/ournal

of Substance

Abuse,

4, 69-90

(1992)

Abuse of Drugs Associated with Eating Disorders Cynthia.M. Bulik University Christchurch,

of Canterbury New Zealand

Concomitant bulimia nervosa and drug abuse are common in women. Drugs used by this group include diuretics, emetics, laxatives, and diet pills, as well as alcohol, cigarettes, and illicit street drugs. This paper applies principles from behavioral pharmacology to the problem of drug use by women with bulimia nervosa. The prevalence of use. primary effects, toxicity, detection, tolerance, withdrawal, and effects on appetite and weight are discussed for drugs used by bulimic women to reduce appetite or weight or to induce purging (e.g., diuretics, emetics, laxatives, and diet aids). Alternatives in the diagnosis and treatment of drug use in women with eating disorders are discussed.

Clinicians and researchers have become increasingly impressed with the high rates of substance use and abuse by women with eating disorders. Studies of drug use in this group focus on two seemingly disparate aspects of drug selfadministration. The first is the use of pharmacologic agents for the purpose of weight loss or to induce purging. Among these drugs are prescription and overthe-counter (OTC) diet pills (Mitchell, Hatsukami, Eckert, & Pyle, 1985) laxatives (Bulik, Epstein & Kaye, 1990; Bulik et al., in press; Pyle, Mitchell, & Eckert, 1981), diuretics (Bulik et al., in press; Mitchell et al., 1985; Pyle et al., 1981) and emetics (Bulik et al., in press; Pope, Hudson, Nixon, 8c Heridge, 1986). Reports have also cited use of thyroid hormone (Bulik et al., in press), fluoxetine (Wilcox, 1987) tobacco (Short & Blinder, 1985), sorbitol (Ohlrich, Aughey, & Dixon, 1989) enemas (Coovert & Powers, 1988), bran (Bulik, in preparation), and heroin (Mitchell, 1987) either for their weight loss effects or their ability to induce emesis. The second area focuses on high rates of use and abuse of more typical drugs such as cigarettes, alcohol, and illicit street drugs. This review focuses primarily on the former category. Given the high rates of use of these drugs by women with eating disorders, strikingly little attention has been given to how their use affects clinical course and outcome. Likewise, there has been insufficient exploration of how these drugs affect appetite, weight, and metabolism. In the absence of these data, this review covers the prevalence of use, primary effects on appetite and weight, toxicity, detection, tolerance and withdrawal reactions associated with diuretics, emetics, laxatives, and diet pills Special thanks to Patrick F. Sullivan and Leonard H. Epstein for their thoughtful manuscript. Correspondence and requests for reprints should be sent to Cynthia M. Bulik, Psychology, Private Bag, University of Canterbury, Christchurch 1, New Zealand.

comments

on

Department

of

this

69

70

.

Table

1.

Drug

Use

Study

with

Eating

Bulik

Disorders

Dx Instrument

Mean

Age

% Users

B

34

DSM

III

-

29

1985

B

275

DSM

III

24.8

34

et al., in press

B A

42 29

DSM

III-R

22 + 6 20 + 11

33 7

1986

B

100

-

-

28

et al., 1985

B

275

DSM

et al., in press

B A

42 29

DSM-III-R

22 e 6 20 f 11

26 4

A AB B

56 49 34

Feighner Clinical

Assessment

20 + 6 20 f 5 -

27 37 53

B

32

Clinical

Assessment

24

75

B

80

Self-report

-

33

724

Self-report

-

50

Use

Mitchell

1981

et al.,

Emetic

Use

Pope

et al.,

Mitchell Bulik

Laxative

Pill

Mitchell 1985

III

24.8

1

Use

Casper et al., 1980 Pyle et al., 1981 Abraham & Beaumont, 1982 Johnson & Berndt. 1983 Fairburn & Cooper, 1984a Fairburn & Cooper, 1984b Lacey & Gibson, 1985 Mitchell et al., 1985 Bulik et al., in press

*A

Women N

Pyle et al.,

Diet

in

Dx*

Diuretic

Bulik

CM

AB B

35

Russell

criteria

24 2 4

31

B

30

Russell

criteria

-

30

B

275

DSMIII

24.8

61

B A

42 29

DSM

III-R

22 + 6 20 2 11

62 19

B

275

DSM

111

24.8

52

Use et al.,

= anorexia

neruosa;

B =

bulimia

or bulimia

nervosa;

AB

= anorexia

and

bulimia

nt-wosa.

pills containing phenylpropanolamine (PPA). In addition, alternatives for the diagnosis and treatment of women with eating disorders and concurrent use of these substances are discussed. Table 1 presents a selection of studies that report rates of use of drugs to produce weight loss or to maintain weight or to induce purging. Overall, the study of drug use in women with eating disorders has been limited by methodology. In general, investigations have relied on self-report or clinical interviews to establish rates of use. No studies have directly measured drug use by employing physiological assay methods such as alkalinization of urine for detecting use of certain types of laxatives. Few studies provide control samples, and many include subjects that vary widely in age and comorbid psychiatric conditions. In addition, the absence of clear definitions of abuse for drugs such

Eating

Disorders

and

Drug

Use

71

as laxatives and diuretics, coupled with the potential inaccuracy of self-report, contribute to the unreliability of estimates. Despite these limitations, most studies show extensive use of drugs in women with eating disorders and substantially more use in bulimic than anorectic women. DIURETICS Prevalence The use of diuretics by individuals with eating disorders was first documented in patients with anorexia nervosa (Davidson & Silverstone, 1972; Wolff, et al., 1968). Approximately 33% of anorectic and bulimic women use diuretics (Powers, Schulman, Gleghorn, & Prange, 1987; Pyle et al., 1981) Mitchell et al. (1985) noted that 1% of 275 women with bulimia reported using diuretics on a daily basis. Bulik et al. (in press) found that 33% of bulimic women and 7% of anorectic women reported using diuretics at least once for weight loss during the course of the illness. It appears that a large number of women with eating disorders try diuretics, but few maintain continued use. Primary

Effects

The use of diuretics for purposes of weight control has received comparatively little attention in individuals with eating disorders. The most common uses of these preparations are for control of weight gain secondary to premenstrual water retention. Several types of diuretics are available both OTC and in prescription form (Table 2). Briefly, three commonly prescribed types are loop, thiazide, and potassium-sparing diuretics. The loop agents include furosemide and ethacrynic acid derivatives. Furosemide is extremely potent and inhibits the reabsorption of sodium and chloride in the proximal and distal tubules in the loop of Henle (Schuster, Weil, Besso, Carpio, & Henning, 1984; Warnock, 1989). Thiazide diuretics (chlorothiazide and hydrochlorothiazide) inhibit sodium reabsorption in the early segments of the distal tubule (Warnock, 1989). Finally, the potassium-sparing diuretics function by antagonizing the effects of aldosterone at the cortical collecting tubule (Warnock, 1989). OTC diuretics generally contain pamabrom, caffeine, ammonium chloride, or all three. Pamabrom and caffeine are xanthine diuretics, which may act directly on the renal tubules, increasing sodium excretion without significant potassium loss (Physicians’ Desk Reference for Nonprescription Drugs, 1989). Toxicity

and Detection

Signs of toxicity from loop agents include hypokalemia, metabolic alkalosis, magnesium depletion, orthostatic hypotension, and ototoxicity (Block, Shiner, & Roman, 1978; Schuster et al., 1984). Signs of toxicity from thiazide diuretics include fatigue, parasthesias, hypokalemia, metabolic alkalosis, hyponatremia, hyperuricemia, and hyperlipidemia (Ashraf, Locksley, 8c Arieff, 1981; Hollifield & Slaton, 1981). Toxic side effects from the potassium-sparing diurectics include hyperkalemia and hyperchloremic metabolic acidosis (Steinmetz & Koeppen, 1984).

.

72

CM.

Table 2. OTC and Prescription

Diuretics

Unit

Active

DimensynT”‘, Midola Extra Strength PMS, and Premesyn

1 Capsule

25 mg pamabrom 500 mg acetaminophen 15 mg pyrilamine maleate

2 Gap/3-4 h IO-day maximum Max. 8 Cap/day

Odrinil”

1 Tablet

25 mg pamabrom

2 Tab/3-4

1 Caplet@

454 mg aspirin 14.9 mg cinnamedrine 32.4 mg caffeine

HCl

2 Gap/3-4 h Max. 8 Cap/day

500 mg aspirin 14.9 mg cinnamedrine 32.4 mg caffeine

HCI

2 Cap14 hours Max. 8 Cap/day

Product

Bulik

Ingredients

Recommended

DosaKe

OVER-THE-COUNTER

Midol@

Midol@

Original

Formula

for Cramps

1 Caplet@

use

h

PRESCRIPTION Loop-diuretics Bumaxa Lasixa Thiazide diuretics Hydrochlorothiazide Potassium-sparing Aldactone” Dyazidea

1 Tablet 1 Tablet

0.5, 1, or 2 mg bumetamide 20, 40. or 80 mg furosemide

1 Tablet

25 or 50 mg hydrochlorothiazide

1 Tablet 1 Capsule

25, 50, or 100 mg spironolactone 25 mg hydrochlorothiazide 50 mg triamterene

diuretics

OTC diuretics are generally considered safe when used within recommended guidelines. When used in greater quantities, ammonium chloride can produce nausea, vomiting, and gastrointestinal distress and is dangerous for individuals with renal or hepatic disease. Obviously, misuse of caffeine can produce the expected effects of caffeine intoxication including restlessness, insomnia, irritability, nervousness, diuresis, and gastrointestinal disturbances. Individuals who use diuretics or are suspected of using them should be carefully evaluated medically for serum electrolyte and cardiac complications due to hypo- or hyperkalemia. Mitchell, Pomeroy, and Huber (1988) recommended checking serum electrolytes, BUN, creatinine, glucose, uric acid and calcium, plus doing an electrocardiogram with rhythm strip. If the clinical situation warrants tests of arterial blood gas, muscle enzymes, lipid levels, magnesium levels, and zinc levels, and an elecromyogram also may be useful. Tolerance

and Withdrawal

Tolerance does develop to the diuretic effects of prescription agents (Cook & Smith, 1987; Hammarlund & Paalzow, 1985; Sjostrom, 1988). often leading the individual to take more of the drug to achieve the same effect or to opt for a stronger preparation. However, continued use may initiate and perpetuate a cycle of diuresis and reflex water retention. As suggested by Mitchell et al. (1988), in individuals with an eating disorder, normal weight fluctuations may

Eating

Disorders

and Drug

Use

73

be cues for diuretic use. Discontinuation of the diuretic then leads to reflex fluid retention, which itself is perceived as fatness or bloatedness and can be a cue for further use. These parameters have been investigated in case reports of women with edema secondary to diuretic abuse. In these studies, discontinuation of diuretics in chronic users initially leads to rebound edema and weight gain, which then normalize over a period of days to weeks (de Wardener, 1981; MacGregor, Markandu, Roulston, Jones, & de Wardener, 1979; MacGregor, Tasker, & de Wardener, 1975). Interestingly, many of the case reports suggest that women with. edema secondary to diuretic abuse may have had undetected eating disorders. The authors hinted at weight concerns, but the diagnosis of an eating disorder was not pursued. Given the discomfort that bulimic and anorectic women have with even temporary weight gain and edema, they are unlikely to allow reequilibration after discontinuation of diuretic use and then may take additional diuretics to counter the reflex edema. Similarly, constipation secondary to diuretic abuse can prompt laxative use, leading to further diuresis and electrolyte abnormalities. As suggested by Mitchell et al. (1988), tapering off of diuretics may be important in conjunction with a sodium-restricted diet to limit water retention. Potassium replacement also may be necessary. Effects

on Appetite

and

Weight

Although no data exist on the efficacy of diuretics for the maintenance or loss of weight, it is highly unlikely that they are effective in producing any real or sustained weight loss. The perceived “benefits” of diuretic use for the eatingdisordered woman stem from their relatively rapid ability to reduce real or perceived water retention and to create a sense of weight loss through diuresis. These effects may produce an immediate feeling of weight loss, accompanied by the shedding of a few pounds of water, but the effects are short-lived. To date, there are no data on the direct effects of diuretics on appetite in individuals with eating disorders. EMETICS Prevalence

The most common emetic agent used by women with eating disorders is syrup of ipecac (Mitchell et al., 1988). For individuals who are unable to selfinduce vomiting, ipecac is a cheap and readily available OTC drug. Pope et al. (1986) found that 28% of 100 bulimic women reported using ipecac at least once. Our survey information confirms these findings, with 26% of women with bulimia nervosa and 4% of women with anorexia nervosa reporting use of ipecac at least once (Bulik et al., in press). Primary

Effects

Ipecac contains the active ingredients emetine, cephaline, and psychotrine. Both cephaline and emetine produce nausea and vomiting; however emetine has greater toxicity (Manno 8c Manno, 1977). Ipecac produces emesis both

74

.

CM

Bulik

through direct peripheral action on the gut and through central activity. Early vomiting (within 30 min. of ingestion) is thought to be due to the direct action on the gastrointestinal tract, whereas later vomiting results from its central action on the medullary chemoreceptor trigger zone (Weaver & Griffith, 1969). The recomended dosage of ipecac is 1 or 2 Tbs as a treatment for oral ingestion of certain poisons or intoxicants. Only the syrup form is currently available in the United States after reported accidental overdoses from the ipecac fluid extract, which was 14 times stronger than the syrup. Toxicity

and Detection

Emetine is cleared from the body very slowly, thus magnifying the risks of toxicity. Gimble, Davison, & Smith (1948) have shown that approximately 35% of the drug is retained in mammals after 35 days. They suggest that toxicity from repeated small doses and from a single large dose is equally dangerous. The slow clearance rate of ipecac can produce severe and even lethal gastrointestinal, cardiac, and neuromuscular complications. Protracted bloody diarrhea and vomiting may occur. The cardiac complications associated with ipecac toxicity include tachycardia, precordial chest pain, dyspnea, hypotension, cardiac dilatation, cardiac arrhythmias, and potential cardiac arrest. In addition to the gastrointestinal and cardiac effects, emetine also produces muscular weakness that can persist for weeks to months after cessation (Bindoff & Culen, 1978; Bradley, Fewings, Harris, &Johnson, 1976; DeVeve 8c Bradley, 1975; Duane & Engle, 1970; Klatskin & Feidman, 1948). Although the myopathy associated with ipecac use is occasionally reversible upon cessation of drug use (Bennett, Spiro, Pollack, 8c Zucker, 1982) lethal doses can be approached with repeated and regular ingestion. Several case reports of severe complications or death from ipecac misuse in individuals with eating disorders have been published (Bennett et al., 1982; Ferguson, 1985; Friedman, 1984; Friedman, Seime, Roberts, & Fremouw, 1987; Mateer, Farrell, Chou, & Gutmann, 1985; Moldowsky, 1985; Palmer & Guay, 1985; Schiff, et al., 1986). The presenting complaints of individuals who use ipecac are usually nausea, vomiting, and muscle weakness. It has been estimated that a single dose of 600-1200 mg of emetine is lethal to an adult. Friedman (1984) reported a case in which death occurred with 60-90 cc/day of ipecac over a S-week period. He suggested that any eating-disorder patient who complains of generalized muscle weakness, dysphagia, and tachycardia and has accompanying elevated hepatic transaminases, creatinine phosphokinase, and erythrocyte sedimentation rates, as well as EKG abnormalities, should be suspected of ipecac use. Tolerance

and Withdrawal

Although little research has been conducted on the behavioral pharmacology of ipecac, case reports of individuals who have used the drug over an extended period of time suggest that tolerance may develop to its emetic effects. A case report by Palmer and Guay (1985) indicated that, after several weeks of regular ipecac use, vomiting was no longer produced by each dose, but diarrhea and

Eating

Disorders

and Drug

Use

75

tachycardia persisted. Adler, Walinsky, Krall, and Cho (1980) also have shown that repeated use of ipecac decreases its capacity to induce vomiting, which can lead to greater systemic absorption and more adverse cardiac and neuromuscular effects. These findings suggest that tolerance to different effects of the drug may develop at different rates or to different extents. Tolerance m.ay develop more rapidly or more completely to the emetic than to the cardiac effects. With emesis being the primary drug effect sought by the eating-disorder patient, the drug dose then would increase in response to tolerance to the desired effect. The combination of taking more drug in response to tolerance, the slow or absent tolerance to the cardiac effects, and the slow clearance rate of the drug, can produce fatal consequences. No data are available concerning withdrawal effects from ipecac. Effects

on Appetite

and Weight Loss

Emetine has been reported to produce weight loss in animals and humans (Salako, 1970a, b); however, it is difficult to separate the direct effects of emetine on body weight from the effects of the disease states that emetine is being used to treat (e.g., dysentery). There are no data that examine the actual effects of ipecac on weight loss or maintenance in individuals with eating disorders. However, the fact that vomiting is an effective method of counteracting. weight gain associated with binge-eating (Lacey & Gibson, 1985), coupled with the possible direct weight-loss effects of emetine, suggest that the use of ipecac may indeed produce the desired effect of immediate weight loss for individuals with eating disorders. Water loss from the secondary diarrhea may also produce sensations of weight loss and shedding of water weight. The fact that short-term weight reduction may be an immediate effect of ipecac increases the likelihood of continued use in these patients. Its associated gastrointestinal, cardiac, and neuromuscular complications make it one of the most lethal methods of weight control. Its potential for misuse has led some to suggest that ipecac should become a prescription medication (Friedman, 1984). However, this view is generally thought to be outweighed by its beneficial use in countering accidental household poisonings. LAXATIVES Prevalence Between 38% and 75% of women with bulimia nervosa use laxatives (Abraham & Beumont, 1982; Casper, Eckert, Halmi, Goldberg, & Davis 1980; Johnson & Berndt, 1983; Mitchell et al., 1985; Pyle et al., 1981). Bulik et al. (in press) found that 62% of 42 inpatient bulimic women and 19% of 27 anorectic women reported regular laxative use. Laxative use occurs in women with bulimia nervosa both as an auxiliary method of purging and as the sole means of purgation. Mitchell, Boutacoff, Hatsukami, Pyle, & Eckert (1986) suggest that eatingdisorder patients who abuse laxatives may be more severely psychiatrically disturbed than those who do not. Furthermore, they found that individuals who

.

76 Table

3.

C.M.

Common

OTC

Category Subclassifications Product examples Stimulant Laxatives Diphenylmethanes Correctol@ & Feen-a-mint” Ex-Lax@ Evac-U-Gena Dulcolaxa Carters Pills@

1

& Little

Bulik

Laxatives

Dosage

Unit

Active

Ingredients

I Tab

1 Tab/bedtime

1 Tab I Tab

100 mg docusate sodium 65 mg phenolphthalein 90 mg yellow phenolphthalein 97.2 mg yellow phenolphthalein

l-2 l-2

Tabs/bedtime Tabs/bedtime or morning

I Tab

5 mg bisacodyl

l-3

Tabs/day

1 Tab

150 mg cascara sagrada 100 mg aloe 30 mg casanthranol 100 mg docusate sodium 50 mg docusate sodium 60 mg docusate sodium 50 me danthron 75 mg danthron

2 Tabs/day

5 ml magnesium hydroxide 3.5 g psyllium. 3.5 g dextrose 2 mg sodium, 37 mg potassium 3.25 g psyllium, 0.74 g senna, 1.8 mg sodium, 35.5 e ootassion

2-4 Tbs 1 tsp l-3

l-3

1 Tbs

30 mg magnesium mineral oil 4.2 g mineral oil

1 Tbs

2 g methylcellulose

I tsp

3.4 g psyllium mucilloid

I

Anthraquinones Natures Remedy@ Peri-colace”

I Cap

Senokot” Doxidana

1 Tab I Cap

Modane@

I Tab

1-2

Caps/bedtime

2 Tabs/bedtime l-2 Caps/bedtime

”

Saline Purges Milk of Magnesia@ Modane@ Bulk Perdiem”

Emollient Haley’s

1 Tbs 1 tsp I tsp

Laxatives Moe’

AgoralaD Bulk-forming Citrucela Metamucila Fiberall’”

I Tbs

hydroxide

1 Tab/each

l-2

meal

Xlday

tsplbedtirne or morning

Tbs/bedtime or morning l-2 Tbs/bedtime

Laxatives

8s

hydrophilic

I Tbs for I tsp for

3-4 2-3 l-3 2-3

S/day days X/day days

who abused laxatives also tended to rely on other pharmacologic agents for weight loss, such as diuretics, emetics, and diet pills. In addition, they more frequently used saunas, chewed and spit out food, engaged in self-injurious behavior, attempted suicide and were hospitalized for depression than patients who relied solely on vomiting as a means of purgation. Primary

Effects

Several different types of OTC laxatives exist that vary in their mechanisms of action, effectiveness, side effects, and medical complications (Table 3). Laxative abuse has been recognized as a syndrome in and of itself, as well,as being secondary to a documented eating disorder (Cummings, 1974; deWolff,

Eating

Disorders

and Drug

Use

77

deHaas, & Verweij, 1981; Mitchell et al., 1986; Oster, Masterson, & Regas, 1980; Sekas, 1987). Stimulant laxatives, especially those containing phenolphthalein, appear to be those most frequently used by women with eating disorders (Bulik et al., in press; Mitchell et al., 1986). Included in the category of stimulant laxatives are castor oil, the diphenylmethanes (phenolphthalein and bisacodyl), and the anthraquinones (cascara, senna, aloe, and danthron). Phenolphthalein, the active ingredient in Corectol@ and ExLax’s’, acts directly on intestinal smooth muscle to increase propulsive peristaltic activity(MacCara, 1982; Sekas, 1987). The anthraquinone laxatives include cascara, senna, aloe, and danthron. These laxatives cause water and electrolytes to accumulate in the colon, thus stimulating laxation (Sekas, 1987). The osmotic laxatives, or saline purges, include magnesium sulfate (Epsom salts), magnesium hydroxide (milk of magnesia), sodium sulfate (Glauber’s salts), magnesium citrate, and sodium potassium tartrate (Rochelle salt, Seidlitz powder). Saline purges are administered orally or as enemas or suppositories. Orally administered agents retain fluid in the bowel lumen and increase stool bulk (Cummings, 1974). The suppositories create carbon dioxide in the bowel, which exerts pressure on the rectum and produces the urge to defecate (Sekas, 1987). The emollient laxatives, also known as stool softeners, are anionic surfactants, which lower fecal surface tension and allow aqueous and fatty substances to mix and soften stool (Sekas, 1987). They also stimulate fluid and electrolyte secretion in the small intestine (Donowitz & Binder, 1975). MacCara (1982) recommended the use of stool softeners in cases where straining upon defecation should be avoided. Pietrusko (1977) suggested that their use be limited to a course of 7-10 days. Mineral oil is also considered an emollient laxative and can be administered either orally or via suppository. Mineral oil coats the stool and facilitates passage (MacCara, 1982). However, oral mineral oil decreases absorption of vitamins A, D, and K and can impair absorption of oral contraceptives (Sekas, 1987). In addition, absorption of mineral oil can occur. It has been detected in mesenteric lymph nodes, intestinal mucosa, liver, and spleen (MacCara, 1982). The bulk-forming laxatives, methylcellulose (Citrucel@), psyllum seeds (Metamucil@), isphagula (Hogel@), sterculia (Normacol@) and agar, act primarily by increasing the stool’s water content and bulk. Larger stool size leads to easier passage. Although bulk agents do not work on stool already in the distal colon, they are generally used to prevent constipation (MacCara, 1982). If not taken with sufficient water, bulk laxatives can cause blockage of the gastrointestinal tract (Berman 8c Schultz, 1980; MacCara, 1982). Toxicity

and Detection

Rarely, chronic abuse of laxatives can be fatal. Common presenting complaints of individuals with occult laxative abuse include diarrhea, weakness, abdominal pain, nausea, vomiting, dehydration, and hypokalemia. Other rare complications include reversible finger clubbing (Cummings, Sladen, James,

78

.

C.M.

Bulik

Sarner, & Misciewicz, 1974), malabsorption, and protein-losing gastroenteropathy (Heizer, Warshaw, Waldman, & Laster, 1968). Several dermatologic complications have been reported in users of phenolfixed drug eruptions, Stevensphthalein-containing laxatives, including Johnson syndrome, sunlight-induced bullous eruptions, and cutaneous hyperpigmentation (Coghill, McAllen, & Edwards, 1959; Fingel, 1975; Fleischer, Brown, Graham, SCDeletia, 1969; Rahman & Cain, 1973; Van Rooyen & Zrady, 1972; Verbov, 1973). Sekas (1987) reported that 5% to 7%) of users develop a deep purple polychromatic rash that may persist for years after discontinuation of the drug. MacCara (1982) considers phenolphthalein-containing laxatives to be the most undesirable, stating “there are no indications for which a laxative containing phenolphthalein can be recommended” (p. 781). Approximately 50% of laxative abusers develop electrolyte disturbances secondary to chronic diarrhea, resulting in water depletion, hypernatremia, and, possibly, severe hypokalemia (Cummings, 1974). The electroyle disturbances are usually reversible; however, severe and potentially fatal cardiac complications can occur. Although some patients readily admit to laxative use, others remain secretive. Several simple tests are available for detection of laxative agents in the urine and feces. Senna and cascara produce a reddish discoloration of the urine (Pietrusko, 1977). Phenolphthalein can be readily detected by adding sodium or potassium hydroxide to the urine or feces. Its presence turns the urine a characteristic pinkish-red color. Phenolphthalein, bisacodyl, danthron, and senna can be detected in the urine by chromatographic analysis up to 32 hours following self-administration (de Wolff et al., 1981). Oster et al. (1980) suggested repeated testing of the urine in an individual suspected of use, as the pattern of usage may be intermittent. One potential side-effect of repeated use of senna laxatives is melanosis coli, a dark pigmentation of the colonic mucosa that usually normalizes after 4-12 months of discontinuation. Such pigmentation is a useful diagnostic tool in detecting this type of laxative abuse. In the absence of these positive signs, frequent and unexplained diarrhea, abdominal cramping, and polyuria are common signs of laxative abuse. In cases of extreme secretiveness and suspected use, a thorough search of the patient’s belongings may be necessary (Oster et al., 1980). In medical settings, the differential diagnosis of unexplained diarrhea should include occult laxative abuse, especially in women who have or are suspected of having an eating disorder. Tolerance

and

Withdrawal

Tolerance and withdrawal from laxatives have not been investigated systematically in patients with eating disorders. In our study of inpatient anorectic and bulimic women (Bulik et al., in press), 62% of bulimic laxative abusers reported requiring increasingly higher doses of laxatives to achieve the desired effect. Some patients escalated to taking up to 200-400 stimulant laxative tablets per week. Many of the women reported continuing laxative use despite aversive side effects such as diarrhea, muscle and abdominal cramping, bloated-

Eating Disorders and Drug Use

79

ness, and dehydration. Common reported withdrawal effects were constipation, rebound edema, and craving for the drugs. Although based on self-report, these data suggest that tolerance does occur to the cathartic effects of laxatives. In addition, the cessation of laxative use often produces problematic withdrawal effects, including constipation, complicating attempts at cessation.

Effects on Appetite and Weight Women with bulimia nervosa self-administer laxatives with the intent to lose weight, decrease gastrointestinal transit time, and reduce feelings of bloatedness following binging. Laxative use may produce a sensation of weight loss via diuresis, but there is little evidence that it is actually effective in decreasing caloric absorption. Two studies examined the effects of laxative use on caloric absorption and weight loss. Lacey and Gibson (1985) performed a cross-sectional study comparing 20 women who used vomiting as the sole method of purging with I0 women who habitually abused laxatives. Women who vomited ate significantly more than women who abused laxatives, yet they weighed significantly less. The laxative abusers were heavier than population norms, and their caloric intake was within the normal population range. These investigators concluded that purgation via laxatives has little effect on intestinal absorption and that weight in this grot, p was primarily dependent on caloric intake. More convincing evidence was provided by Bo-Linn, Santa-Ana, Morawski, & Fordtran (1983), who used a novel technique to measure actual caloric absorption tollowing purging with Correctol ® in two women with bulimia nervosa. This method involves total gut lavage prior to the study to enable determintion of actual number of calories absorbed. They found that purging with high doses of Correctol ® (35-50 tablets/day) produced 4--6 liters of diarrhea and caused caloric absorption to decrease by only 19% of caloric intake. They suggested that Correctol ® may be inefficient at decreasing caloric absorption because its primary site of action is the colon, causing water secretion and rapid evacuation of feces. These studies indicate that, although laxative use may create a sensation of weight loss secondary to water loss through diarrhea, in actuality, it has minimal effect on caloric absorption, and, ultimately laxatives are ineffective weight loss agents.

PHENYLPROPANOLAMINE (PPA) Prevalence Several O T C diet aids are used by women with eating disorders to curb appetite. T h e majority of these contain e p h e d r i n e , caffeine, or phenylpropanolamine either alone or in combination. This section focuses on phenylpropanolamine as it can be found in numerous O T C preparations in the forms of diet pills and cough and cold preparations, as well as in amphetamine "look alikes" (Lake & Quirk, 1984). Table 4 presents a number of O T C diet pills and their ingredients.

. 80 Table

CM 4.

OTC

Diet

Aids

Containine

PPA

Product

Unit

Active

Acutrim”J Maximum Strength Dexatrim a Extra-Strength Caffeine-Free Dietac Dexatrima Extra Strength

1 Tab

75 mg PPA

Dexatrima Extra-Strength Plus Vitamins Super Odrinex” Prolamine” Maximum

1 Tab

Strength

Bulik

1 Tab

1 Tab I Tab

Ingredients

75 mg PPA Vitamin C 75 mg PPA mulitple vitamins 25 mg PPA 37.5 mg PPA

Recommended 1 Tab/24 3 months

1 3 1 3 1 1

Dosage

h maxium

Tab/24 h months maximum Tab/24 h months maximum Tab SX/day with Tab PX/day

use

use use meals

According to Mitchell et al. (1985), of 275 patients with bulimia, 52.2% reported a prior history of diet pill use for weight control and 25.1% had used a minimum of one pill per day for an extended period of time. A later report, by Mitchell et al. (1988) showed that a majority of eating-disorder patients selfadministered OTC diet pills and that relatively few relied on prescription amphetamines. In the general young female population, 42% of senior high school women had consumed PPA-containing products at least once in their lifetime (Johnston, Bachman, & O’Malley, 1982). Krupka & Vener (1983) found that 30% of 944 college females had taken OTC diet pills in the year prior to the interview. These general-population studies probably include some women with clinical and subclinical eating disorders, thereby inflating the estimates. Mitchell et al. (1988) suggested that, although many eating-disorder patients experiment with OTC diet pills, significantly fewer self-administer these drugs chronically due either to their side-effects or to their inefficacy as weight-loss agents. Primary

Effects

The majority of OTC diet pills contain PPA in varying strengths. Some preparations also include caffeine and supplementary vitamins, minerals, and iron (Table 4). These drugs are recommended as adjunctive treatments for obesity in conjunction with dieting and regular exercise. PPA is a sympathomimetic amine that was first synthesized as a substitute for ephedrine. It inhibits the reuptake of norepinephrine by the nerve terminals (Iversen, 1964; Levitt, Cumiskey, & Shargel, 1974) and has effects on many body systems. At high doses, PPA has some central nervous system stimulant effects, albeit significantly fewer than amphetamine or ephedrine (Davis & Pinkerton, 1972; McLaurin, Shipman, & Rosedale, 1961; Wellman & Peters, 1980). The relative absence of these effects could induce the individual to take greater quantities of the drug to achieve a desired high. PPA is found in many “look alike” drugs sold as legal substitutes for illicit amphetamines (Lake & Quirk, 1984). The recommended dose of PPA in humans to achieve the anorexiant effect is 25-75 mg. The estimated minimum lethal dose is 50 mg/kg orally. PPA is well absorbed by the gastrointestinal tract and is excreted primarily through the

Eating

Disorders

and Drug

Use

81

urine. The half-life of PPA is approximately 3.0-4.6 hours (Heimlich, MacDonnell, Flanagan, & O’Brien, 1961; Rhodes, Wai, & Banker, 1970). Peak blood levels occur approximately one hour following oral ingestion of 25 mg of PPA, decrease exponentially, and are barely detectable 24 h post-ingestion (Mason & Amick, 1981). Toxicity

and Detection

The safety of PPA-containing preparations has been debated widely. Several studies suggest that, if taken within the recommended guidelines, PPA is a relatively safe compound. Other case reports and empirical studies contest this statement. Animal and human studies have indicated that PPA has low abuse liability. Baboons (Griffiths, Brady, & Snell, 1978) and monkeys (Woolverton et al., 1986) did not find PPA to be reinforcing, as judged by their failure to self-administer the drug at a rate higher than saline. In human studies, PPA has been consistently shown to be less reinforcing, to be self-administered at a lower rate, and to produce minimal subjective drug effects (Bigelow, 1985; Chait, Ulenhuth, Blackburn, & Noble, 1989; & Johanson, 1986, 1988; Morgan, Funderburk, Schuster & Johanson, 1985). In a controlled study, Horowitz et al., (1980) examined the effects of two doses of PPA on normal human volunteers. They described significant and occasionally dangerous increases in systolic and diastolic blood pressure following only one dose. The reaction was dose dependent. These findings have not been replicated universally (Barrett, Hanigan, & Snyder, 1981; Broms & Maim, 1982; Renvall & Lundqvist, 1979). Complications may arise with the self-administration of PPA in higher doses and in combination with caffeine or other sympathomimetic drugs, although these findings are not consistent. The use of PPA with monoamine oxidase inhibitors (Cuthbert & Vere, 1971; Harrison, McGrath, Stewart, & Quitkin, 1989; Smookler & Bermudez, 1982; Terry, Kaye, & McDonald, 1975; Tonks & Lloyd, 1965), indomethacin (Lee, Beilin, & Vandongen, 1979a, b) and foods containing tyramine (Rudzik & Eble, 1967) can produce hypertensive crises. The use of PPA-containing preparations has been associated with hypertension, intracerebral hemorrhage, seizures, and psychotic reactions (Bernstein & Diskant, 1982; Hoaken, 1987; Mueller, 1983; Shaffer 8c Pauli, 1980; Twerski, 1987). A review of the literature between 1965 and 1984 by Lake and Quirk (1984) revealed 25 cases of hypertension (five with cerebral hemorrhage), 11 cases of PPA-related symptoms such as cardiac arrhythmias, respiratory distress, and psychotic episodes including acute mania. Lake, Alagna, Quirk, Moriarity, and Reid (1985) proposed a synergistic reaction between caffeine and PPA, increasing the risk of adverse effects. In contrast, Silverman et al. (1980) demonstrated nonsignificant effects on heart rate and blood pressure when 25 mg of PPA was taken in combination with 100 mg of caffeine. Noble (1982) had similar negative results with obese patients. The inconsistencies in findings across studies are undoubtedly related to several controllable factors. In future studies of the effects of PPA, other drug

. CM.

a2

Bulik

use, caffeine consumption, fasting versus fed conditions, blood pressure, and psychiatric history should be controlled. Cross tolerance may develop between caffeine and PPA, making individuals with regular high use of caffeine less likely to show increases in blood pressure in experimental situations. In summarizing the effects of PPA, Lasagna (1988) warned that individuals who are sensitive to caffeine; who are using monoamine oxidase inhibitors, indomethacin, or other cold remedies; who have ingested foods high in tyramine; and whose past or family history contains schizophrenia, affective disorder, or cardiovascular disease may be at greater risk for adverse effects. Finally, in determining whether an individual has used PPA-containing products, the presence or absence of PPA can be detected in the urine. The halflife of the drug is relatively short. Repeated or well-timed sampling may be necessary in attempting to determine whether an individual has ingested a PPAcontaining product. Tolerance

and Withdrawal

Few data exist on the development of tolerance or withdrawal from PPA. Wellman and Sellers (1986) reported that tolerance did not develop to the weight loss or anorexiant effects of PPA in rats over a 12-day trial. In contrast, Tainter (1944) stated that tolerance did occur to the anorexiant effects of PPA in rats; however, no clear data were presented to substantiate this claim. Tachyphylaxis, or rapid tolerance to acute drug administrations, is characteristic of many sympathomimetic amines. Moya-Huff, Kiritsky, & Maher (1987) failed to demonstrate tachyphylaxis with repeated administration of PPA to rats. Further laboratory and field studies clearly are required to determine the tolerance and withdrawal profiles associated with PPA administration in animals, as well as with normal weight and obese human populations. Effect

of Phenylpropanolamine

on Appetite

and Weight

PPA has been used as an anorexiant since at least the 1930s (Hirsch, 1939, cited in Lasagna, 1988); however, its effectiveness as a long-term weight-loss agent is equivocal. In controlled laboratory studies, Wellman and Sellers (1986) showed that rats given the relatively high twice daily dose of 20 mg/kg of PPA over 12 days showed significant decreases in both body weight and food intake, but this did not replicate at lower doses (5 and 10 mg/kg). Decreased food intake as a function of PPA has been demonstrated in rats (Hoebel, Hernandez, 8c Thompson, 1975; Wellman 8c Sellers, 1986), mice (Cairns, Foldys, 8c Rees, 1984), and monkeys (Schuster & Johanson, 1985) and has been shown in free feeding and operant conditioning experimental approaches (Hoebel, Hernandez, & Thompson, 1975; Wellman 8c Peters, 1980). Dose and route of administration affect the anorexiant effects of PPA (Morgan, Kagan, 8c Brody, 1985; Schuster & Johanson, 1985). The mechanism of action of PPA as an anorexiant is not completely understood. Although PPA stimulates metabolism, inhibits gastrointestinal smooth muscle, and produces small effects on blood glucose utilization,

Eating

Disorders

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Use

83

Lasagna (1988) suggested that the magnitude of these effects is not sufficient to account for its anorexiant action. An alternative hypothesis has been forwarded that the anorexiant effects are secondary to conditioned taste aversion (Wellman, Malpas, 8c Wikler, 1981); however, these findings have not been consistently upheld (Wellman & Levy, 1988). Clinical trials of the anorexiant effects of PPA have examined both body weight and food intake as outcome measures. Hoebel, Cooper, Kamin, & Willard (1975) presented data comparing amounts of a liquid meal consumed by overweight volunteers. These studies were double blind, placebo-controlled, crossover designs. In the first two studies, PPA significantly decreased food intake. In a third study, with normal-weight volunteers and with PPA labeled as a decongestant, there was no difference in amount of food consumed in the drug and no-drug conditions. Treatment studies for obesity using PPA either alone or in combination with caffeine have been reviewed by Blumberg & Morgan (1985) and Lasagna (1988). There have been several studies employing double-blind, placebo-controlled, crossover designs that have measured weight loss and perceived appetite suppression. Comparison of efficacy across studies is difficult due to inconsistencies in research design including premorbid weight of the treatment population, dosage and schedule of administration, and concurrent dietary therapy; however, Lasagna (1988) concluded that, overall, PPA alone or in combination with caffeine produces modest weight loss and appetite suppression and that increasing doses of PPA do not necessarily lead to increased weight loss. The major flaw in studies examining the efficacy of PPA in the treatment of obesity is the absence of adequate follow-up to determine whether weight loss is sustained in the absence of life-style change (e.g., increased exercise or dietary modification).

DISCUSSION Those drugs related to purging such as diuretics, emetics, and laxatives have been shown to be either ineffective or dangerous methods of accomplishing weight loss or maintenance. In addition the literature suggests that tolerance and withdrawal occur with laxatives, diuretics, possibly diet pills, and emetics. The development of this type of drug use in women with eating disorders may begin with experimentation. For example, an individual may try laxatives in response to perceived constipation or bloatedness. Initially the drugs may serve as negative reinforcers by removing the uncomfortable somatic and psychological postbinge feelings. Their ability to create a sense of weight loss and a real decrease in measured weight increases the likelihood of further use. Over time, laxative use may become less tied to the postbinge state and may develop into a dependency that is at least partially independent of the eating disorder. For example, not only can individuals become dependent on laxatives for normal bowel function, but they can also begin to crave the specific effects and sensations associated with laxative self-administration (Bulik et al., 1990). In such an instance, the positively reinforcing aspects of the drug may contribute to maintenance of use. This may also hold true for the other drugs discussed. If

84

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CM.

Bulik

such a dependency does develop, the use of these drugs begins to resemble the pattern of use of more traditional drugs of abuse. Currently, individuals with eating disorders and laxative or diuretic abuse are treated with abrupt or gradual supervised discontinuation, electrolyte replacement and stabilization, and psychoeducation regarding the dangers associated with taking these drugs (Mitchell et al., 1988). Although these approaches may suffice for some individuals, the high rates of use and reports of withdrawal and craving suggest that there is little reason to believe that simple discontinuation of the drug would result in permanent abstinence after treatment. Studies have not been conducted to examine whether treatment for the eating disorder per se generalizes to discontinuation of the use of drugs associated with the disorder. Likewise, the extent to which slips or relapses in drug use (e.g., laxatives and diuretics) prompts reinitiation of disordered eating is unknown. We have noted anecdotally that reinstatement of laxative use was the first step in relapse for several bulimic patients. This observation requires further empirical validation. These drugs may serve as pharmacological cues for binge-eating, and their use may be a major liability in the relapse of disordered eating behavior. Adequate treatment of the eating-disordered individual who uses these drugs may require specific steps to extinguish craving and reactivity to cues associated with self-administration (Bulik et al., 1990). Without such specific treatments, patients may remain reactive to drug cues (e.g., the laxative section of a pharmacy, television commercials), thereby risking a relapse into drug-taking behavior that may then act as a pharmacological cue for binge-eating and perpetuate the eating-disorder cycle. As Vuchinich & Tucker (1988) have suggested in the treatment of alcoholism, successful intervention will require finding adequate alternative reinforcers to replace the food and associated drugs. To detect and treat associated drug use in women with eating disorders, clear definitions of abuse and dependence must be established. Direct application of DSM III-R (American Psychiatric Association, 1987) criteria is insufficient, as these drugs generally are not considered to be psychoactive. Table 5 presents an adaptation of the DSM III-R psychoactive substance use and dependence criteria, to be used as a guideline in establishing whether an individual presents with a symptom profile including abuse or dependence on laxatives, diuretics, emetics, or diet pills. To enhance diagnostic specificity and treatment planning, the diagnostic schema for eating disorders should indicate whether concurrent use of these substances exists. In summary, the use of drugs by individuals with eating disorders deserves further clinical and research attention. Clinicians must be aware of the interactive nature of drug use and disordered eating. It will become increasingly important to determine whether specific treatments for associated drug use are required and how best to treat individuals who present with bulimia and drug dependencies. The importance of the work is highlighted by recent trend data indicating that the number of women presenting with bulimia and laxative abuse has increased over the past several years (Mitchell, Soll, Eckert, Pyle, & Hatsukami, 1989). Further research should be directed toward understanding basic behavioral pharmacologic principles associated with the drugs commonly

Eating

Disorders

Table 5. Disorders

and

Guidelines

Drug

Use

for Abuse

85

and Dependence

on Drugs

use (e.g.,

diuretics,

Associated

with

Eating

Substance Abuse A. A maladaptive by at least one

pattern of substance of the following:

laxatives,

emetics,

diet

pills)

indicated

1. Continued use despite knowledge of having a persistent or recurrent social, occupational, psychological, or physical problem that is caused or exacerbated by use of the substance 2. Use for purposes other than that recommended by the manufacturer (e.g., use of laxatives for weight loss rather than for constipation) B. Some symptoms of the disturbance have persisted for repeatedly over a longer period of time C. Never met criteria for dependence for this substance Substance

at least

one

month

or have

occurred

Dependence

A. This is indicated by at least three of the following: I. Substance often taken in larger amounts or over a longer period than the person intended 2. Persistent desire or one or more unsuccessful efforts to cut down or control substance use 3. A great deal of time spent in activities necessary to get the substance (e.g., shoplifting), in taking the substance, or in recovering from its effects (e.g., spending hours in the bathroom with diarrhea) 4. Frequent experiencing of the effects of the drug or withdrawal symptoms when expected to fulfill major role obligations to work, school, or home (e.g., not going to work due to chronic diarrhea secondary to laxative self-administration) 5. Important social, occupational, or recreational activities given up or reduced because of substance abuse 6. Continued substance use despite knowledge of having a persistent or recurrent social, psychological, or physical problem that is caused or exacerbated by the use of the substance (e.g., continued use of laxatives despite being caught stealing them or chronic cramps and dehydration) 7. (Once determined empirically): marked tolerance; need for markedly increased amounts of the substance (i.e.. at least a 50% increase) to achieve the desired effect or markedly diminished effect with continued use of the same amount 8. (Once determined empirically): characteristic withdrawal symptoms (may not apply to emetics) 9. Substance often taken to relieve or avoid withdrawal symptoms B. Some symptoms of this disturbance have persisted for at least one month or have occurred repeatedly over a longer period of time

efforts should be made to complete our used by this group. In addition, understanding of the effects of disordered eating on drug consumption and the effects of drug consumption on appetite, weight, and metabolism. Finally, the behavioral economic perspective emphasizes the importance of finding adequate alternative reinforcers for the individual who is attempting to quit both binging and associated drug use. REFERENCES Abraham,

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Davidson, C.. & Silverstone. T. (1972). Diuretic dependence. Brifbh Medical Journal, 282, 505. Davis, W.M., & Pinkerton, J.T. (1972). Synergism by atropine of central stimulant properties of phenylpropanolamine. Toxicology U Applied Pharmacology, 22, 130-145. DeVeve. R., & Bradley, W.G. (1975). Polymyositis: Its presentation, morbidity and mortality. Brain, 98, 637-666. de Wardener, H.E. (1981). Idiopathic edema: Role of diuretic abuse. Kidney Inlernafional, 19, 882-892. deWolff. EA., deHaas. E.J.M., & Verweij, M. (1981). A screening method for establishing laxative abuse. Clinical Chemisfry, 27, 914-917. Donowitz, M., & Binder, H.J. (1975). Effect of dioctyl sodium sulfosuccinate on colonic fluid and electrolyte movement. Gastroenterofogy, 69, 941-950. Duane, D.D., & Engle. A.G. (1970). Emetine myopathy. Neurology, 20, 733-739. Fairburn. C.G., & Cooper, P.J. (1984a). The clinical features of bulimia nervosa. Btiliclr Journal of Psychiatry, 144, 238-246. Fairburn. C.G., & Cooper, P.J. (1984b) Binge-eating, self-induced vomiting, and laxative abuse: A community survey. Psychological Review, 14, 401-410. Ferguson, J.M. (1985). Bulimia: A potentially fatal syndrome. Psychosomnfics, 26, 252-253. Fingel, E. (1975). Laxatives and cathartics. In L.S. Goodman & A. Goodman (Eds.), Pharmarological basis oflherapeubcs (pp. 976-986). New York: MacMillan. Fleischer, N., Brown, H., Graham, D.Y.. & Deletia. S.A. (1969). Chronic laxative-induced hyperaldosteronism and hypokalemia simulating Bartter’s syndrome. Annals of Internal Medicine, 70, 791-798. Friedman, A.G., Seime, R.J., Roberts, T.. & Fremouw. W.J. (1987). Ipecac abuse: A serious complication in bulimia. General Hospital Psychic&y, 9, 225-228. Friedman, E.J. (1984). Death from ipecac intoxication in a patient with anorexia nervosa. American Journal of Psychiatry, 141, 702-703. Gimble, A.I., Davison, C.. & Smith, P.K. (1948). Studies on the toxicity, distribution and excretion of emetine. Journal of Pharmacology and Experimenlal Therapeutics, 94, 431-438. Griffiths, R.R.. Brady, J.V., & Snell, J.D. (3978). Relationship between anorectic and reinforcing properties of appetite suppressant drugs: Implications for assessment of abuse liability. Biological Psychiaky, Ijr, 283-290. Hammarlund, M., & Paalzow, L.K. (1985). Acute tolerance development to the diuretic effect 01 furosemide in the rat. Biopharmaceutics and Drug Disposibon. 6, 9-21. Harrison, W.M., McGrath, P.J., Stewart, J.W., & Quitkin, F. (1989). MAOls and hypertensive crises. Journal of Clinical Psychialry, 50, 64-65. Heimlich. K.R.. MacDonnell, D.R., Flanagan, T.L., & O’Brien, P.D. (1961). Evaluation of a sustainedrelease form of phenylpropanolamine hydrochloride by urinary excretion studies. Journal 01 Pharmaceutical Sciences, 50, 232-237. Heizer. W.D. Warshaw, A.L.. Waldman, T.A., & Laster, 1. (1968). Protein-losing gastroenteropathy and malabsorption syndrome with factitious diarrhea. Annals of fnlernal Medicine, 68, 839-852. Hoaken, P.C. (1987). Secondary mania: Aggravation of a sub-clinical condition. Psychiakic Journal of the University of Ottawa. 12, 47-48. Hoebel, B.C., Cooper, J., Kamin, M.C., & Willard, D. (1975). Appetite supression by phenylpropanolamine in humans. Obesify & Bark&c Medicine, 4, 192-197. Hoebel. B.C., Hernandez, L., &Thompson, R.D. (1975). Phenylpropanolamine inhibits feeding but not drinking, induced by hypothalamic stimulation. Journal a/ Comparafive Ptrysiology U Psychology, 89, 1046-1052. Hollifield, J.W., & Slaton. P.E. (1981). Thiazide diuretics, hypokalemia and cardiac arrythmias. A& Medica Scandinavica, 647 (Supp.). 67-73. Horowitz, J.D., Lang, W.J., Howes, L.C., Fennessey. M.R.. Christophidis. N.. Rand, M.J., & Louis, W.J. (1980). Hypertensive responses induced by phenylpropanolamine in anorectic and decongestant preparations. Lance& 1, 60-61. Iversen. L.L. (1964). Inhibition of noradrenaline uptake by sympathomimetic amines [Letter to the editor]. Journal of Pharmacy E3 Pharmacology, 16, 435-437. Johnson, C., & Berndt, D.J. (1983). Preliminary investigation of bulimia and life adjustment. American Journal of Psychiatry, 140. 774-777.

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