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Drugs of abuse
Alan I. Green, Eric J. Watsky and Carl Salzman
4 Amphetamines (SEDA-15, 27) (see also Chapter 1)
As noted in previous Annuals, amphetamines, which are used recreationally, can be taken orally, intravenously, or by nasal inhalation. Their sympathomimetic properties can produce vascular complications, including intracerebral hemorrhage, stroke, myocardial infarction, cardiac failure, and arterial occlusion (1R). One recent report described a 47-year-old man who had been given dextroamphetamine for narcolepsy and developed an ischemic colitis. Treatment was switched to methylphenidate, with a good result. The authors noted that gastrointestinal toxicity from amphetamine use can be unpredictable. A second report described a 30-year-old man who developed an intraventricular hemorrhage after intravenous amphetamine (2c). A third report described 2 patients, both in their mid-thirties, who developed acute femoral neuropathy with iliopsoas infarction after intravenous substance abuse, including amphetamines. Although the mechanism involved in the development of the muscle ischemia was uncertain, the authors speculated that necrotizing arteritis associated with the abuse of amphetamines may have been involved (3c). Lastly, there has been a report of a man in his twenties who sustained an acute myocardial infarction after intravenous amphetamine (4c). Two recent reports have highlighted the dangers that can arise from the intentional swallowing of large amounts of amphetamine to avoid detection. The first report was of a 42year-old man who ingested a packet of amphetamines in order to avoid arrest, and developed colonic pseudo-obstruction, characterized by increased abdominal girth, nausea, vomiting, constipation, and abdominal pain. The syn9 1993 ElsevierSciencePublishers. All rights reserved Side Effects of Drugs Annual 16 M.N.G. Dukes and J.K. Aronson, eds. 22
Drugs of abuse drome resolved with medical management. The pathophysiology was thought to be related to an amphetamine-induced change in the parasympathetic/sympathetic balance in the gut (5c). A second report described a patient who swallowed 20 condoms containing amphetamine in an attempt to smuggle the drug. This practice, which has been referred to as 'body packing', has been described for other drugs. In the case reported, the packages began to leak and the patient developed symptoms of amphetamine toxicity. Surgical removal was required (6c). In previous Annuals the recent increase in the use of 'ice', a smokable crystalline form of amphetamine, has been noted. This year's literature included a report of 2 patients who developed toxic cardiovascular effects after smoking amphetamine. One patient, a 34-yearold woman, developed pulmonary edema and a dilated cardiomyopathy and the second, a 31year-old woman, had a myocardial infarction with cardiogenic shock and eventually died. The authors noted that although a direct causal relationship between the smoking of methamphetamine and these cases of cardiotoxicity could not be made unquestionably, it appeared that the drug was involved in the symptoms, perhaps through the development of systemic vasospasm (7R). A second report described a case of acute myocardial infarction which occurred shortly after the inhalation of crystal methamphetamine (8c). Taken together, these reports strongly suggest that cardiovascular complications of amphetamine abuse do not occur solely in people who use amphetamine by injection (8c). Congeners of amphetamine may have psychedelic properties. 3,4-methylenedioxyamphetamine (MDA), which produces both sympathomimetic and mescaline-like effects (9 R) and which has been abused for over 25 years, has been reported to have caused the death of a 26-year-old man secondary to apparent cardiac insufficiency (9R). A related
Drugs of abuse Chapter 4 compound, methylene-dioxymethamphetamine (MDMA or 'ecstasy'), also has hallucinogenic properties. Some investigators have suggested that MDMA can cause lasting destruction of the serotonergic system (10R - 12R). There has been a report of chronic paranoid psychosis in 2 men after the chronic use of MDMA. It was unclear whether the MDMA precipitated these psychoses in people who would ultimately have become psychotic even without the MDMA or whether it produced psychosis de novo (13c). In a second report the death of a 16-year-old girl who developed hyperthermia, hallucinations, agitation, and coagulopathy after the oral use of MDMA has been described. The authors emphasized that MDMA, which has been reported to produce a feeling of calmness and increased interpersonal sensitivity, can have dangerous adverse effects (14c). Finally, there have been 2 reports about amphetamine use which emphasized that doctors need to be alert to unusual effects of these drugs at unexpected times. The first report was of a man in his twenties who required surgery for a gunshot wound. When an intravenous line was inserted before surgery, he covertly selfinjected an amphetamine/heroin mixture. Shortly after, he was taken to surgery, where his heart rate and blood pressure increased. It was not until some time later that his pre-surgery substance abuse became known (15c). The second report was of a 40-year-old man who took what he thought was amphetamine, but was in fact a combination of p-methylamphetamine and N, p-dimethylamphetamine, before being given the beta-blocker practolol. The practolol produced a paradoxical increase in blood pressure, most likely because of an unopposed c~-agonistic effect from the amphetamines (16c). Cannabis (SED-12, 86; SEDA-12, 34; SEDA-
13, 24; SEDA-15, 28) The development of oral Candida infections in cannabis smokers has recently been studied (17c). The prevalence of positive cultures of Candida albicans and the density of these cultures were evaluated in 55 cannabis smokers, 58 tobacco smokers, and 50 non-smoking control subjects. The cannabis smokers had a higher rate of positive cultures for Candida
23
albicans than the cigarette smokers or control subjects. In addition, among the carriers of Candida infection, those who were cannabis smokers had a greater density of Candida albicans colonies than the carriers who were tobacco smokers or non-smokers, although the difference was not statistically significant. There has been a report of 13 chronic cannabis smokers, all younger than 55 years, who developed head and neck cancers (18R). The authors suggested that cannabis use might be associated with a risk of cancer of the upper airways. Cocaine (SEDA-12, 35; SEDA-13, 25; SEDA-14, 28; SEDA-15, 29) (see also Chapter 1) As in previous years, reports of the effects of cocaine abuse have dominated the literature. The manifestations of cocaine toxicity are farreaching and extend to most of the body's organs. In a review of the use of crack cocaine, Smart has noted the attractiveness of this type of cocaine for many users (19R). The adverse effects which distinguish the use of crack from the use of other forms of cocaine include pulmonary toxicity and the potential development of neurological symptoms in children passively exposed to cocaine smoke. Although crack cocaine is usually smoked, oral ingestion can produce toxicity. This may occur most commonly when law enforcement officers arrest cocaine smokers who are carrying the substance with them (20c). This should be remembered when such subjects develop unexplained cardiac, central nervous system, gastrointestinal, or autonomic symptoms (20c). Cardiovascular In a study of the pathology of the cardiac effects of cocaine abuse, Kolodgie et al. examined 5871 autopsy records, of which 495 (8.4o70) demonstrated cocaine abuse (21c). Acute coronary thrombosis was the cause of death in 6 patients. The autopsy findings in these patients were compared with those of 6 patients whose deaths were associated with atherosclerosis and coronary thrombosis without evidence of cocaine abuse. The authors suggested that adventitial mast cells, which were increased in the cocaine users, might have
24
potentiated the thrombosis and vasospasm and increased the risk of death in these patients (21c). Although coronary artery spasm has been proposed as a basis for cocaine-induced chest pain, the authors of a recent report of II patients who presented with chest pain at rest after cocaine use, have questioned this mechanism (22c). Coronary arteriography failed to demonstrate spasm, and ergonovine maleate challenge did not provoke a vasoconstrictive response in these patients. In addition, there was no evidence of myocarditis in endomyocardial biopsies. However, there was a significant thickening of the small coronary vessel walls, which suggested that cocaine-induced platelet thombosis may have plugged these narrowed vessels. Chest pain after cocaine has also been studied in 70 patients, 22 of whom developed acute myocardial infarction (23c). In 65070 of the patients who did not progress to myocardial infarction, the serum CK activity was increased, but the CK-MB fraction was not. Eight patients with infarctions were evaluated by cardiac catheterization; 4 had underlying coronary artery narrowing. Finally, there has been a report of a patient with a prolonged QT interval in whom torsades d e p o i n t e s developed after intravenous cocaine (24c). The increase in adrenergic tone following cocaine use may have triggered this episode of polymorphous ventricular tachycardia.
Respiratory
Four cases of an acute pulmonary syndrome after the inhalation of cocaine smoke have recently been described (25c). Two of the patients had prolonged pulmonary injury with alveolar damage and an inflammatory infiltration with a large number of eosinophils. The other 2 patients presented with diffuse infiltrates which resolved spontaneously within 36 hours. There has also been a report of 6 patients in whom pre-existing asthma was exacerbated by cocaine smoking (26c). The authors suggested that this complication of cocaine smoking, which could be fatal, has been generally under-estimated.
system The literature on the neurological effects of cocaine continues to expand. Neurovascular insult has been studied in 979 cocaine-related hospital admissions (27c). In 3070 of the admissions there was
Chapter 4 A . L Green et al.
neurovascular insult; 54070 of these were ischemic and 46070 were hemorrhagic. Since angiography failed to demonstrate vasculitis, the authors suggested that repeated use of cocaine may result in a gradually developing injury to the vascular endothelium. In another study, 24 cases of stroke in users of crack (or alkaloidal) cocaine were examined (28c). Ten of the patients had a hemorrhage; the remaining sustained cerebral infarctions, predominantly in the territory of the middle cerebral artery. The most common symptom before the stroke was headache. Again, cerebral angiography failed to reveal evidence of vasculitis. There have also been some interesting single case reports of cerebrovascular injury associated with cocaine. A case of dorsal pontine intraparenchymal hemorrhage was described after the use of crack in a 35-year-old man (29c). The presenting symptoms included diplopia, right-sided dysmetria, and an ataxic gait. Another case of cerebral infarction, in a 39-year-old woman, appeared to be due to an embolism from an atrial thrombns after the use of crack (30c). The authors suggested that a predisposing cardiomyopathy may have been due to cocaine use. In other reports, occlusion of the right cerebellar artery (31 c) and spinal cord infarction (32 c) have been noted in cocaine users. Movement disorders have been described in cocaine abusers, including a dystonia which developed shortly after the use of cocaine (33 c) and exacerbation of Tourette's syndrome with emergence of multifocal tics after the use of cocaine (34c). A study of computed axial tomographic scans of the brains of cocaine users showed cerebral atrophy in chronic cocaine users but not in first-time users or in nonusers with headache (35c). There was a positive correlation between the duration of use and the amount of atrophy. Finally, a population of inpatient polysubstance abusers with chronic migraine-type headaches has been described (36c). Although cocaine gave rapid initial relief from headache, it was also associated with an exacerbation of headache several hours after.
Nervous
Psychiatry
Cocaine commonly causes psychiatric complications. In a recent study more than one-third of the patients coming to the emergency room after taking cocaine had psy-
Drugs of abuse Chapter 4
chiatric complaints (37c). Obsessive thoughts and compulsive behavior emerged exclusively in a 34-year-old man during cocaine intoxication (38c); he was free of these symptoms otherwise. Interestingly, he had 2 brothers with obsessive compulsive disorder. A new onset panic disorder has also been reported after the use of cocaine (39c); the panic attacks recurred daily for 3 months before being controlled with drugs.
Hematological A case of splenic infarction following cocaine use has been described in a patient with sickle-cell trait (40c). The cocaine was thought to have caused a reduction in oxygen tension in the spleen, with resulting sickling. Gastrointestinal There is growing interest in the effects of cocaine on the gastrointestinal tract. Acute mesenteric ischemia has been reported in a 38-year-old cocaine abuser who sustained intestinal infarction after the intravenous use of cocaine (41c). The patient had 160 cm of infarcted bowel. Segmental intestinal ischemia has also been reported after cocaine and alcohol abuse (42c); pathological examination showed protrusion of the elastic membrane of the arterioles in the intestinal submucosa, which produced arteriolar narrowing. The authors suggested that the pathology supported the notion that cocaine abuse can result in vascular spasm. Unlike the report of Kolodgie (21c), there was no mention of the presence of adventitial mast cells. Last year we described a series of 4 patients in whom histopathological examination demonstrated centrilobular hepatic necrosis associated with cocaine abuse (43c). In a recent study of 46 nonparenteral cocaine users an attempt was made to confirm this finding, but significant liver function test abnormalities were found to be rare (occurring in 3 of 46 subjects, 2 of whom were carriers of hepatitis B)
(44c).
Special senses The ophthalmological literature on cocaine continues to grow. There has been a report of a ease of infection of the cornea with Candida albicans (45r possibly secondary to defects of the corneal epithelium, related to alkali burns from smoking crack cocaine. Bilateral staphylococcal ulcers, resulting
25 in visual defects, have also been described in a cocaine user (46c). In a third report, a case of iritis after the use of cocaine was described in a patient with a positive titer for HLA-B27 (47c). The authors proposed that the patient may have had a genetic predisposition to the development of iritis, which emerged with cocaine use. A report of 11 cocaine users has noted that their sense of smell was unimpaired; the authors suggested that most cocaine users, even those with intranasal damage, have normal olfaction (48c). In another report 2 cases of laryngeal burns from cocaine smoking have been described (49c). The difficulty of distinguishing these lesions from squamous cell carcinoma on magnetic resonance imaging was discussed.
Second-generation effects As noted in previous Annuals, cocaine can have profound effects on the developing fetus; this has continued to be emphasized in several recent reviews and case reports. Rosenak et ai. have noted that the use of cocaine during pregnancy 'creates a variety of grave medical problems which necessitate immediate attention' (50R). Handler et al. (51 R) have suggested that cocaine can cause spontaneous abortion, fetal death, prematurity, abruptio placenta, congenital malformations, and decreased fetal growth (51R). The recent literature has provided a number of reports which further support the dangers to the fetus of maternal cocaine use. The incidence of abruptio placenta among cocaine-using pregnant women has been reported to be nearly double the normal rate (52c); in 67 infants born to cocaine-abusing mothers there were asymmetries of brain growth (53c), and fatal hypoxemia has been reported in a fetus born to a mother who was using cocaine (54c). In 2 other reports (55 c, 56c) the use of cocaine during pregnancy has been linked with congenital cardiac abnormalities. There has also been a report of 7 infants born with congenital limb defects associated with the use of cocaine during pregnancy (57c). Lastly, there has been a report of an infant with hydrocephaly born to a cocaineusing mother (58c). However, despite these reports one reviewer noted that separating the effect of the drug on the development of congenital defects from the effects of inadequate maternal care is not always easy (59R). In addition, one investigator did not find an increased frequency of renal ab-
26 normalities in infants exposed to cocaine in utero, despite previous reports of such a finding (60c). The difficulty of doing adequate studies must be acknowledged. Assessment of the effects of cocaine on pregnant mothers may be more straightforward. There has been a report of a 26-year-old pregnant woman (at 32 weeks of gestation) who collapsed after first using cocaine and then having sexual intercourse (61c); both the mother and the fetus died. The authors suggested that the effects of sexual intercourse, pregnancy, and cocaine combined to produce a severe dysrhythmia with cardiac failure (61c). In another case a 19-year-old pregnant woman (at 32 weeks of gestation) presented with a ruptured uterus shortly after taking intravenous cocaine (62c). The authors suggested that cocaine-induced placental vasoconstriction and uterine contractility may have contributed to the event (62c). Cocaine can also produce severe toxicity in young children, often following accidental ingestion. There have been 3 reports of 5 cases of seizures in toddlers with cocaine toxicity (63 r - 65c). Three of the toddlers had eaten cocaine powder; 1 child had passively inhaled smoke while the parents were using free-base cocaine; in the last case the source of the cocaine was unknown. Two other reports have appeared: in the first, a 4-year-old child developed hemorrhagic diarrhea and cardiovascular col-
Chapter 4 A.I. Green et al.
lapse after eating crack cocaine (66c); in the second, a 20-month-old child developed esophagitis and epiglottitis after passively inhaling crack (67c). It is obvious from these reports that accidental ingestion of cocaine represents an extreme danger and should be thought of as an environmental hazard in homes in which cocaine is used.
HALLUCINOGENS There have been 2 recent and unusual reports of adverse effects of hallucinogens. A hypermetabolic state has been reported in a patient who had used lysergic acid diethylamide and alcohol (68c). The patient's presentation was similar to the neuroleptic malignant syndrome, with fluctuating consciousness, visual hallucinations, fever, and rigidity. The patient's creatine phosphokinase activity peaked at 3090 IU/1. The hallucinogenic properties of bufoterine (69R), which is present in the skin glands of a number of B u f o toad species, including the Australian cane toad, have been noted. Bufoterine can be obtained through licking the skin of the excited toad. When ingested, bufoterine, which inhibits monoamine oxidase, can cause sweating, palpitation, and gastrointestinal distress.
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diomyopathy associated with the smoking of crystal methamphetamine. J. Am. Med. Assoc. 265, 1152- 1154. 8. Furst SR, Fallon SP, Reznik GN, Shah PK (1990) Myocardial infarction after inhalation of methamphetamine. N. Engl. J. Med., 323, 1147
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9. Nichols GR, Davis GJ, Corrigan CA, Ransdell JS (1990) Death associated with abuse of a 'designer drug.' J. KY. Med. Assoc., 88, 601- 603. 10. Seiden LS (1990) MDMA and related compounds: session summary. Ann. N Y Acad. Sci., 600, 711-715. 11. Gibb JW, Johnson M, Stone D, Hanson GR (1990) MDMA: historical perspectives. Ann. N Y Acad. Sci., 600, 601-612. 12. Kramer RE (1991) Excitotoxins. Curt. Opin. Neurok Neurosurg., 4, 447- 452. 13. McGuire P, Fahy T (1991) Chronic paranoid
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ivied. J., 302, 697. 14. Chadwick IS, Linsley A, Freemont AJ, Doran B (1991) Ecstasy, 3,4-methylenedioxymethamphetamine (MDMA), a fatality associated with coagulopathy and hyperthermia. J. R. Soc. Med., 84, 371. 15. Samuels J, Schwalbe SS, Marx GF (1991) Speedballs: a new cause of intraoperative tachycardia and hypertension. Anesth. A nulg., 72, 397 - 398. 16. Bal TS, Gutteridge DR, Johnson B (1989) Adverse effects of the use of unusual phenethylamine compounds sold as illicit amphetamine. Med. Sci. Law, 29, 186- 188. 17. Darling MR, ArendorfTM, Coldrey NA (1990) Effect of cannabis use on oral candidal carriage. J. Oral PathoL Med., 19, 319-321. 18. Caplan GA (1991) Marijuana and mouth cancer. J. R. Soc. Med., 84, 386. 19. Smart RG (1991) Crack cocaine use: a review of prevalence and adverse effects. Am. J. Drug Alcohol Abuse, 17, 13 - 26. 20. Riggs D, Weibley RE (1990) Acute toxicity from oral ingestion of crack cocaine: a report of four cases. Pediatr. Emerg. Care, 6, 2 4 - 26. 21. Kolodgie FD, Virmani R, Cornhill JF, Herderick EE, Smialek J (1991) Increase in atherosclerosis and adventitial mast cells in cocaine abusers: an alternative mechanism of cocaineassociated vasospasm and thrombosis. J. Am. Coll. CardioL, 17, 1553- 1560. 22. Majid PA, Patel B, Kim H-S, Zimmerman JL, Dellinger RP (1990) An angiographic and hi stologic study of cocaine-induced chest pain. Am. J. Cardiol., 65, 812-814. 23. Amin M, Gabelman G, Karpel J, Buttrick P (1990) Acute myocardial infarction and chest pain syndromes after cocaine use. Am. J. CardioL, 66, 1434- 1437. 24. Schrem SS, Belsky P, Schwartzman D, Slater W (1990) Cocaine-induced torsades de pointes in a patient with the idiopathic long QT syndrome. Am. Heart J., 120, 980- 984. 25. Forrester JM, Steele AW, Waldron JA, Parsons PE (1990) Crack lung: an acute pulmonary syndrome with a spectrum of clinical and histopathological findings. Am. Rev. Respir. Dis., 142, 462 - 467. 26. Rubin RB, Neugarten J (1990) Cocaineassociated asthma. Am. J. Med., 88, 4 3 8 - 439. 27. Peterson PL, Roszler M, Jacobs I, Wilner HI (1991) Neurovascular complications of cocaine abuse. J. Neuropsychiatry Clin. Neurosci., 3, 143 - 149. 28. Levine SR, Brust JCM, Futrell N, Ho K-L, Blake D, Millikan CH, Brass LM, Fayad P, Schultz LR, Selwa JF, Welch KMA (1990) Cerebrovascular complications of the use of the 'crack' form of
27 alkaloidal cocaine. N. EngL J. Med., 323, 699 - 704. 29. Ramadan NM, Levine SR, Welch KMA (1991) Pontine hemorrhage following 'crack' cocaine use. Neurology, 41, 946- 947. 30. Petty GW, Brust JCM, TatemichiTK, Barr ML (1990) Embolic stroke after smoking 'crack' cocaine. Stroke, 21, 1632-1635. 31. Deringer PM, Hamilton LL, Whelan MA (1990) A stroke associated with cocaine use (Letter to the Editor). Arch. Neurol., 47, 502. 32. Sawaya GR, Kaminski MJ (1990) Spinal cord infarction after cocaine use (Letter to the Editor). South. Med. J., 83, 6 0 1 - 602. 33. Kumor K (1990) Cocaine withdrawal dystonia (Letter to the Editor). Neurology, 40, 863. 34. Pascual-Leone A, Dhuna A (1990) Cocaineassociated multifocal tics. Neurology, 40, 999- 1000. 35. Pascual-Leone A, Dhuna A, Anderson DC (1991 ) Cerebral atrophy in habitual cocaine abusers: a planimetric CT study. Neurology, 41, 34 - 38. 36. Dhopesh V, Maany I, Herring C (1991) The relationship of cocaine to headache in polysubstance abusers. Headache, 31, 17 - 19. 37. Brody SL, Slovis CM, Wrenn KD (1990) Cocaine-related medical problems: consecutive series of 233 patients. Am. J. Med., 88, 325- 331. 38. Satel SL, McDougle CJ (1991) Obsessions and compulsions associated with cocaine abuse (Letter to the Editor). Am. J. Psychiatry, 148, 947. 39. Geracioti TD, Post RM (1991) Onset of panic disorder associated with rare use of cocaine. BioL Psychiatry, 29, 403- 406. 40. Novielli KD, Chambers CV (1991) Splenic infarction after cocaine use (Letter to the Editor). Ann. Intern. Med., 114, 251-252. 41. Freudenberger RS, Cappell MS, Hurt DA (1990) Intestinal infarction after intravenous cocaine administration. Ann. Intern. Meal., 113, 715-716. 42. Garfia A, Valverde JL, Borondo JC, Candenas I, Lucena J (1990) Vascular lesions in intestinal ischemia induced by cocaine-alcohol abuse: report of a fatal case due to overdose. J. Forens. Sci., 35, 740- 745. 43. Wanless IR, Dore D, Gopinath N, Tan J, Cameron R, Heathcote EJH, Blendis LM, Levy G (1990) Histopathology of cocaine hepatotoxicity: report of four patients. Gastroenterology, 98, 497 - 501. 44. Tabasco-Minguillan J, Novick DM, Kreek MJ (1990) Liver function tests in non-parenteral cocaine users. Drug Alcohol Depend., 26, 169 - 172. 45. Zagelbaum BM, Tannenbaum MH, Hersh PS (1991) Candida albicans corneal ulcer associated with crack cocaine (Letter to the Editor). Am. J. Ophthalmol., 111, 248 - 249. 46. Strominger MB, Sachs R, Hersh PS (1990)
28 Microbial keratitis with crack cocaine. Arch. Ophthalmol., 108, 1672. 47. Wang ESJ (1991) Cocaine-induced iritis. Ann. Emerg. Med., 20, 192-193. 48. Gordon AS, Moran DT, Jafek BW, Eller PM, Strahan RC (1990) The effect of chronic cocaine abuse on human olfaction. Arch. Otolaryngol. Head Neck Surg., 116, 1415 - 1418. 49. Snyderman C, Weissmann J, Tabor E, Curtin H (1991) Crack cocaine burns of the larynx. Arch. Otolaryngol. Neck Surg., 117, 792-795. 50. Rosenak D, Diamant YZ, Yaffee H, Hornstein E (1990) Cocaine: maternal use during pregnancy and its effect on the mother, the fetus, and the infant. Obstet. GynecoL Surv., 45, 348- 359. 51. Handler A, Kistin N, Davis F, Ferre C (1991) Cocaine use during pregnancy: perinatal outcomes. Am. J. Epidemiol., 133, 818-825. 52. Dombrowski MP, Wolfe HM, Welch RA, Evans MI (1991) Cocaine abuse is associated with abruptio placentae and decreased birth weight, but not shorter labor. Obstet. GynecoL, 77, 139 - 141. 53. Little BB, Snell LM (1991) Brain growth among fetuses exposed to cocaine in utero: asymmetrical growth retardation. Obstet. Gynecol., 77, 361 - 364. 54. Sztulman L, Ducey J J, Tancer ML (1990) Intrapartum, intranasal cocaine use and acute fetal distress: a case report. J. Reprod. Med., 35, 917-918. 55. Lipshultz SE, Frassica J J, Orav EJ (1991) Cardiovascular abnormalities in infants prenatally exposed to cocaine. J. Pediatr., 118, 44-51. 56. Shaw GM, Malcoe LH, Lammer EJ (1991) Maternal use of cocaine during pregnancy and congenital cardiac anomalies (Letter to the Editor). J. Pediatr., 118, 167- 168. 57. Bays J (1991) Fetal vascular disruption with prenatal exposure to cocaine or methamphetamine (Letter to the Editor). Pediatrics, 87, 4 1 6 - 417. 58. Rais-Bahrami K, Naqvi M (1990) Hydranen-
Chapter 4 A.L Green et al. cephaly and maternal cocaine use: a case report. Clin. Pediatr., 29, 729- 730. 59. Hutchings DE (1990) Issues of risk assessment: lessons from the use and abuse of drugs during pregnancy. Neurotoxicol. Teratol., 12, 183- 189. 60. Rosenstein BJ, Wheeler JS, Heid PL (1990) Congenital renal abnormalities in infants with in utero cocaine exposure. J. Urol., 144, 110 - 112. 61. Burkett G, Bandstra ES, Cohen J, Steele B, Palow D (1990) Cocaine-related maternal death. Am. J. Obstet. GynecoL, 163, 40-41. 62. Gonsoulin W, Borge D, Moise KJ, Jr (1990) Rupture of unscarred uterus in primigravid woman in association with cocaine abuse. Am. J. Obstet. Gynecol., 163, 5 2 6 - 527. 63. Conway EE, Jr, Mezey AP, Powers K (1990) Status epilepticus following the oral ingestion of cocaine in an infant. Pediatr. Emerg. Care, 6, 189- 190. 64. Rivkin M, Gilmore HE (1989) Generalized seizures in an infant due to environmentally acquired cocaine. Pediatrics, 84, 1100- 1102. 65. Dinnies JD, Darr CD, Saulys AJ (1990) Cocaine toxicity in toddlers (Letter to the Editor). Am. J. Dis. Child., 144, 743- 744. 66. Riggs D, Weibley RE (1991) Acute hemorrhagic diarrhea and cardiovascular collapse in a young child owing to environmentally acquired cocaine. Pediatr. Emerg. Care, 7, 154-155. 67. Kharasch S, Vinci R, Reece R (1990) Esophagitis, epiglottitis, and cocaine alkaloid ('crack'): 'accidental' poisoning or child abuse?
Pediatrics, 86, 117 - 119. 68. Bakheit AMO, Behan PO, Prach AT, Rittey CD, Scott AJ (1990) A syndrome identical to the neuroleptic malignant syndrome induced by LSD and alcohol (Letter to the Editor). Br. J. Addict., 85, 150- 151. 69. Howard R, Foerstl H (1990) Toad-lickers psychosis - - a warning (Letter to the Editor). Br. J. Psychiatry, 157, 779- 780.
4 Amphetamines (SEDA-15, 27) (see also Chapter 1)
As noted in previous Annuals, amphetamines, which are used recreationally, can be taken orally, intravenously, or by nasal inhalation. Their sympathomimetic properties can produce vascular complications, including intracerebral hemorrhage, stroke, myocardial infarction, cardiac failure, and arterial occlusion (1R). One recent report described a 47-year-old man who had been given dextroamphetamine for narcolepsy and developed an ischemic colitis. Treatment was switched to methylphenidate, with a good result. The authors noted that gastrointestinal toxicity from amphetamine use can be unpredictable. A second report described a 30-year-old man who developed an intraventricular hemorrhage after intravenous amphetamine (2c). A third report described 2 patients, both in their mid-thirties, who developed acute femoral neuropathy with iliopsoas infarction after intravenous substance abuse, including amphetamines. Although the mechanism involved in the development of the muscle ischemia was uncertain, the authors speculated that necrotizing arteritis associated with the abuse of amphetamines may have been involved (3c). Lastly, there has been a report of a man in his twenties who sustained an acute myocardial infarction after intravenous amphetamine (4c). Two recent reports have highlighted the dangers that can arise from the intentional swallowing of large amounts of amphetamine to avoid detection. The first report was of a 42year-old man who ingested a packet of amphetamines in order to avoid arrest, and developed colonic pseudo-obstruction, characterized by increased abdominal girth, nausea, vomiting, constipation, and abdominal pain. The syn9 1993 ElsevierSciencePublishers. All rights reserved Side Effects of Drugs Annual 16 M.N.G. Dukes and J.K. Aronson, eds. 22
Drugs of abuse drome resolved with medical management. The pathophysiology was thought to be related to an amphetamine-induced change in the parasympathetic/sympathetic balance in the gut (5c). A second report described a patient who swallowed 20 condoms containing amphetamine in an attempt to smuggle the drug. This practice, which has been referred to as 'body packing', has been described for other drugs. In the case reported, the packages began to leak and the patient developed symptoms of amphetamine toxicity. Surgical removal was required (6c). In previous Annuals the recent increase in the use of 'ice', a smokable crystalline form of amphetamine, has been noted. This year's literature included a report of 2 patients who developed toxic cardiovascular effects after smoking amphetamine. One patient, a 34-yearold woman, developed pulmonary edema and a dilated cardiomyopathy and the second, a 31year-old woman, had a myocardial infarction with cardiogenic shock and eventually died. The authors noted that although a direct causal relationship between the smoking of methamphetamine and these cases of cardiotoxicity could not be made unquestionably, it appeared that the drug was involved in the symptoms, perhaps through the development of systemic vasospasm (7R). A second report described a case of acute myocardial infarction which occurred shortly after the inhalation of crystal methamphetamine (8c). Taken together, these reports strongly suggest that cardiovascular complications of amphetamine abuse do not occur solely in people who use amphetamine by injection (8c). Congeners of amphetamine may have psychedelic properties. 3,4-methylenedioxyamphetamine (MDA), which produces both sympathomimetic and mescaline-like effects (9 R) and which has been abused for over 25 years, has been reported to have caused the death of a 26-year-old man secondary to apparent cardiac insufficiency (9R). A related
Drugs of abuse Chapter 4 compound, methylene-dioxymethamphetamine (MDMA or 'ecstasy'), also has hallucinogenic properties. Some investigators have suggested that MDMA can cause lasting destruction of the serotonergic system (10R - 12R). There has been a report of chronic paranoid psychosis in 2 men after the chronic use of MDMA. It was unclear whether the MDMA precipitated these psychoses in people who would ultimately have become psychotic even without the MDMA or whether it produced psychosis de novo (13c). In a second report the death of a 16-year-old girl who developed hyperthermia, hallucinations, agitation, and coagulopathy after the oral use of MDMA has been described. The authors emphasized that MDMA, which has been reported to produce a feeling of calmness and increased interpersonal sensitivity, can have dangerous adverse effects (14c). Finally, there have been 2 reports about amphetamine use which emphasized that doctors need to be alert to unusual effects of these drugs at unexpected times. The first report was of a man in his twenties who required surgery for a gunshot wound. When an intravenous line was inserted before surgery, he covertly selfinjected an amphetamine/heroin mixture. Shortly after, he was taken to surgery, where his heart rate and blood pressure increased. It was not until some time later that his pre-surgery substance abuse became known (15c). The second report was of a 40-year-old man who took what he thought was amphetamine, but was in fact a combination of p-methylamphetamine and N, p-dimethylamphetamine, before being given the beta-blocker practolol. The practolol produced a paradoxical increase in blood pressure, most likely because of an unopposed c~-agonistic effect from the amphetamines (16c). Cannabis (SED-12, 86; SEDA-12, 34; SEDA-
13, 24; SEDA-15, 28) The development of oral Candida infections in cannabis smokers has recently been studied (17c). The prevalence of positive cultures of Candida albicans and the density of these cultures were evaluated in 55 cannabis smokers, 58 tobacco smokers, and 50 non-smoking control subjects. The cannabis smokers had a higher rate of positive cultures for Candida
23
albicans than the cigarette smokers or control subjects. In addition, among the carriers of Candida infection, those who were cannabis smokers had a greater density of Candida albicans colonies than the carriers who were tobacco smokers or non-smokers, although the difference was not statistically significant. There has been a report of 13 chronic cannabis smokers, all younger than 55 years, who developed head and neck cancers (18R). The authors suggested that cannabis use might be associated with a risk of cancer of the upper airways. Cocaine (SEDA-12, 35; SEDA-13, 25; SEDA-14, 28; SEDA-15, 29) (see also Chapter 1) As in previous years, reports of the effects of cocaine abuse have dominated the literature. The manifestations of cocaine toxicity are farreaching and extend to most of the body's organs. In a review of the use of crack cocaine, Smart has noted the attractiveness of this type of cocaine for many users (19R). The adverse effects which distinguish the use of crack from the use of other forms of cocaine include pulmonary toxicity and the potential development of neurological symptoms in children passively exposed to cocaine smoke. Although crack cocaine is usually smoked, oral ingestion can produce toxicity. This may occur most commonly when law enforcement officers arrest cocaine smokers who are carrying the substance with them (20c). This should be remembered when such subjects develop unexplained cardiac, central nervous system, gastrointestinal, or autonomic symptoms (20c). Cardiovascular In a study of the pathology of the cardiac effects of cocaine abuse, Kolodgie et al. examined 5871 autopsy records, of which 495 (8.4o70) demonstrated cocaine abuse (21c). Acute coronary thrombosis was the cause of death in 6 patients. The autopsy findings in these patients were compared with those of 6 patients whose deaths were associated with atherosclerosis and coronary thrombosis without evidence of cocaine abuse. The authors suggested that adventitial mast cells, which were increased in the cocaine users, might have
24
potentiated the thrombosis and vasospasm and increased the risk of death in these patients (21c). Although coronary artery spasm has been proposed as a basis for cocaine-induced chest pain, the authors of a recent report of II patients who presented with chest pain at rest after cocaine use, have questioned this mechanism (22c). Coronary arteriography failed to demonstrate spasm, and ergonovine maleate challenge did not provoke a vasoconstrictive response in these patients. In addition, there was no evidence of myocarditis in endomyocardial biopsies. However, there was a significant thickening of the small coronary vessel walls, which suggested that cocaine-induced platelet thombosis may have plugged these narrowed vessels. Chest pain after cocaine has also been studied in 70 patients, 22 of whom developed acute myocardial infarction (23c). In 65070 of the patients who did not progress to myocardial infarction, the serum CK activity was increased, but the CK-MB fraction was not. Eight patients with infarctions were evaluated by cardiac catheterization; 4 had underlying coronary artery narrowing. Finally, there has been a report of a patient with a prolonged QT interval in whom torsades d e p o i n t e s developed after intravenous cocaine (24c). The increase in adrenergic tone following cocaine use may have triggered this episode of polymorphous ventricular tachycardia.
Respiratory
Four cases of an acute pulmonary syndrome after the inhalation of cocaine smoke have recently been described (25c). Two of the patients had prolonged pulmonary injury with alveolar damage and an inflammatory infiltration with a large number of eosinophils. The other 2 patients presented with diffuse infiltrates which resolved spontaneously within 36 hours. There has also been a report of 6 patients in whom pre-existing asthma was exacerbated by cocaine smoking (26c). The authors suggested that this complication of cocaine smoking, which could be fatal, has been generally under-estimated.
system The literature on the neurological effects of cocaine continues to expand. Neurovascular insult has been studied in 979 cocaine-related hospital admissions (27c). In 3070 of the admissions there was
Chapter 4 A . L Green et al.
neurovascular insult; 54070 of these were ischemic and 46070 were hemorrhagic. Since angiography failed to demonstrate vasculitis, the authors suggested that repeated use of cocaine may result in a gradually developing injury to the vascular endothelium. In another study, 24 cases of stroke in users of crack (or alkaloidal) cocaine were examined (28c). Ten of the patients had a hemorrhage; the remaining sustained cerebral infarctions, predominantly in the territory of the middle cerebral artery. The most common symptom before the stroke was headache. Again, cerebral angiography failed to reveal evidence of vasculitis. There have also been some interesting single case reports of cerebrovascular injury associated with cocaine. A case of dorsal pontine intraparenchymal hemorrhage was described after the use of crack in a 35-year-old man (29c). The presenting symptoms included diplopia, right-sided dysmetria, and an ataxic gait. Another case of cerebral infarction, in a 39-year-old woman, appeared to be due to an embolism from an atrial thrombns after the use of crack (30c). The authors suggested that a predisposing cardiomyopathy may have been due to cocaine use. In other reports, occlusion of the right cerebellar artery (31 c) and spinal cord infarction (32 c) have been noted in cocaine users. Movement disorders have been described in cocaine abusers, including a dystonia which developed shortly after the use of cocaine (33 c) and exacerbation of Tourette's syndrome with emergence of multifocal tics after the use of cocaine (34c). A study of computed axial tomographic scans of the brains of cocaine users showed cerebral atrophy in chronic cocaine users but not in first-time users or in nonusers with headache (35c). There was a positive correlation between the duration of use and the amount of atrophy. Finally, a population of inpatient polysubstance abusers with chronic migraine-type headaches has been described (36c). Although cocaine gave rapid initial relief from headache, it was also associated with an exacerbation of headache several hours after.
Nervous
Psychiatry
Cocaine commonly causes psychiatric complications. In a recent study more than one-third of the patients coming to the emergency room after taking cocaine had psy-
Drugs of abuse Chapter 4
chiatric complaints (37c). Obsessive thoughts and compulsive behavior emerged exclusively in a 34-year-old man during cocaine intoxication (38c); he was free of these symptoms otherwise. Interestingly, he had 2 brothers with obsessive compulsive disorder. A new onset panic disorder has also been reported after the use of cocaine (39c); the panic attacks recurred daily for 3 months before being controlled with drugs.
Hematological A case of splenic infarction following cocaine use has been described in a patient with sickle-cell trait (40c). The cocaine was thought to have caused a reduction in oxygen tension in the spleen, with resulting sickling. Gastrointestinal There is growing interest in the effects of cocaine on the gastrointestinal tract. Acute mesenteric ischemia has been reported in a 38-year-old cocaine abuser who sustained intestinal infarction after the intravenous use of cocaine (41c). The patient had 160 cm of infarcted bowel. Segmental intestinal ischemia has also been reported after cocaine and alcohol abuse (42c); pathological examination showed protrusion of the elastic membrane of the arterioles in the intestinal submucosa, which produced arteriolar narrowing. The authors suggested that the pathology supported the notion that cocaine abuse can result in vascular spasm. Unlike the report of Kolodgie (21c), there was no mention of the presence of adventitial mast cells. Last year we described a series of 4 patients in whom histopathological examination demonstrated centrilobular hepatic necrosis associated with cocaine abuse (43c). In a recent study of 46 nonparenteral cocaine users an attempt was made to confirm this finding, but significant liver function test abnormalities were found to be rare (occurring in 3 of 46 subjects, 2 of whom were carriers of hepatitis B)
(44c).
Special senses The ophthalmological literature on cocaine continues to grow. There has been a report of a ease of infection of the cornea with Candida albicans (45r possibly secondary to defects of the corneal epithelium, related to alkali burns from smoking crack cocaine. Bilateral staphylococcal ulcers, resulting
25 in visual defects, have also been described in a cocaine user (46c). In a third report, a case of iritis after the use of cocaine was described in a patient with a positive titer for HLA-B27 (47c). The authors proposed that the patient may have had a genetic predisposition to the development of iritis, which emerged with cocaine use. A report of 11 cocaine users has noted that their sense of smell was unimpaired; the authors suggested that most cocaine users, even those with intranasal damage, have normal olfaction (48c). In another report 2 cases of laryngeal burns from cocaine smoking have been described (49c). The difficulty of distinguishing these lesions from squamous cell carcinoma on magnetic resonance imaging was discussed.
Second-generation effects As noted in previous Annuals, cocaine can have profound effects on the developing fetus; this has continued to be emphasized in several recent reviews and case reports. Rosenak et ai. have noted that the use of cocaine during pregnancy 'creates a variety of grave medical problems which necessitate immediate attention' (50R). Handler et al. (51 R) have suggested that cocaine can cause spontaneous abortion, fetal death, prematurity, abruptio placenta, congenital malformations, and decreased fetal growth (51R). The recent literature has provided a number of reports which further support the dangers to the fetus of maternal cocaine use. The incidence of abruptio placenta among cocaine-using pregnant women has been reported to be nearly double the normal rate (52c); in 67 infants born to cocaine-abusing mothers there were asymmetries of brain growth (53c), and fatal hypoxemia has been reported in a fetus born to a mother who was using cocaine (54c). In 2 other reports (55 c, 56c) the use of cocaine during pregnancy has been linked with congenital cardiac abnormalities. There has also been a report of 7 infants born with congenital limb defects associated with the use of cocaine during pregnancy (57c). Lastly, there has been a report of an infant with hydrocephaly born to a cocaineusing mother (58c). However, despite these reports one reviewer noted that separating the effect of the drug on the development of congenital defects from the effects of inadequate maternal care is not always easy (59R). In addition, one investigator did not find an increased frequency of renal ab-
26 normalities in infants exposed to cocaine in utero, despite previous reports of such a finding (60c). The difficulty of doing adequate studies must be acknowledged. Assessment of the effects of cocaine on pregnant mothers may be more straightforward. There has been a report of a 26-year-old pregnant woman (at 32 weeks of gestation) who collapsed after first using cocaine and then having sexual intercourse (61c); both the mother and the fetus died. The authors suggested that the effects of sexual intercourse, pregnancy, and cocaine combined to produce a severe dysrhythmia with cardiac failure (61c). In another case a 19-year-old pregnant woman (at 32 weeks of gestation) presented with a ruptured uterus shortly after taking intravenous cocaine (62c). The authors suggested that cocaine-induced placental vasoconstriction and uterine contractility may have contributed to the event (62c). Cocaine can also produce severe toxicity in young children, often following accidental ingestion. There have been 3 reports of 5 cases of seizures in toddlers with cocaine toxicity (63 r - 65c). Three of the toddlers had eaten cocaine powder; 1 child had passively inhaled smoke while the parents were using free-base cocaine; in the last case the source of the cocaine was unknown. Two other reports have appeared: in the first, a 4-year-old child developed hemorrhagic diarrhea and cardiovascular col-
Chapter 4 A.I. Green et al.
lapse after eating crack cocaine (66c); in the second, a 20-month-old child developed esophagitis and epiglottitis after passively inhaling crack (67c). It is obvious from these reports that accidental ingestion of cocaine represents an extreme danger and should be thought of as an environmental hazard in homes in which cocaine is used.
HALLUCINOGENS There have been 2 recent and unusual reports of adverse effects of hallucinogens. A hypermetabolic state has been reported in a patient who had used lysergic acid diethylamide and alcohol (68c). The patient's presentation was similar to the neuroleptic malignant syndrome, with fluctuating consciousness, visual hallucinations, fever, and rigidity. The patient's creatine phosphokinase activity peaked at 3090 IU/1. The hallucinogenic properties of bufoterine (69R), which is present in the skin glands of a number of B u f o toad species, including the Australian cane toad, have been noted. Bufoterine can be obtained through licking the skin of the excited toad. When ingested, bufoterine, which inhibits monoamine oxidase, can cause sweating, palpitation, and gastrointestinal distress.
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28 Microbial keratitis with crack cocaine. Arch. Ophthalmol., 108, 1672. 47. Wang ESJ (1991) Cocaine-induced iritis. Ann. Emerg. Med., 20, 192-193. 48. Gordon AS, Moran DT, Jafek BW, Eller PM, Strahan RC (1990) The effect of chronic cocaine abuse on human olfaction. Arch. Otolaryngol. Head Neck Surg., 116, 1415 - 1418. 49. Snyderman C, Weissmann J, Tabor E, Curtin H (1991) Crack cocaine burns of the larynx. Arch. Otolaryngol. Neck Surg., 117, 792-795. 50. Rosenak D, Diamant YZ, Yaffee H, Hornstein E (1990) Cocaine: maternal use during pregnancy and its effect on the mother, the fetus, and the infant. Obstet. GynecoL Surv., 45, 348- 359. 51. Handler A, Kistin N, Davis F, Ferre C (1991) Cocaine use during pregnancy: perinatal outcomes. Am. J. Epidemiol., 133, 818-825. 52. Dombrowski MP, Wolfe HM, Welch RA, Evans MI (1991) Cocaine abuse is associated with abruptio placentae and decreased birth weight, but not shorter labor. Obstet. GynecoL, 77, 139 - 141. 53. Little BB, Snell LM (1991) Brain growth among fetuses exposed to cocaine in utero: asymmetrical growth retardation. Obstet. Gynecol., 77, 361 - 364. 54. Sztulman L, Ducey J J, Tancer ML (1990) Intrapartum, intranasal cocaine use and acute fetal distress: a case report. J. Reprod. Med., 35, 917-918. 55. Lipshultz SE, Frassica J J, Orav EJ (1991) Cardiovascular abnormalities in infants prenatally exposed to cocaine. J. Pediatr., 118, 44-51. 56. Shaw GM, Malcoe LH, Lammer EJ (1991) Maternal use of cocaine during pregnancy and congenital cardiac anomalies (Letter to the Editor). J. Pediatr., 118, 167- 168. 57. Bays J (1991) Fetal vascular disruption with prenatal exposure to cocaine or methamphetamine (Letter to the Editor). Pediatrics, 87, 4 1 6 - 417. 58. Rais-Bahrami K, Naqvi M (1990) Hydranen-
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