounsaville, B. J., et al. (1987). Psychopathology as a predictor of treatment outcome in alcoholics. Archives of General Psychiatry, 44, 505-513.
Schuckit, M. A. (1985). The clinical implications of primary diagnostic groups among alcoholics. Archives of General Psychiatry, 42, 1043-1049.
Schuckit, M. A., Irwin, M., & Brown, S. A. (1990). The history of anxiety symptoms among 171 primary alcoholics. Journal of the Study of Alcohol, 51, 24-51.
Winokur, G., Rimmer, J., & Reich, T. (1971). Alcoholism IV: Is there more than one type of alcoholism? British Journal of Psychiatry, 118, 525-531.
Brian L. Cook
Revised by Daniel P. Hayes
Alcohol (ethanol, also called ethyl alcohol) and other psychotropic drugs are taken because of their ability to affect the central nervous system (CNS) and thereby alter mental functioning. However, the possible reinforcing effects are offset by a cost: it is now well established that CNS structural and functional integrity can be compromised by heavy or prolonged intake of many abused substances. This article addresses the effects of alcohol and other psychotropic drugs on nervous system structure and function. It will briefly review and synthesize information from studies using various methods and technologies, including neurological examination, postmortem examination of the brain, neuropsychological tests, and neuroradiological techniques such as magnetic resonance imaging (MRI), which shows the living brain in fine detail, and positron-emission tomography (PET), which indicates the level of functioning of particular brain regions while the individual is at rest or is engaged in a cognitive task. Both acute and chronic effects of substances on brain and behavior and the reversibility of drug-related impairments are addressed. Because most of the relevant research on this issue has been conducted with Alcohol, more limited information is presented regarding the effects of other drugs of abuse on CNS.
ALCOHOL: ACUTE EFFECTS
Blood Alcohol Concentrations (BAC) above the legal limit (0.08%) typically impair the operation of complex machinery, as should be obvious from public information and programs regarding Driving while intoxicated. The signs of intoxication, such as impaired judgment, slurred speech, and motor incoordination, are due to CNS depression. Sensitive testing also reveals impairments in a number of specific cognitive operations, including selective attention, decision making, and hand-eye coordination, at lower blood alcohol concentrations. Intoxication can increase risk-taking, aggressive, or dangerous behaviors because of diminished inhibitory control coupled with the person's inability to evaluate the consequences of his or her actions. Therefore, it is not surprising that intoxication is frequently associated with traumatic injuries, including traumatic brain injuries, and is a common factor in fatal motor vehicle accidents and violent incidents.
A binge of heavy drinking can lead to Memory lapses or alcoholic blackouts, in which the individual is unable to recollect events that took place during the period of intoxication even though he or she may have seemed "normal" to observers at the time. Although the pathogenesis of these episodes is not yet defined, it appears that the mechanisms underlying memory storage are temporarily disrupted during the blackout. Less severe difficulties with storage of new information can be seen even when drinking is below the legal limit of intoxication.
Very high doses of alcohol depress consciousness, leading to sleepiness, coma, respiratory depression, and death. The acute effects outlined here are clearly dose-dependent and are due to depression of successively more regions of the nervous system with the increasing dose.
ALCOHOL: TOLERANCE AND WITHDRAWAL
Dependence on alcohol, and many other drugs, is characterized by Tolerance and Withdrawal. Tolerance refers to the fact that with chronic use, increasing doses of the drug are needed to achieve the same behavioral effects. Thus, the degree of acute impairment outlined above will vary with the individual's tolerance. People who have developed alcohol tolerance also show cross-tolerance to other CNS depressants, including general anesthetics. Loss of tolerance appears to occur in the Elderly and in alcoholics who have developed organic brain impairments due to alcohol use or other factors, such as head injury. However, tolerance does not appear to develop to the direct neurotoxic effects of long-term alcohol abuse.
Following heavy drinking, many alcoholics experience a tremulous-hyperexcitable withdrawal syndrome, which is characterized by postural tremor, agitation, confusion, and ataxia. Generalized seizures can also appear in withdrawal, typically 10 to 48 hours after cessation of drinking. It has been hypothesized that long-term alcohol use may establish an epileptogenic state of the brain that becomes manifest upon alcohol withdrawal. For this reason, it has become common practice in many treatment facilities to guard against withdrawal seizures in patients with known susceptibility by giving prophylactic anticonvulsants or tranquilizers. Long-term treatment is usually not indicated because the withdrawal syndrome is self-limiting. In some patients, the acute withdrawal syndrome can progress to Delirium Tremens (DTs). This more severe form of withdrawal is characterized by delirium, Hallucinations, and a hyperautonomic state manifested by sweating and tachycardia. DTs are associated with approximately 15 percent mortality rate, possibly due to cardiac toxicity caused by the hyperadrenergic state. Treatment of the disorder involves rehydration and haloperidol (a neuroleptic drug) as well as medication to control withdrawal.
ALCOHOL: CHRONIC EFFECTS
Alcohol has direct toxic effects on neurons and, in association with other medical consequences of alcohol abuse, such as liver damage and inadequate nutrition, can result in significant and lasting cognitive deficits. There is no clear indication of the level of consumption that might put one at risk for such consequences, but "safe" drinking guidelines of no more than twelve to fourteen drinks per week probably represent a minimum level. Although there are no precise data on the incidence of neurological or cognitive impairment in alcohol abusers, it is estimated that 50 to 70 percent of individuals seeking treatment may present with some form of neurocognitive impairment. Most of these report drinking more than thirty standard drinks (each containing 13.6 grams of ethanol) per week and at least a five-year history of such use.
Victor and his colleagues (1989) have made the definitive studies of the best-known disorder associated with alcohol abuse, the Wernicke-Korsakoff syndrome (WKS). There are three major symptoms in the acute phase, known as Wernicke's encephalopathy: abnormalities of eye movements; ataxia; and a confusional state that includes poor responsivity, disorientation, and deficits in attention and memory. The disorder has been demonstrated to be caused by a thiamin (Vitamin B1) deficiency that is probably due to decreased B1 in the diet and decreased absorption or utilization of B1 induced by alcohol-related gastrointestinal disorders or other mechanisms. These symptoms usually improve substantially when the patient is immediately treated with thiamin. The chronic phase, known as Korsakoff's syndrome, is marked by a profound memory deficit that includes both retrograde amnesia (an inability to recall information from the remote past) and anterograde amnesia (an inability to learn and retain new information). It should be noted that there is frequently no prior Wernicke's encephalopathy recognized in Korsakoff patients. Although there may be difficulties in other cognitive capacities, the levels of general intellectual functioning, verbal abilities, and many other specific skills remain intact in these patients. Although partial or complete recovery from the amnesia is seen in some individuals, at least 50 percent of cases show slight or no recovery.
Postmortem analysis indicates that the lesions in Korsakoff patients generally involve diencephalic areas known to be important to memory functioning. These include the mammillary bodies and the dorsomedial nuclei of the thalamus. Neuronal loss is also prominent in other areas surrounding the cerebral ventricles, such as the periaqueductal gray of the mesencephalon, hippocampus, and basal forebrain. Modern imaging techniques that permit in vivo examination of the neuropathology of WKS are consistent with the neuropathological data. Analysis of MRI scans reveals small or absent mammillary bodies, as well as more general cerebral atrophy.
Estimates of the prevalence of WKS, based on hospital records, suggest that it is relatively rare. However, it appears that the diagnosis is often missed during life, despite its seemingly dramatic presentation. Autopsy series by Harper and his colleagues (1987) have indicated that less than 20 percent of patients with the characteristic brain lesions of WKS had been correctly identified ante-mortem.
A second profile of alcohol-related brain dysfunction, which is much more common than WKS, has been described by many investigators since the 1970s. These individuals may not show overt neurological symptoms, but selective impairments are seen in cognitive functions when sensitive neuropsychological tests are used. Extensive reviews of these effects are available in a book edited by Parsons, Butters, and Nathan (1987). The most prominent deficits are in complex visual-motor functions, particularly when speed of response is important. Thus, visual search, manual tracking, symbol copying, and other psychomotor functions are marked by imprecision and slowness. Problem-solving abilities, such as abstraction, hypothesis generation, and mental flexibility are also deficient. Mild deficits are apparent in new learning and memory, especially for nonverbal material. The memory difficulties are increased when the task requires the patient to use strategies for organizing and retrieving the information.
Studies of Brain Structures in these chronic alcoholics reveal apparent atrophy of the cortex, with enlargement of ventricles and sulci. For example, autopsy studies demonstrate that cerebral atrophy and low brain weight are associated with alcoholism, and some studies even show loss of cerebral tissue in "moderate" drinkers. Although such damage may be relatively widespread, several lines of research implicate a predominant involvement of frontal cortical regions in alcohol-related cerebral dysfunction. Autopsy studies show significant reduction in neuronal counts in the superior frontal cortex but not the motor cortex. Research with MRI and PET scanning in vivo reveals a consistent decrease in brain volume and functioning at rest in frontal regions, although most studies have implicated other brain areas as well. This evidence is generally consistent with studies using neuropsychological techniques, which also suggest impairments through tests sensitive to frontal-lobe dysfunction. However, further research is necessary to refine and correlate these different sources of evidence before strong conclusions can be made regarding selective effects of alcohol on localized cortical regions.
Many investigators recognize a more severe and global impairment in mental functioning that is different from both the "typical" picture of chronic alcoholic brain dysfunction and from WKS. This is generally referred to as alcoholic dementia, to underscore the severe and global nature of the cognitive deficits. However, it is not known whether alcoholic dementia exists as a separate pathological entity, which represents the end point of chronic alcoholism in some older individuals, or is an extension of WKS to other brain regions and cognitive domains. Some research at the end of the 1990s suggested that alcoholic dementia may be a more severe form of WKS.
There is no clear set of clinical diagnostic or neuropathological criteria for alcoholic dementia. However, a relatively high prevalence of alcohol-related dementias among residents of several long-term care institutions in northern Ontario were found. In that study, 24 percent of cognitively impaired residents fit this diagnostic profile, a figure substantially higher than had been reported previously. Given that the proportion of elderly individuals in North America is growing, we might expect an increase in research activity associated with this disorder in years to come.
ALCOHOL: RECOVERY OF FUNCTION
When alcoholics stop drinking, their presenting neurocognitive impairment can often show marked recovery over weeks to months with maintained abstinence. Substantial recovery has been demonstrated in only a minority of patients with WKS, given appropriate thiamin treatment and abstinence from alcohol use. In 1978, Carlen and colleagues were the first to report reversibility in measured cerebral atrophy on computerized tomography (CT) scans in chronic alcoholics after several months of abstinence. This reversibility has been replicated by several other research groups. Many studies have also reported recovery in the cognitive performance deficits for a majority of patients, with improvements depending critically on abstinence. In general, the more novel, complex, and rapid the information-processing requirements of the task, the longer the time for recovery to normal levels of function. As of the mid-1990s, only modest correlations between the measures of brain atrophy and cognitive functioning had been shown. The mechanisms underlying the pathogenesis and reversibility of cerebral atrophy remained under study.
ALCOHOL: SUMMARY AND FURTHER QUESTIONS
Chronic alcohol ingestion has potentially devastating effects on neurocognitive functioning. Impairments associated with alcohol use range from transient deficits observed in acute intoxication to potentially permanent and severe disorders, such as alcoholic dementia. There are also various other neurological conditions associated with chronic alcohol abuse. Some of these are relatively common in alcoholics, including cerebellar degeneration, peripheral neuropathies, movement disorders, and hepatic encephalopathy. Alcohol-related conditions that are relatively rare include central pontine myelinolysis, pellegra encephalopathy, and Marchiafava Bignami disease. Although some important relationships between alcohol misuse and neurocognitive functioning have been discerned since the 1970s, many important questions remain. Outstanding issues include the prevalence of impairment in the alcohol-dependent population; individual risk factors that mediate the expression of deficits; the relation between levels and patterns of consumption and resulting impairments; the rate and extent of recovery of function and treatments that may enhance recovery; precise specification of the profiles of cognitive impairment in different clinical syndromes and their relation to measures of brain damage; and implications of cognitive dysfunction for prevention and treatment of substance abuse.
OTHER CNS DEPRESSANTS
Several other classes of drugs act as depressants on the central nervous system. The profile of impairment with barbiturate intoxication largely resembles the acute effects of alcohol. Because of the relatively high abuse potential and severe withdrawal associated with these drugs, the Benzodiazepines have largely displaced Barbiturates in prescriptions for Sedative-Hypnotic drugs. Currently the most prescribed class of Psychoactive drugs in Western industrialized countries, they are typically used for muscle relaxation, sedation, and reduction of Anxiety. It has become clear that benzodiazepines (e.g., Valium) can be associated with adverse behavioral changes, particularly in older individuals. In acute administration, they can cause impaired memory, slowing of reaction time and decision making, and disrupted attention. These effects are similar to those produced by drinking alcohol, and the effects of these two drugs taken together can be additive. Although patients appear to develop some tolerance to the sedating effects of benzodiazepines when they are administered for long periods, new evidence suggests that memory and cognitive impairments can remain or even increase with chronic administration. At present, it does not appear that these drugs have direct toxic effects on brain structures, so that their effects on behavior are likely mediated by a temporary and reversible pharmacological blocking of normal routes of neural information processing.
Cannabis (Marijuana) intoxication leads to widespread changes in cognitive functioning, including disrupted attention, memory, and perceptual-motor abilities. For example, individuals may be unable to remember information learned while intoxicated, even when tested in drug-free conditions. Like alcohol, there is also impairment in the complex visual, motor, and decision-making skills needed to operate complex machinery. Numerous reports from the 1970s indicated a lack of enduring cognitive impairment associated with chronic cannabis use. However, later work reported poor learning and memory in newly abstinent users, with recovery of function documented over a six-week period. Although further research is needed, there is clearly not the same degree of brain and behavioral dysfunction that has been associated with alcohol.
Primarily used for therapeutic management of severe pain, the Opioids can have a profound mood-altering euphoric effect that can lead to dependence. Administration of opioids (Heroin, Morphine, or Demerol) to relatively naive users leads to a generalized depression of cognition that can be referred to as "mental clouding." Impairments in perception, learning and memory, and reasoning accompany the drowsiness and mood changes induced by the drug. Generally, tolerance develops to the depression in mentation with chronic administration. Thus, there appears to be little long-term performance or brain dysfunction associated with this drug class.
AMPHETAMINES AND COCAINE
Amphetamines and Cocaine act as CNS stimulants, which means that they generally increase arousal and psychomotor activity. As might be expected, acute administration can improve performance on many tasks, particularly when vigilance or speed of response is important. It can also reverse the effects of fatigue, which suggests that attentional resources are enhanced. However, this increase in arousal can be coupled with a dysfunction in higher-order control processes used to monitor or inhibit ongoing behavior, such that there is a corresponding increase in errors, impulsivity, and hyperactivity. Neurological consequences of a single dose of cocaine can include intracerebral hemorrhages, seizures, and strokes. These complications appear in only a small proportion of cocaine users, but the factors that place one at risk are not yet known. Although there is little research on the existence or nature of cumulative effects of chronic stimulant use, some recent evidence indicates mild impairments in memory and attention. A few studies have documented the recovery of function with abstinence and a correlation between the level of consumption and impairment, suggesting a direct relationship between drug use and behavioral deficiency. Convergent evidence for a transient disruption in brain function is provided by the work of Volkow and colleagues (1988). Their PET studies indicated decreased blood flow in the prefrontal cortex of cocaine users and an apparent return to normal levels with abstinence. In animal models, high doses of amphetamines, particularly Methampetamine, can produce damage to serotonergic and dopaminergic neurons.
Solvents are chemical compounds, such as benzene and toluene, typically used to dissolve oils or resins. Although a small proportion of young people voluntarily abuse or inhale these substances (e.g., sniffing glue or gasoline), many more individuals are exposed to them as workers in an industrial setting. These chemicals are unique in their ability to cause damage to the CNS after fairly limited exposure. Clinical observation of acute effects of these drugs shows that users experience euphoria, dizziness, and "drunkenness," which are usually accompanied by fatigue, muscle weakness, and impairments in concentration, memory, and reasoning. This can progress through loss of self-control, disorientation, and coma. Chronic neuropsychological impairments are seen in a variety of domains, including motor coordination, memory, and attention, and can resemble the symptoms of dementia. Neurological impairments include diminished sensitivity to pain and touch, shrinkage of the cortex, and lesions in the cerebellum. Although there is not yet sufficient evidence to be conclusive, it is likely that much of the damage and disruption to function are permanent.
Although much is known about the effects of drugs on the brain and behavior, many important questions remain to be answered. Even given the intensive research on alcohol, there is still lack of consensus regarding the durability of impairments, the risk factors that determine individual susceptibility, and the relationship between consumption and brain damage. In particular, the separation of any neurocognitive dysfunction that may precede drug abuse from that which is consequent to chronic drug use remains an important issue that is difficult to address without prospective studies. Research attempting to discover the relationships among a given drug's effects on various indices of brain integrity is also a relatively new area and requires further elaboration. For example, only a few studies attempting to relate brain atrophy in specific regions to particular cognitive impairments in chronic alcoholics have shown significant and reliable correlations. It is also increasingly common to find that individuals will use and abuse several different drugs, yet research on the interacting effects of various drug combinations is in its infancy. In the final analysis, much of the work summarized here prepares us to ask better questions regarding the consequences of drug use on neurocognitive functioning.
(See also: Accidents and Injuries from Alcohol ; Imaging Techniques )
Carlen, P. L., et al. (1978). Reversible cerebral atrophy in recently abstinent chronic alcoholics measured by computed tomography scans. Science, 200, 1076-1078.
Chesher, G. B. (1989). Understanding the opioid analgesics and their effects on skills performance. Alcohol, Drugs and Driving, 5, 111-138.
Emsley, R., et al. (1996). Magnetic resonance imaging in alcoholic Korsakoff's syndrome: evidence for an association with alcoholic dementia. Alcohol, 5, 479-486.
Fornazzari, L., Wilkinson, D. A., Kapur, B. M., & Carlen, P. L. (1983). Cerebellar, cortical, and functional impairment in toluene abusers. Acta Neurologica Scandinavica, 67, 319-329.
Harper, C. G., Kril, J., & Daly, J. (1987). Are we drinking our neurons away? British Medical Journal, 294, 534-536.
Hartman, D. E. (1988). Neuropsychological toxicology: Identification and assessment of human neurotoxic syndromes. New York: Pergamon.
Lishman, W. A. (1990). Alcohol and the brain. British Journal of Psychiatry, 156, 635-644.
Mody, C. K., et al. (1988). Neurologic complications of cocaine abuse. Neurology, 28, 1189-1193.
O'Malley, S., Adamse, M., Heaton, R.K., & Gawin, F. H. (1992). Neuropsychological impairment in chronic cocaine abusers. American Journal of Drug and Alcohol Abuse, 18, 131-144.
Parsons, O. A., Butters, N., & Nathan, P. E. (1987). Neuropsychology of alcoholism: Implications for diagnosis and treatment. New York: Guilford Press.
Thomas, P. K. (1986). Alcohol and disease: Central nervous system. Acta Medica Scandinavica (suppl.), 703, 251-264.
Victor, M., Adams, R.D., & Collins, G. H. (1989). The Wernicke-Korsakoff syndrome and related neurological disorders due to alcoholism and malnutrition (2nd ed.). Philadelphia: F. A. Davis.
Volkow, N. D., et al. (1988). Cerebral blood flow in chronic cocaine users: A study with positron emission tomography. British Journal of Psychiatry, 152, 641-648.
Woods, J. H., Katz, J. L., & Winger, G. (1992). Benzodiazepines: Use, abuse and consequences. Pharmacological Reviews, 44, 151-347.
Peter L. Carlen
Mary Pat McAndrews
Revised by Mary Carvlin
This entry discusses nutritional complications in alcoholics, smokers, and abusers of other addictive drugs.
Alcoholic beverages were long used as a source of nourishment for the sick, as a means of promoting appetite, and as a treatment for pain and infection—all before other means and medications were developed for these situations. Traditionally, wine and Beer were foods, used ceremonially and as part of ceremonial healing for the ailing (and pregnant) who refused or could not tolerate a solid diet. Eventually, alcoholic beverages moved from purely ceremonial occasions to a reason for social occasions in some cultures, among some classes, and for some individuals. Alcoholic beverages have a habit-forming or addictive element for some people that may become life threatening to fatal.
Use of Alcohol in Medicine: Recent History.
In 1900, Atwater and Benedict reported on their experiments at Wesleyan University, which attempted to define whether Alcohol could actually be considered a food; they showed that alcohol is oxidized in the body and that the energy so derived can be used as a fuel for metabolic purposes. Before that, F. E. Anstie (1877) had written his treatise On the Uses of Wine in Health and Disease, and, in fact, the long tradition of using alcoholic beverages within the medical profession persisted into the twentieth century. Sir Robert Hutchison, a noted British physician, wrote in 1905 that there was reason to believe (not that there was evidence) that alcohol increases disease resistance. Alcohol was actually used to treat serious infectious disease, such as typhus, into the late 1920s—until it was shown that patients treated with milk and beef tea had greater survival rates.
The use of alcohol to treat such disease was linked to a supposition that debility would somehow be overcome and strength regained. Other than this, the major indication for alcohol was for analgesia (pain suppression). The basic analgesic properties of alcohol and alcoholic beverages were utilized for hundreds of years in the management of the injured and those requiring surgery. For example, prior to the time of anesthetics, patients were offered brandy to reduce the agonizing pain of amputations. Decline and cessation of these medical uses of alcohol came about with the development of inhalation anesthetics and more efficient analgesics.
Alcohol, Obesity, and Wasting.
In nonalcoholics, calories from alcohol are utilized as efficiently as calories from carbohydrates or fats (and alcohol provides more calories per gram than does carbohydrate). Indeed, while carbohydrate yields 4 kilocalories per gram (kcal/gm) on combustion, when alcohol is combusted in a bomb calorimeter it yields 7.1 kcal/gm. This suggests that when alcohol is consumed in addition to a diet that maintains body weight, weight gain occurs. Fictitious characters such as Shakespeare's Sir John Falstaff provide evidence that obesity was already in the 1600s considered a characteristic of heavy drinkers.
The realization came about gradually that in fact chronic heavy drinking leads not to obesity but to weight loss and an inability to sustain adequate nutritional status. Wasted alcoholics were first portrayed by artists such as William Hogarth (1697-1764) who were intent on showing both the social and medical evils of drinking gin—a recent import from Holland that became a fad. All ages and classes indulged in the new drink at all hours of the day and night. In eighteenth and nineteenth century England, when artists were portraying the physical deterioration associated with heavy gin drinking, it was assumed that drinking eventually led to wasting only because the drunkard was disinterested in food. This idea persisted into the twentieth century. By the 1940s, it was also well recognized that chronic alcoholics are malnourished because of impaired utilization of nutrients.
It is well-known today that, whereas obesity may occur in heavy eaters who consume alcohol, chronic alcoholics are undernourished. Furthermore, studies have shown that long-term, heavy consumption of alcohol in addition to food is not associated with the gain in body weight that would be expected from the calorie intake (Lieber, 1991). In addition, if dietary carbohydrate is replaced by alcohol, weight loss occurs (as in the so-called Drinking Man's Diet of the 1960s and 1970s). This energy deficit has been attributed to induction of the system that metabolizes alcohol and at the same time uses chemical energy and generates heat. Lieber, in reviewing current knowledge of the question, notes that this does not explain the fact that there is little or no weight deficit when alcohol is consumed with a very low-fat diet.
Alcohol and Malnutrition.
Diet-related causes of malnutrition in alcoholics include low dietary intake of calories and nutrients—because of poor appetite, inebriation, and diversion of food dollars into support of the alcohol habit. In addition, malnutrition may be caused by impaired absorption of nutrients, poor nutrient utilization, and increased nutrient losses in body wastes. In 1940, it was suggested that Alcoholism is the major cause of malnutrition in the industrialized world (Jolliffe, 1940). Malnutrition in alcoholics may be caused by impaired absorption of nutrients because of the reduced absorptive capacity of the alcohol-dam-aged gut. Nutrients that are poorly absorbed by alcoholics include the B vitamins—folic acid, thiamin (Vitamin B1), and riboflavin (Vitamin B2). Folic acid deficiency, which causes an anemia, is particularly common in heavy drinkers. Multiple nutritional deficiencies, including deficiencies of water and fat-soluble vitamins, are also common in those alcoholics who have pancreatic and liver disease. Chronic alcoholic pancreatitis (inflammation of the pancreas) develops commonly in people who consume 150 grams or more of alcohol per day for at least ten years and at the same time eat a high-fat diet. The digestive functions of the pancreas become impaired, and therefore food is not broken down into nutrients that can be absorbed. This type of pancreatitis is a major cause of malabsorption of nutrients in alcoholics. Alcoholic cirrhosis is a condition in which liver cells that are responsible for the conversion of nutrients to active forms are replaced by fibrous tissue. Cirrhosis develops slowly in heavy drinkers and is a special risk in those who consume about 35 percent or more of their total caloric intake as alcohol. Cirrhosis is the chief cause of impaired nutrient utilization (Morgan, 1982); however, cirrhosis is caused not by a nutritional deficiency but by the toxic effects of alcohol on the liver (Lieber, 1988).
Mineral and trace-element deficiencies, particularly zinc deficiency, are common in alcoholics. Contributory causes are low intake and increased losses in the urine.
Alcohol, Nutrition, and Brain Damage.
Alcoholics are at risk for brain damage when they go on drinking sprees without food. Evidence exists for this condition only in Caucasians who are genetically predisposed. An acute confusional state may occur, called Wernicke's encephalopathy; this condition can be rapidly reversed if the patient is given massive doses of thiamin, intravenously, within a period of forty-eight hours from the onset of the symptoms. If this acute condition is not treated with thiamin, a chronic state of irreversible brain damage develops, in which there is moderate to severe dementia (Victor et al., 1957).
Alcohol and Heart Disease.
Through the 1990s, evidence indicated that while moderate drinking may reduce the risk of heart disease, alcohol abuse is associated with an increased risk of heart disease. Alcohol has the effect of increasing blood (plasma) levels of high-density lipoproteins (HDL)—and elevation of these blood lipids is associated with a lower risk of heart disease. In a British study (Razay et al., 1992), it was shown that women consuming a moderate amount of alcohol (1-20 gm/day) have lower fat (triglyceride) levels in their blood and higher HDL levels. The authors consider this strong evidence for supporting a lower risk of heart disease. It is important to note that in this study the women who were the moderate drinkers were slimmer than the non-drinking group. Lower body weight, found in this study among the moderate drinkers, is also a known factor in reduced risk of heart disease. Heart disease in alcoholics is due to the direct toxic effects of alcohol on heart muscle (Brigden and Robinson, 1964).
Alcohol and Osteoporosis.
The formation of new bone tissue is reduced in heavy drinkers, and this causes a marked decrease in bone mass and strength, leading to severe osteoporosis. Alcohol abuse is recognized as a risk factor for osteoporosis in both men and women. Because inebriation is also associated with a high risk of falls, alcoholics who have osteoporosis are likely to sustain hip fractures. Low intake of calcium in foods is an additional risk factor for osteoporosis in alcoholics (Bikle et al., 1985).
Methods for Assessing Nutritional Status in Alcoholics.
The methods required for the assessment of caloric and nutrient intake in actively drinking alcoholics include direct observation (seldom feasible outside a treatment facility) and so-called tray weigh back (also feasible only in the detoxification section of a rehabilitation facility, hospital, or nursing home). The term tray weigh back means weighing the food served to a patient, weighing the uneaten food, then computing intake from the difference.
When alcoholics are asked to recount what they have eaten, they tend to confabulate: When asked leading questions, they provide answers that the question indicates are correct or ideal. They may provide the questioner with an account of a make-believe diet, or they exaggerate the amounts of food they have eaten. These responses, which are worthless for the purpose of assessing the amount of calories consumed from food or for assessing the nutrients consumed, are given by alcoholics who may not remember what was eaten and also because they may want to please the dietitian, physician, or nurse seeking information. Not only do alcoholics confabulate, they may also exaggerate the amount they eat, reporting what is served to them rather than what was consumed. (This is also the type of over-reporting of food intake frequently found in people consuming other drugs that suppress appetite.)
The presence of malnutrition is assessed in alcoholics (as well as nonalcoholics) by using anthropometric (body) measurements—including weight-for-height measurements, calculation of the body—mass index (the weight/height squared), and the circumference of the upper arm and the thickness of the fat on the back of the arm. Alcoholics show muscle wasting in the upper arms, which may suggest malnutrition even when body weight is not markedly decreased. Although alcoholics with advanced liver disease are frequently wasted, weight loss may not register in numerical terms because of fluid retention within the abdominal cavity (ascites).
Biochemical measurements are valuable for assessing the nutritional status of alcoholics. The measurement of plasma albumin levels is particularly important—a value of less than 3.5 grams per 100 milliliters of plasma indicates that protein-energy malnutrition exists.
Nutrient Intolerance in Alcoholics with Liver Disease.
Alcoholics with liver disease are very intolerant of high-protein diets. If high-protein diets are provided during periods of nutritional rehabilitation, such alcoholics may develop signs of liver failure. Such alcoholics are also intolerant of Vitamin A if this vitamin is taken in amounts that exceed 10,000 international units (IU) per day. Continued intake of Vitamin A at a high daily dosage level leads to further liver damage and may also precipitate liver failure (Roe, 1992).
Nutritional Rehabilitation of Alcoholics.
Nutritional rehabilitation of alcoholics can be carried out successfully only when abstinence is enforced or the alcoholic voluntarily stops drinking. If the alcoholic has advanced liver disease or impairment of pancreatic function such that digestion and absorption of nutrients is impaired, optimal nutritional status cannot be maintained. The goal of nutritional rehabilitation is the treatment of existing protein-energy malnutrition by increasing caloric intake from carbohydrates and the treatment of existing vitamin, mineral, and trace-element deficiencies. Appetite returns after alcohol withdrawal symptoms have abated; however, recovery of efficient absorption of vitamins may not occur until ten to fourteen days after drinking ceases. Initially, intolerance of milk and other dairy foods is common during rehabilitation, because of lactose intolerance, and extreme caution has to be exercised in diet prescription because of protein intolerance (Roe, 1979).
Smoking diminishes appetite and on average, smokers have lower body weights than nonsmokers. Nevertheless, on average, smokers have greater waist-to-hip circumference ratios than nonsmokers. This suggests that smoking may have an effect on body-fat distribution. Central (torso) adiposity, reflected by this change in circumferential measurements, has been shown to worsen the risk of cardiovascular disease. Cessation of smoking is usually associated with moderate weight gain, caused at least in part by increased food intake (Troisi et al., 1991).
OTHER ADDICTIVE DRUGS
Multiple Substance Abuse and Nutrition. Drug abuse includes the experimental use of various addictive drugs as well as chronic addiction to one or more of these social drugs. The term addiction here refers both to Physical Dependence on the drug, such that when the drug is withdrawn specific physical withdrawal symptoms occur, and to Psychological Dependence on the drug—even without physical dependence. Alcohol has been called the Gateway Drug, because its early use is frequently accompanied by and/or followed by use of other drugs.
Effects of multiple-drug use on nutrition depend on the properties and toxic characteristics of the drug most used, as well as on doses, frequencies, and duration of use/abuse, and the time in life when the drug or drugs are abused. Narcotic drugs, such as Heroin, impair appetite—so food intake is often diminished. If the drug is injected intravenously, malnutrition may be secondary to blood-borne bacterial infection or Acquired Immunodeficiency Syndrome (AIDS). Amphetamine ("speed") is the stimulant drug that has the most inhibitory effect on appetite; if taken in large doses, it also prevents sleep and stimulates activity—therefore energy expenditure may be high and weight loss is common. Cocaine and Crack are also stimulants, they reduce appetite and may in addition induce gastrointestinal symptoms such as nausea, which further lessen food intake (Brody et al., 1990).
Substance Abuse and Nutrition in Pregnancy.
Relationships between substance abuse and impaired nutrition of the fetus and newborn have been summarized in a 1990 report by the National Academy of Sciences, Nutrition during Pregnancy.
Alcohol use during Pregnancy has led to poor birth outcomes. One condition is infants with specific defects in neuronal and cranial development, designated Fetal Alcohol Syndrome. Even the daily drinking of more than two glasses of wine or a daily mixed drink has led to fetal alcohol syndrome, but this condition is most common among the offspring of mothers who are chronic drinkers or binge drinkers.
Alcohol use during pregnancy is also known to be associated with prenatal and postnatal growth retardation. After birth, infants of heavy drinkers may fail to suck, either because of the presence of withdrawal symptoms or because of cleft palate (which may be part of the fetal alcohol syndrome).
Cigarette smoking during pregnancy can affect both maternal and fetal nutrition (Werler et al., 1985). Effects are due to increased metabolic rate in smokers and to toxic effects from tobacco that impair the mother's utilization of certain nutrients, including iron, Vitamin C, folic acid (part of the B complex), and zinc. Low-birthweight infants are more likely to be the offspring of smokers than of nonsmokers—because their caloric intake is likely to be less and because the transfer of nutrients from the mother to the fetus via the placenta may be reduced in smokers.
Cocaine and amphetamine use in pregnancy also lead to increased numbers of low-birthweight infants. This may be caused by low food intake by the mother, since these drugs reduce appetite. The risk of malnutrition in the newborns of women who have used cocaine during pregnancy is caused by the abnormal development of the infant's small intestine. These intestinal disorders in the infant may be extremely severe and may be associated with enterocolitis or bowel perforation, which may be fatal. If these infants survive, special methods of feeding via a vein are required. Although drugs other than cocaine are known to cause constriction of blood vessels in the pregnant woman, none other than cocaine have been shown to produce these bowel disorders in infants (Telsey et al., 1988; Spinazzola et al., 1992).
Anstie, F. E. (1877). On the uses of wine in health and disease. London: Macmillan.
Atwater, W.O., & Benedict, F. B. Experiments on the metabolism of matter and energy in the human body. (Bulletin No. 69). Washington, DC: U.S. Department of Agriculture.
Bikle, D.D. et al. (1985). Bone disease in alcohol abuse. Annals of Internal Medicine, 103, 42-48.
Brigden, W., & Robinson, J. (1964). Alcoholic heart disease. British Medical Journal, 2, 1283-1289.
Brody, S. L., Slovis, C. M., & Wrenn, K. D. (1990). Cocaine-related medical problems: Consecutive series of 233 patients. American Journal of Medicine, 88, 325-330.
Hutchison, R. (1905). Food and the principles of dietetics. New York: W. Wood.
Jolliffe, N. (1940). The influence of alcohol on the adequacy of B vitamins in the American diet. Quarterly Journal of the Study of Alcohol, 1, 74-84.
Lieber, C. S. (1991). Perspectives: Do alcohol calories count? American Journal of Clinical Nutrition, 54, 976-982.
Lieber, C. S. (1988). The influence of alcohol on nutritional status. Nutrition Review, 241-251.
Morgan, M. Y. (1982). Alcohol and nutrition. British Medical Bulletin, 38, 21-29.
Nutrition During Pregnancy. (1990). Washington, DC: National Academy Press.
Razay, G., et al. (1992). Alcohol consumption and its relation to cardiovascular risk factors in British women. British Medical Journal, 304, 80-83.
Roe, D. A. (1992). Geriatric nutrition. Englewood Cliffs, NJ: Prentice Hall.
Roe, D. A. (1979). Alcohol and the diet. Westport, CT:AVI.
Spinnazola, R., et al. (1992). Neonatal gastrointestinal complications of maternal cocaine abuse. New York State Journal of Medicine, 92, 22-23.
Telsey, A. M., Merrit, A., & Dixon, S. D. (1988). Cocaine exposure in a term neonate: Necrotizing enterocolitis as a complication. Clinical Pediatrics, 27, 547-550.
Troisi, R. J., et al. (1991). Cigarette smoking, dietary intake and physical activity: Effects on body fat distribution—the Normative Aging Study. American Journal of Clinical Nutrition, 53, 1104-1111.
Victor, M., Adams, R.D., & Collins, G. H. (1971). The Wernicke-Korsakoff syndrome: A clinical and pathological study of 245 patients, 82 with post-mortem examination. Philadelphia: F. A. Davis.
Werler, M. M., Pober, B. R., & Holmes, L. B. (1985). Smoking and pregnancy. Teratology, 32, 473-481.
Revised by Mary Carvlin
Route of Administration
The mode of drug administration—ingestion (by mouth), insufflation (snorting), inhalation (smoking), or injection (intravenous, subcutaneous, or intramuscular)—can be responsible for a number of medical complications to alcohol and other drug use. In the following, these complications are discussed as direct and indirect results of the various modes (route) of administration in the above order.
COMPLICATIONS DUE TO INGESTION
Ingestion is the way Alcohol, liquid medicines, pills and capsules are usually taken. Ingested drugs enter the gastrointestinal (GI) system, undergo some digestive processing, and enter the bloodstream through the walls of the stomach and intestines. Most medical complications from drug ingestion are a result of the corrosive and irritant effects of the drugs on the GI system. Alcohol and a variety of medicines, including aspirin, can cause intense, localized irritation to the GI mucous membranes, leading to ulceration and GI bleeding. Pharmaceutical manufacturers attempt to decrease the danger of GI irritation by adding buffers to their pills and capsules. Buffers are inert or nonactive ingredients that cushion the corrosive effect of the active ingredients. However, if drug users attempt to dissolve pills intended for oral use and inject them, these buffers will often cause problems, such as abscesses or embolisms.
COMPLICATIONS DUE TO INSUFFLATION (SNORTING)
Medical complications from insufflation (snorting) are usually caused by stimulant drugs, such as the Amphetamines or Cocaine. These drugs are breathed into the nose and absorbed into the blood stream through the capillaries in the nasal mucous membrane. While these drugs cause a certain amount of surface irritation, the major damage is caused by their action as vasoconstrictors—they reduce the diameter of blood vessels, and with chronic use can severely limit the delivery of blood through the capillaries to the inner membranes of the nose. The result of this is that tissue damaged by contact with the drugs is unable to repair itself, and progressive necrosis (tissue death) follows. With chronic cocaine use, this process can result in actual holes through the septum (the dividing tissue) between the nostrils. When tobacco is insufflated as snuff, the risk of cancer of the nasal passages is increased.
COMPLICATIONS DUE TO SMOKING (INHALING)
The fastest delivery of large amounts of drug directly to the brain is through smoking (inhaling). Drugs taken in this way go directly to the lungs and are absorbed along with oxygen directly into the blood heading for the brain. The two terms, smoking and inhaling, as a means of drug intake, are clearly differentiated when, on the one hand, material is actually burned and the resulting smoke is taken into the lungs—as with Tobacco or Marijuana—or on the other hand, when fumes from volatile substances are inhaled, such as glue or gasoline. They may be confused or used interchangeably, however, when material is vaporized through heat and the vapor is inhaled—as with cocaine Freebase (crack).
Smoke from any material will act as an irritant to the lungs and bronchial system, eventually causing problems that can range from chronic bronchitis to emphysema or cancer of the mouth, throat and/or lungs. Both tobacco and marijuana contain a number of tars and potential carcinogens (cancer-triggering substances) and both produce potentially toxic concentrations of carbon monoxide. While it has been argued that tobacco is the worst danger because it is smoked very frequently, it has also been pointed out that the use mode of marijuana is worse—holding the smoke in the lungs for a long time. The argument is moot, since both can produce profound damage. As a vasoconstrictor, nicotine in tobacco promotes mouth ulceration and gum disease. It can be said that people who smoke lose their teeth, while those who don't, don't. Besides its irritant effects, the smoking of tobacco may also promote respiratory disease by weakening the immune system and by paralyzing the cilia (the tiny hairlike organs) in the lungs that push out foreign matter.
The inhalation (sniffing) of volatile hydrocarbons, such as solvents, can cause death by asphyxiation or suffocation, can impair judgment, and may produce irrational, reckless behavior. Abnormalities also have occurred in liver and kidney functions, and bone-marrow damage has occurred. These may be due to hypersensitivity to the substances or chronic heavy exposure. Chromosome damage and blood abnormalities have been reported, and solvents have been cited as a cause of gastritis, hepatitis, jaundice, and peptic ulcers—such effects are due more to the actions of the drugs than to the route of administration. Chronic users have developed slow-healing ulcers around the mouth and nose, loss of appetite, weight loss, and nutritional disorders. Irreversible brain damage has been reported, too. Many deaths attributed to solvent inhalants are caused by suffocation when users pass out with the plastic bags containing the substance still glued to their noses and mouths. There is also a very real danger of death from acute solvent poisoning or aerosol inhalation. The mere provision of adequate ventilation and the avoidance of sticking one's head in a plastic bag are by no means sufficient safeguards against aerosol dangers.
Other hazards may include freezing the larynx or other parts of the airway when refrigerants are inhaled, and potential spasms as these areas defrost. Blockage of the pulmonary membrane, through which oxygen is absorbed into the lungs, can occur. Death may also result from the ingestion of toxic ingredients along with the aerosol substance. The possibility is made more likely by the fact that commercial products not produced for human consumption are not required to list their ingredients on the label. Individual substances may produce a spectrum of toxic reactions depending on their contents. These have included gastric pain, headaches, drowsiness, irritability, nausea, mucous-membrane irritation, confusion, tremors, nerve paralysis, optic-nerve damage, vomiting, lead poisoning, anemia, and so on. The inhaling of aerosol fluorocarbons can cause "sudden-sniffing death" (SSD), wherein the heart is hypersensitized to the body's own hormone epinephrine (adrenaline), leading to a very erratic heartbeat, increased pulse rate, and cardiac arrest.
The inhaling of amyl, butyl or isobutyl nitrites can cause intense headaches, an abrupt drop in blood pressure, and loss of consciousness through orthostatic hypotension (increased heart rate and palpitations), with a threat of myocardial infarction (heart attack).
COMPLICATIONS DUE TO INJECTION
The injection of drugs generally involves the use of the hypodermic needle, first invented in the early nineteenth century and used initially for the medical delivery of the opiate painkiller Morphine, for the rapid control of intense Pain. This combination was first used extensively for battlefield wounds during the Crimean War (1853-1856) and the American Civil War (1861-1865). As its name implies, the hypodermic needle pierces the skin—the dermis. Hypodermic injections may be subcutaneous, directly beneath the skin surface; intramuscular, into the muscle tissue; or intravenous, into a blood vessel. (Note : Although a number of injection-related medical complications are directly skin-related, these are discussed in the article Complications: Dermatological.
While the hypodermic needle is the primary means of drug injection, drug addicts who do not have access to hypodermics have made use of a number of ingenious, and often very dangerous, substitutes. Nonhypodermic-needle means of injection may involve such paraphernalia as lancets or scalpels, or any small sharp blade to make an opening, and the insertion of an eyedropper, tubing and bulb, or any means of squirting the drug into the resultant wound. In extremes, addicts have used such implements as a pencil, ballpoint or fountain pen, or the sharpened end of a spoon.
Injections are never made intentionally into arteries. Accidental intra-arterial injection will produce intense pain, swelling, cyanosis (blueness), and coldness of the body extremity injected. Intra-arterial injection resulting in these symptoms is a medical emergency and, if untreated, may produce gangrene of the fingers, hands, toes, or feet and result in loss of these parts.
Transmittal of Disease through Injection.
The greatest number and variety of medical complications of drug use caused by the mode of administration occur as a result of injection. Among the highest risk, and that with the most frequent fatal and disabling consequences is the transmittal of disease through the use of unsterile needles and the sharing of such needles.
Human Immunodeficiency Virus (HIV). Needle-using drug abusers comprise one of the primary high-risk populations for contracting human immunodeficiency virus (HIV). The primary recognized routes of transmission for HIV are (1) sexual contact through unprotected anal or vaginal inter-course—particularly if there are damaged tissue or sores present that provide direct access to the bloodstream; (2) contact with infected blood through needle sharing or through transfusions of blood or blood products; and (3) in utero or at-birth transmission from a mother to her baby. Acquired Immunodeficiency Syndrome (AIDS), the most severe and life-threatening result of HIV infection, involves the destruction of a person's immune system and the development of cancers and infections that can no longer be fought off.
The incidence of HIV infection among needle-using drug abusers is closely related to local use traditions, habits, and the prevalence of HIV infection among other addicts. The highest incidence is in areas such as New York City, where there is a tradition of needle sharing or where "shooting galleries"—places where users can rent or share "works"—are commonly utilized and where there was a high prevalence of HIV among the homosexual population. Users in other geographical locations, such as San Francisco, seem to be more conservative in their social-usage patterns, and when they do share needles, tend to keep the same "shooting partners" over a longer period of time. HIV-prevention efforts in some areas have focused on Needle and Syringe Exchange, while others, particularly where needle exchange is not legalized, have community-outreach workers teaching users how to sterilize their needles between each use with household bleach. The gist of both campaigns is that users who share their needles or who use dirty needles are at risk for contracting HIV through their drug use. Those who use sterile needles are not. Both approaches are considered stopgap, however, and are apt to be condemned as "encouraging of drug abuse."
All needle-using drug abusers are considered at extremely high risk for HIV infection, and HIV screening is performed routinely at most drug-treatment centers. The virus has a very long incubation period and may be present for seven or more years before active symptoms of opportunistic disease appear. Early symptoms may include: a persistent rash or lesion; unexplained weight loss; persistent night sweats or low-grade fever; persistent diarrhea or fatigue; swollen lymph glands: Depression or states of mental confusion.
Hepatitis and Other Liver Disorders. Hepatitis B, and related strains, often referred to as serum (fluid-related) hepatitis, are the most common medical complication of needle drug use. Like HIV, hepatitis can spread in other ways than needle use, such as sexual intercourse or other direct sharing of blood and bodily fluids. Several strains, however, can be spread by contaminated foods, particularly shellfish, or by unhygenic practices in food handling. Current research indicates that some forms of hepatitis spread via an anal/oral progression—so it is recommended that hands are washed thoroughly after all bowel movements or any other anal-area or fecal-matter handling, as a means of prophylaxis.
Unlike AIDS, hepatitis is often not fatal if it is detected and treated at an early stage. Symptoms of all forms of hepatitis include fatigue, loss of appetite, pain in the upper abdomen, jaundice—yellow skin and a yellowish-to-chartreuse tinge to the sclerae (white of the eye), general itching, dark urine reaching the color of cola drinks with light-tan to cream-colored feces, and mental depression. Gamma globulin injection can provide short-term immunity to all forms of hepatitis and can reduce the symptoms of serum hepatitis if it is given during the gestation period. Treatment includes bed rest, nutritional support, and avoidance of alcohol or any other substance that may further irritate the liver. Caregivers should wear rubber gloves for handling patients. Patients with any form of hepatitis should avoid preparing food for others and use separate towels, bedlinens, and eating utensils until symptoms disappear. Toilet seats and any spilled bedpan matter should be disinfected and hands should then be washed thoroughly with soap. Condoms should be used for any genital contact.
Hepatitis can cause hepatic fibrosis—the development of fibrous tissue in the liver. It can also cause or exacerbate cirrhosis (scarring of the liver), although this is most often a result of chronic alcohol abuse. Symptoms of cirrhosis include jaundice (yellowish skin and eye whites), fatigue, ankle swelling, enlargement of the abdomen, and a full feeling in the right upper abdomen.
Tetanus and Malaria. According to Senay and Raynes, the first case of tetanus associated with needle-using substance abuse was reported in England in 1886. By the 1990s, between 70 and 90 percent of tetanus cases have occurred to drug abusers. As a medical complication to drug injection, tetanus most often occurs from "skin-popping"—which is cutaneous injection. A majority of cases occur in women, and this is attributed to less-substantial venous development than in men and a smaller population with tetanus immunization.
Malaria (caused by the Plasmodium parasite) was first reported among drug users in the United States in 1926. It affects intravenous drug abusers and was brought to this country by needle-sharing sailors who had been exposed to malaria in Africa. The initial outbreak in New Orleans spread to New York City in the 1930s and resulted in several hundred deaths from tertian malaria among drug abusers. A second outbreak occurred in the 1970s, as a result of malaria-infected veterans returning from Vietnam.
The spread of both these diseases among needle-sharing drug abusers has been kept somewhat in check, particularly on the East Coast and in Chicago, by the inclusion of 15 to 30 percent quinine (a natural antimalarial), as filler, to stretch profits in illicit opioid drug mixtures in those areas. Quinine (an alkaloid from chinchona bark) is a protoplasmic poison that prevents the germination of the fastidious tetanus anaerobe, Clostridium tetani, under the skin and in adjacent muscle tissue. Although the quinine amount is not sufficient to eradicate malaria once it has taken hold in the body, it does help prevent the disease by killing the malarial parasites in the hypodermic syringe.
COMPLICATIONS TO HEART AND BLOOD VESSELS
Drug abuse is related to a number of heart and blood vessel medical complications. Some of these, such as alcohol cardiomyopathy, are a direct result of the drug's toxic effects. Others are at least partially related to needle use.
Endocarditis, an infection of the tissues in the heart, usually a heart valve, is a progressive disease characterized by frequent embolization (obstruction of blood vessels) and severe heart-valve destruction that can be fatal if not treated. This disease can result from repeated injection of the infective agents into the blood system, usually from nonsterile needles and/or unusual methods of injection. Infective endocarditis is highly prevalent among drug abusers and should be suspected in any needle-using abuser who shows such symptoms as the following: fever of unknown origin; heart murmur; pneumonia; embolic phenomena; blood cultures that are positive for Candida, Staphylococcus aureus or enterococcus, or Gram-negative organisms.
Blood-vessel changes caused by necrotizing angiitis (polyarteritis—the inflammation of a number of arteries) or a swelling that leads to tissue loss have been demonstrated in intravenous amphetamine abusers, resulting in cerebrovascular occlusion (blockage in brain blood vessels) and intracranial hemorrhage or stroke.
Problems in the lungs often develop from inert materials that are included as cutting agents or as buffers and binding agents in drugs that come in pill form but are liquified and injected. These substances do not dissolve, so their particles may become lodged in the lungs, causing chronic pulmonary fibrosis and foreign-body granulomas. These same buffers and binding agents may as well become lodged in various capillary systems, including the tiny blood vessels in the eye.
Finally, injection-induced infections reaching the skeleton can be responsible for such bone diseases as septic arthritides and osteomyelitis. Gangrene can develop from cutting off circulation to the extremities and may necessitate amputation or be fatal.
(See also: Inhalant Abuse and Its Dangers ; Needle and Syringe Exchange and HIV/AIDS )
Cohen, S., & Gallant, D. M. (1981). Diagnosis of drug and alcohol abuse. Brooklyn: Career Teacher Center, State University of New York.
Senay, E. C., & Raynes, A. E. (1977). Treatment of the drug abusing patient for treatment staff physicians. Arlington, VA: National Drug Abuse Center.
Seymour, R. B., & Smith, D. E. (1990). Identifying and responding to drug abuse in the workplace. Journal of Psychoactive Drugs, 22 (4), 383-406.
Seymour, R. B., & Smith, D. E. (1987). The physician's guide to psychoactive drugs. New York: Hayworth.
Wilford, B. B. (1981). Drug abuse: A guide for the primary care physician. Chicago: American Medical Association.
David E. Smith
Richard B. Seymour
Revised by Ralph Myerson
REGAN, TIMOTHY; SAPORITO, ROBERT; HOMBURG, ANDREW J.; MARTIN, PETER; MATHEWS, GEORGE; SMITH, DAVID E.; SEYMOUR, RICHARD B.; MYERSON, RALPH; BROWN, LAWRENCE S.; MYERSON, RALPH; WATSON, RONALD R.; LIEBER, CHARLES S.; MYERSON, RALPH; DEVENYI, PAUL; MYERSON, RALPH; SULLIVAN, JOHN T.; MYERSON, RALPH; COOK, BRIAN L.; WINOKUR, GEORGE; HAYES, DANIEL P.; CARLEN, PETER L.; MCANDREWS, MARY PAT; CARVLIN, MARY; ROE, DAPHNE; CARVLIN, MARY; SMITH, DAVID E.; SEYMOUR, RICHARD B.; MYERSON, RALPH. "Complications." Encyclopedia of Drugs, Alcohol, and Addictive Behavior. 2001. Encyclopedia.com. 26 Aug. 2016 <http://www.encyclopedia.com>.
REGAN, TIMOTHY; SAPORITO, ROBERT; HOMBURG, ANDREW J.; MARTIN, PETER; MATHEWS, GEORGE; SMITH, DAVID E.; SEYMOUR, RICHARD B.; MYERSON, RALPH; BROWN, LAWRENCE S.; MYERSON, RALPH; WATSON, RONALD R.; LIEBER, CHARLES S.; MYERSON, RALPH; DEVENYI, PAUL; MYERSON, RALPH; SULLIVAN, JOHN T.; MYERSON, RALPH; COOK, BRIAN L.; WINOKUR, GEORGE; HAYES, DANIEL P.; CARLEN, PETER L.; MCANDREWS, MARY PAT; CARVLIN, MARY; ROE, DAPHNE; CARVLIN, MARY; SMITH, DAVID E.; SEYMOUR, RICHARD B.; MYERSON, RALPH. "Complications." Encyclopedia of Drugs, Alcohol, and Addictive Behavior. 2001. Encyclopedia.com. (August 26, 2016). http://www.encyclopedia.com/doc/1G2-3403100132.html
REGAN, TIMOTHY; SAPORITO, ROBERT; HOMBURG, ANDREW J.; MARTIN, PETER; MATHEWS, GEORGE; SMITH, DAVID E.; SEYMOUR, RICHARD B.; MYERSON, RALPH; BROWN, LAWRENCE S.; MYERSON, RALPH; WATSON, RONALD R.; LIEBER, CHARLES S.; MYERSON, RALPH; DEVENYI, PAUL; MYERSON, RALPH; SULLIVAN, JOHN T.; MYERSON, RALPH; COOK, BRIAN L.; WINOKUR, GEORGE; HAYES, DANIEL P.; CARLEN, PETER L.; MCANDREWS, MARY PAT; CARVLIN, MARY; ROE, DAPHNE; CARVLIN, MARY; SMITH, DAVID E.; SEYMOUR, RICHARD B.; MYERSON, RALPH. "Complications." Encyclopedia of Drugs, Alcohol, and Addictive Behavior. 2001. Retrieved August 26, 2016 from Encyclopedia.com: http://www.encyclopedia.com/doc/1G2-3403100132.html