Drugs of abuse

A.I. Green and C. Salzman

4 GENERAL

Drug use among physicians and medical students A recent exhaustive survey looked at patterns of psychoactive drug use by physicians and medical students in the United States. Recreational drug use (at some time in their lives) occurred in 35% of physicians and 73% of medical students. Three per cent of physicians and 5% of medical students admitted to a history of drug dependence. Although these figures are similar to or lower than the percentages for many other professional groups in society, the report noted that as today's medical students become physicians, the proportion of all physicians using drugs recreationally may increase. The authors of the study and the author of an accompanying editorial recommended increased education about drug problems for both physicians and medical students

(1 R, 2R).

Ocular effects of drug abuse Ocular manifestations of drug abuse are quite varied, extending from purely pharmacological effects to those secondary to infections or vascular insult. Opiates cause miosis of the pupil. Cannabinols reduce intraocular pressure by an average of 25 % from baseline; the mechanism of this effect is not well understood. Stimulants such as amphetamines or cocaine may produce mydriasis and decreased accommodation. Phencyclidine can produce ptosis, decreased eye movements and corneal reflexes, and nystagmus on upward gaze (3R). Street drugs may be adulterated with quinine, which can have important ophthalmological effects. Quinine amblyopia has been described in drug abusers. Blindness results from the toxic effect of quinine on retinal ganglion cells. Permanent blindness as a sequela is rare, but a persistent reduction in visual acuity may occur (3R).

Side Effectsof DrugsAnnual 12 M.N.G. Dukes and L. Beeley,editors 9 ElsevierSciencePublishersB.V., 1988

Drugs of abuse Endophthalmitis may follow intravenous drug use. It results from use of unsterile needles or the dislodging of septic emboli from heart valves. Candida endophthalmitis has been reported in patients without systemic disease or immunodeficiency. It may present with uveitis, papillitis or vitritis. The prognosis depends on when treatment is initiated. Aspergillus endophthalmitis has also been described, but appears to be less common. Bacterial endophthalmitis is rarer than either of the mycotic varieties; the cases reported have been in conjunction with bacterial endocarditis in intravenous drug abusers. When the bacterial form does occur, however, it tends to be explosive; diagnosis requires a high index of suspicion (3R). Talc retinopathy has been reported following the intravenous abuse of methylphenidate, heroin, methadone, codeine, meperidine and pentazocine. Talc particles embolize to the lungs; eventually they may get into the systemic circulation. In the eye, they settle in the posterior retinal and choroidal circulation (3R). Lastly, psychiatric effects of the drugs may result in solar retinopathy , e.g. after users of hallucinogens have attempted to stare at the sun. Self-enucleation has also been reported in patients taking street drugs (3n).

Pulmonary complications in intravenous drug abusers In chronic intravenous users, superficial veins may no longer provide a reliable route for injection. For this reason, and also to provide an added 'rush', some users inject drugs directly into central veins in the groin or neck. Neck injections can result in abscesses, aneurysms and pneumothorax. A recent review from an urban hospital described no less than 84cases of injection-related pneumothorax occurring over a 2-year period; this collection represented approximately 20% of all their cases of pneumothorax during that time. Ten of the patients had more than 1 episode; one patient had 7. The authors noted that physicians treating intravenous drug abusers need to be alert to this potentially serious problem (4rt). A related complication was described in a recent report of a 36-year-old intravenous drug abuser

34 who developed fever, chills and a productive cough. X-ray examination revealed many subcutaneous needles; another needle was lodged in the lung tissue. History revealed that the patient had injected drugs into central veins (both the femoral and internal jugular) for the past 2 years. A number of the needles had broken off during use and had apparently then embolized from the injection site (5c).

INDIVIDUAL DRUGS Cannabis (SED-IO, 70; SEDA-8, 45; SEDA-9,34; SEDA-lO, 34; SEDA-11,32) Intravenous use The toxic effects of marijuana continue to be an important public health issue. Although most commonly smoked, it can be used intravenously; the injection of boiled marijuana has been associated with a distinct clinical syndrome - the 'intravenous marijuana syndrome'. A recent case-report detailed the 25th known case and reviewed the literature on this syndrome. Of the reported cases, 17 contained enough information to allow for analysis. The symptoms appear shortly following injection and include myalgia, nausea and vomiting, diarrhea, abdominal pain and weakness. Signs noted in over 40% of the cases include tachycardia, hypotension, fever, leukocytosis and tachypnea. Altered sensorium was found in only 12% of the cases. All patients recovered with supportive care. The pathogenesis is unclear, but may be due either to injection contaminants or to the high doses of cannabinoids used (6R). Respiratory Pulmonary complications in marijuana smokers continue to be described. The recent literature suggests (as noted before in the Annuals) that inhalation of marijuana may add to the risk of bacterial or fungal infection in immunosuppressed patients. An invasive pulmonary aspergillosis infection was described in a 60-year-old man undergoing chemotherapy for small-cell lung cancer. The patient died from the infection, which was possibly due to the use of 3-4 marijuana cigarettes per day for control of chemotherapy-induced nausea (7c). Another report evaluated the pulmonary effects of marijuana smoking, tobacco smoking, or both. It has been estimated that approximately 7% of people in the United States between ages 18 and 25 use marijuana daily. As many as one-halfofthese people smoke heavily, and, as they get older, could be exposing themselves to cumulative adverse health effects. In

Chapter 4 A.I. Green and C. Salzman the study reported, it was found that heavy, habitual marijuana smoking, whether combined with tobacco smoking or not, is associated with symptoms of chronic bronchitis and bouts of acute bronchitis. Marijuana smoking appears to have an adverse effect on large airway function, while tobacco smoking negatively impacts on small airway function. There are no apparent interactive effects between the two types of smoking. The long-term implication of the marijuana effects on pulmonary function is unknown (8R). Tumor induction A series of cases of head and neck tumors in young marijuana smokers (average age, 27.1 yr) was reported by a surgeon from California. Although it is difficult to be certain of the causal connection, the report described the unusual presentation of the tumors and reviewed the scant preliminary evidence linking marijuana smoking to human cancers. The author suggested that the level of suspicion should be raised (9R). Nervous system Psychiatric syndromes from marijuana use have been described in previous Annuals; new reports continue to appear in the literature. A recent report noted the case of a 26-year-old woman who developed 2 acute psychotic episodeswith thought disorder, delusions and ideas of reference during periods of moderate marijuana use; when not using the substance, she was free of psychosis (10c). Another report described a young man, with no previous psychiatric history, who became acutely psychotic aider smoking marijuana. The psychosis persisted for 2 weeks and then cleared (1 lC). Two other reports addressed the subject of depersonalization following marijuana use. One described 2 cases of prolonged depersonalization, each lasting over 10 months (12c). The second described 6 cases of depersonalization occurring during marijuana use. In each case the subject eventually experienced depersonalization when not using the drug. Fear of these unexpected episodes of depersonalization seemed to trigger anticipatory anxiety, panic attacks and agoraphobia. The authors noted that patients who developed agoraphobia following marijuana use tended to have a severe form and to differ from other agoraphobies in premorbid factors and demographic characteristics. They suggested that uncontrolled depersonalization from the marijuana might be instrumental in the development of agoraphobia (13c). The question of possible cerebral effects of chronic cannabis use has been debated for many years. The emotionality of the topic and the political overtones surrounding its discussion often make an adequate assessment difficult. A

Drugs of abuse Chapter4 recent extensive two-part review (14 R, 15R) evaluated the available information and delineated the methodological problems inherent in most of the studies. Many of the studies reviewed did not separately consider use of other drugs, which may have contributed to the effects observed. The issues of differential vulnerability to toxic effects, secondary effects of the drug use or drug lifestyle, amounts of drug used, and pre-existing 'toxic' effects in some subjects have been difficult to assess in many of the studies. Other sources of misinterpretation may have included experimenter bias (especially in such a political field) or withdrawal effects of the drugs themselves (14R). The authors of the review concluded that although subtle neurological signs (e.g. lateral gaze nystagmus) may be found, chronic marijuana-using subjects do not display gross structural or neurological deficits (14rt). Only 1 of 15 studies of psychological or neurological performance of chronic cannabis users found differences between the users and controls not readily explainable by various uncontrolled factors. The authors emphasized that the limitations of the existing studies allow for various interpretations, including the presence of subtle defects easily overcome by the subject, the presence of defects in a very small percentage of subjects, or the possibility that the tests used were not sensitive enough to detect defects. The greatest weakness of the existing studies is their retrospective design. The authors noted, however, that future prospective studies, which could test the issue of differential vulnerability, would be enormously expensive. The general conclusion from the review was that there is no convincing evidence that cannabis use causes chronic cerebral impairment (14R, 15R). One recent Swedish study addressed the question of cerebral blood flow in 9 chronic cannabis users and a matched set of controls. The investigators reported a moderate global reduction of cerebral blood flow in the heavy cannabis users. Re-examination in 4 subjects suggested that the reduction was reversible and may have been a result of decreased cerebral functioning during early detoxification (16c).

Endocrine, metabolic Two recent studies dealt with the hormonal effects of marijuana. In the first, it was noted that plasma luteinizing hormone (LH) was depressed and plasma cortisol elevated in 4 men after marijuana smoking. Non-significant changes occurred in prolactin, follicle-stimulating hormone, testosterone, free testosterone, and growth hormone. These

35 effects occurred at the same time as the subjective and psychomotor effects of smoking (17c). The second study examined LH in 17 healthy women who smoked marijuana cigarettes in a controlled setting. In these subjects, a 30% reduction of plasma LH levels was noted during the luteal phase of the menstrual cycle. The authors suggested that a shortened luteal phase may be associated with this LH suppression in women who use marijuana (18c).

Second-generation effects A recent U.S. study of nearly 4000 pregnancies addressed the question of the effect of maternal marijuana use on fetal growth. In the group studied, 9.5% of the women reported marijuana use. White women who were marijuana users had a higher risk of delivering a low-birth-weight infant than white non-users. There was also a tendency toward premature delivery in the white user group. Among non-whites, however, these differences were not seen. Whether non-whites were underreporting marijuana use, had other more important risk factors, or had raciallybased differential effects from marijuana could not be determined (19R). Therapeutic use Lastly, possible therapeutic effects of the cannabinoids have been discussed in previous volumes (SEDA-7, 9, 10). A recent letter suggested that the non-psychoactive cannabinoid, cannabidiol, may have beneficial effects in dystonic movement disorders. Two cases were described. The authors called for further studies in human movement disorders

(20c).

Cocaine (SED-IO, 77; SEDA-8, 46; SEDA-9, 35; SEDA-IO, 34; SEDA-I I, 32) Cocaine abuse continues to be an epidemic problem. It is now estimated that 30 million people in the United States have abused the drug and that each day another 5000 people use it for the first time. At one time, it was known as the 'champagne of drugs' - but now that it is less expensive and available in potent forms, it is a more commonly used 'recreational drug'. In the 1970s and early 1980s, many users were certain that the drug was non-addicting and generally quite safe. With increasingly pure cocaine available and an increase in smoking as the route of administration (21R), it has become obvious that an abstinence syndrome occurs with cessation of use (22c), that the drug has powerful reinforcingproperties, that the phenomenon of "reverse tolerance" may occur with heavy binge

36 use, and that the drug has important and dangerous toxicity (23a). Cardiovascular A number of recent reports and reviews have suggested that myocardial ischemia, acute myocardial infarction, ventrieular arrhythmias and sudden death occurring after the use of cocaine may be much more common than previously thought (23R--25 R, 26C--28 c, 29R). Twenty-one cases of acute myocardial infarction, temporally related to cocaine use, have been reported since 1982 (23R, 24R). Average age was in the low 30s. A number of these patients had normal coronary arteries by arteriography. Recent reviews have suggested that the mechanism may involve a coronary thrombosis or spasm (23R, 24R). It seems clear that cocaine use may be hazardous to people with underlying coronary artery disease; the damage probably comes from the increased heart rate, blood pressure and myocardial oxygen demand. Cocaine can produce cardiac arrhythmias. Sinus tachycardia, ventricular premature contractions, ventricular tachycardia, ventricular fibrillation or asystole have been described (23 R, 24R). Increased catecholamine activity secondary to the cocaine may be responsible, as may direct toxic effects of the drug. The arrhythmias may be secondary to a myocardial infarction or to hyperpyrexia that can occur after cocaine use. Cocaine-induced arrhythmias have been treated with propranolol, amitriptyline or nitrendipine (23R). There has been a recent report of ventricular tachycardia, cardiac arrest and death following cocaine use in a 20-year-old man with documented muscle-biopsy susceptibility to malignant hyperthermia (30c). [There has been speculation that the hyperpyrexia seen in some cocaine overdose cases might represent a variant of the neuroleptic malignant syndrome. If confirmed~ it would imply that treatment with standard dopamine antagonists such as chlorpromazine might be ineffective or possibly detrimental (310.] A recent report described an acute rupture of the ascending aorta following cocaine smoking. The man was known to have had chronic hypertension, but had been otherwise healthy. A large increase in systolic blood pressure was thought to be the cause (32c). Nervous system Numerous CNS effects following the use of cocaine have also been described. Cerebrovascular accidents (CVAs) following cocaine use have been described in 5patients; 4 of these had a subarachnoid hemorrhage, 3 from aneurysms and 1 from an arteriovenous malformation. A cerebral infarction has been reported in the infant of a woman

Chapter 4 A.I. Green and C. Salzman who used cocaine 15 hours before delivery. These CVAs may be the result of adrenergic stimulation and a sudden increase in blood pressure. It has been suggested that anyone with an arteriovenous malformation or an aneurysm may be at risk from cocaine-induced hypertension (23R). Seizures can occur after even a single dose of cocaine. This may be due to a lowering of the seizure threshold by cocaine; animal research also suggests that cocaine produces 'reverse tolerance' which could increase the likelihood of seizures over time. Diazepam appears to be helpful for the acute management of cocaine-induced seizures (23R). Sexual effects Possible effects of cocaine use on sexual activity are part of its street lore. Anecdotal reports suggest it may increase libido, delay ejaculation and intensify orgasm. But chronic use may produce sexual dysfunction. A recent study noted hyperprolactinemia with sexual dysfunction in 7 out of 10 chronic cocaine users. Bromocriptine given during cocaine abstinence reversed both abnormalities (33c). Miscellaneous effects Two brief reports deserve mention. The first involves rhabdomyolysis occurring in a young man following a cocaine (and opiate) overdose (34c). This series has previously reported on rhabdomyolysis as a consequence of phencyclidine overdose (SEDA-7, 38; SEDA-8, 46; SEDA-9, 34; SEDA-10, 36). The second describes madarosis (or bilateral loss of eyebrow and eyelash hair) in a cocaine smoker. The madarosis appeared to be secondary to hot cocaine vapors which singed the hair. Cocaine abstinence allowed the hair to regrow (35c). Second-generation effects Cocaine use by pregnant women can have important deleterious effects. Abruptioplacentae has been reported shortly after cocaine use, perhaps related to acute hypertension secondary to the drug (23~). A recent study assessed the toxic effect of maternal cocaine use on the fetus; control groups were pregnant polydrug abusers and pregnant non-drug users (36R). Stillbirth related to abruptio placentae was significantly more likely in the cocaine group; the rate of congenital malformations (skull defects) was higher as well. As noted in SEDA-11, neurobehavioral impairments have also been detected in infants born to cocaine-abusing women. Lastly, a recent ophthalmologic survey of 10 cocaine-intoxicated neonates showed increased dilated or tortuous ir~ vessels after birth (37c).

Drugs of abuse Chapter4 Diphenhydramine (see also Chapter 16) Diphenhydramine hydrochloride is available 'over the counter' in many countries; it is found in non-prescription soporifics. There was a recent report of a 34-year-old man who took 1600 mg/d for 1 month, after building up the dose over a period of 6 months. The medication was then reduced over 9 days; the patient (who was also taking thiothixene) experienced irritability, excessive blinking and increased defecation. The authors advised caution in prescribing this generally safe medication in patients at risk for substance abuse (38r

Inhalants (SEDA-9, 33; SEDA-11, 34) The inhalants are a group of substances which emit psychoactive vapors at room temperature. As noted in previous Annuals, as many as 17% of high school seniors in the United States have tried them at least once for recreational purposes. Children and adolescents may inhale vapor from such common substances as gasoline, paint, naphtha, lighter fluid, nail polish remover, typewriter correction fluid, aerosols, nitrous oxide, thinners, and other solvents. In addition, adults who work with solvent-inhalants, including shoemakers, cabinetmakers, printers, hair stylists, painters, drycleaners, gas station workers, doctors, and researchers, may be at risk for abuse. Toxic effects from inhalation of these substances inelude neurologic, respiratory, cardiac, hematologic, renal and hepatic problems (39R).

Toluene Toluene, a chemical commonly found in many solvent-inhalants, is known to cause multifoeal neurological disorders (40R). In heavy, chronic abusers, particularly those over the age of 20, there is evidence that abnormalities may persist (41R). Cerebellar signs may be found; in some cases CT abnormalities in the cerebellum have been detected. A recent review concluded that very prolonged exposure to toluene may also produce persistent cognitive changes - in memory, abstract ability and perceptual motor functions (41R). A recent paper has provided additional information on neurologic effects of toluene. A study was performed on 20 chronic toluene abusers, with a mean age of 27, who were free of the substance for at least 4 weeks prior to evaluation. The mean duration of toluene abuse for the group was over 10 years. Sixty-five percent had some neurological impairment. Sixty percent had cognitive difficulties includingattention, memory and visuospatial deficits.

37 The pattern was similar to that seen in subcortical dementias. Apathy and flattened affect were present. Forty-five percent had cerebellar signs; 25% had cranial nerve or brainstem abnormalities; 15~/o had tremor. No peripheral neuropathy was found. In the 5 patients followedfor at least 6 months of abstinence, some continued improvement was noted over time (40R, 42r).

Nitrous oxide (SEDA-9,33)

Nitrous oxide abuse may similarly have neurological effects.

A 25-year-oldstudent had been a he~{vyabuser of nitrous oxide, but had reportedly stopped the heavy use 6-7 months prior to the evaluation. He developed sensorimotor polyneuropathy and myelopathy. Electrophysiological studies showed impairment in nerve conduction, which improved over time with continued abstinence. Although his vitamin B~2was normal, the nitrous-oxide-inducedcondition resembled combined system disease seen in patients with vitamin Bt2 deficiency (43c).

Pentazoeine and tripelennamine (SEDA-IO, 130; SEDA-11,34) As noted previously in this series (SEDA-7-11), the intravenous use of the combination ofpentazocine and tripelennamine has been popular in some areas of the United States for over a decade. Known on the streets as 'Ts and Bs' or 'Ts and Blues', the combination tends to be used by addicts at times of limited heroin availability. Toxicity resulting from intravenous use has been particularly severe. This had led the manufacturer ofpentazocine to reformulate the tablet with 0.5 mg ofnaloxone in each 50 mg pentazocine tablet, in the hope of discouraging intravenous abuse. (Naloxone will block pentazocine's effects during intravenous, but not oral, use). Despite reports that this reformulation of pentazocine has decreased the use of the combination, two recent articles describe further complications. The first described 3 cases of nephrotic syndrome secondary to the intravenous abuse of Ts and Bs. Light microscopy showed focal to diffuse giomerulosclerosis; visceral epithelial cell foot process effacement and microvillusformation was seen on electronmicroscopic examination.The authors suggested that immune complex formation, secondary either to the narcotic itself or to some component of the injected substance, may have initiated glomerular damage; repeated insults would have allowed for the development of chronic glomerulonephritis.Since the lesions resembled those seen in heroin addicts, the authors proposed the generic term 'opiate nephropathy' (44c). The second report reviewed the prenatal and postnatal effects of Ts and Bs abuse in pregnant women. The study took place during a 2-year period prior to

38 the addition of naloxone to the pentazocine tablet. FiRy subjects were studied and compared to nondrug-using controls. Anemia, syphilis, hepatitis and gonorrhea were more common in the subjects than in the control women. Growth retardation in the fetus produced low-birth-weightinfants. Withdrawal symptoms occurred in 35% of the infants, but were generally short-lived. The authors advocated improved prenatal care for'Is and Bs mothers as well as close monitoring of their children in the postnatal period (45R). Phencyclidine (SED-1 O, 77; SEDA-8, 46; SEDA-9,34; SEDA-IO, 35; SEDA-II,35) Phencyclidine, as discussed in previous Annuals (SEDA-7, I 1), is a commonly abused drug. Reports in the past year discussed two aspects of the clinical toxicity of this compound in human abusers: rhabdomyolysis and psychosis. Over the past decade, a number of reports have appeared in the literature about the renal effects of phencyclidine abuse, including myoglobinuria and rhabdomyolysis. A recent review summarized the literature on this important topic. It reported on 30 eases of rhabdomyolysis associated with pheneyclidine intoxication. Their data suggest that 0.5-1.0% of patients who come to the hospital for treatment ofphencyclidine intoxication are at risk of developing rhabdomyolysis-associated acute renal failure; approximately 2.5% of patients will develop rhabdomyolysis without renal failure. The role of physical restraints (used to control violent behavior) in the etiology of these effects has been suggested by a number of investigators; sedation rather than physical restraints has been recommended. Although acidification will increase the rate of excretion of the phencyclidine, acidification of the urine

Chapter 4 A.L Green and C. Salzman may also increase nephrotoxicity in patients who have developed myoglobinuria. Therefore, in patients with myoglobinuria or si~ificant hyperuricemia, restoration of volume loss, use of mannitol and alkalinization of urine may be of benefit (46R). Phencyclidine-stimulated psychosis is an important clinical problem. It can mimic schizophrenia or affective psychoses (47R), and can present in cases with no prior history of psychiatric problems. A recent case-report described a 30-year-old woman who had attempted to drown her son after a 5-6 day agitated, delusional and confused period. Although she gave no history of prior street drug use, a screen of CSF and blood (using a gas chromatography-mass spectroscopy assay) was positive for phencyclidine.The patient responded to haloperidol (48c). A second case-report described a 21-year-oldman who had a history of prior phencyclidine-indueed psychotic episodes, generally responsive to neuroleptie agents. In the episode described, however, the psychosis was unresponsive to high-dose neuroleptics and benzodiazepines. Eleetroconvulsivr therapy (ECT) was then used for control of the patient's violence; the ECT produced a dramatic improvement in the symptomatology. The authors suggested that the therapeutic benefit may have been related to ECT's effects on sigma-opioid receptors (49c). Propylhexedrine (SEDA-IO, 4, 13) Propylhexedrine, for most users an innocent nasal decongestant in 'inhaler form' (but in fact pharmacologically similar to methamphetamine), has been linked with serious toxicity following abuse. This subject is reviewed in Chapter 1.

REFERENCES 1. McAuliffe WE, Rohman M, Santangelo Set al (1986) Psychoactive drug use among practicing physicians and medical students. N. Engl. J. Meal., 315, 805. 2. Lewis DC (1986) Doctors and drugs. N. Engl. J. Med., 315, 826. 3. McLane NJ, Carroll DM (1986) Ocular manifestations of drug abuse. Surv. Ophthalmol., 30, 298. 4. DouglassRE, Levison MA (1986) Pnenmothorax in drug abusers: an urban epidemic? Am. Surg., 52, 377. 5. AngelosMG, Sheets CA, Zych PR (1986) Needle emboli to lung followingintravenous drug abuse. J. Emerg. Med., 4, 391.

6. Brandenburg D, Wernick R (1986) Intravenous marijuana syndrome. West. I. Med., 145, 94. 7. Sutton S, Lum BL, Torti FM (1986) Possible risk of invasive pulmonary asperglllosis with marijuana use during chemotherapy for small cell lung cancer. Drug Intell. Clin. Pharra., 20, 289. 8. Tashkin DP, Coulson AH, Clark VA et al (1987) Respiratory symptoms and lung function in habitual heavy smokers of marijuana alone, smokers of marijuana and tobacco, smokers of tobacco alone, and nonsmokers. Am. Rev. Respir. Dis., 135, 209. 9. Donald PJ (1986) Marijuana smoking - possible cause of head and neck carcinoma in youngpatients. Otolaryngol. Head Neck Surg., 94, 517.

Drugs of abuse Chapter 4 10. Drummond LM (1986) Cannabis psychosis: a case report. Br. J. Addict., 81, 139. 11. Onyango RS (1986) Cannabis psychosis in young psychiatric inpatients. Br. J. Addict., 81,419. 12. Keshavan MS (1986) Prolonged depersonalization following cannabis abuse. Br. J. Addict., 81,140. 13. Moran C (1986) Depersonalization and agoraphobia associated with marijuana use. Br. J. Med. Psychol., 59, 187. 14. Wert RC, Raalin ML (1986) The chronic cerebral effects of cannabis use. I. Methodological issues and neurological findings. Int. J. Addict., 21,605. 15. Weft RC, Raulin ML (1986) The chronic cerebral effects of cannabis use. II. Psychological findings and conclusions. Int. J. Addict., 21,629. 16. Tunving K, Thulin SO, Risberg J et al (1986) Regional cerebral blood flow in long-term heavy cannabis use. Psychiatry Res.. 17, 15. 17. Cone El, Johnson RE, Moore JD etal (1986) Acute effects of smoking marijuana on hormones, subjective effects and performance in male human subjects. Pharmacol. Biochem. Behav., 24, 1749. 18. Mendeison JH, MeUo NK, Ellingboe J e t al (1986) Marijuana smoking suppresses luteinizing hormone in women. J. Pharmacol. Exp. Ther., 237, 862. 19. Hatch EE, Bracken MB (1986) Effect of marijuana use in pregnancy on fetal growth. Am. J. Epidemiol., 124, 986. 20. Sandyk R, Snider SR, Cosroe P (1985) Cannabidiol in dystonic movement disorders. Psychiatry Res., 18, 291. 21. Kuiberg A (1986) Substance abuse: clinical identification and management. Pediatr. Clin. North Am., 33, 325. 22. Gawin FH, Kleber HD (1986) Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Arch. Gen. Psychiatry, 43, 107. 23. Cregler LL, Mark H (1986) Medical complications of cocaine abuse. N. Engl. J. Med., 315, 1495. 24. Cregier LL, Mark H (1986) Cardiovascular dangers of cocaine abuse. Am. J. Cardiol., 57, 1185. 25. Isner JM, Estes NA, Thompson PD et al (1986) Acute cardiac events temporally related to cocaine abuse. N. Engl. J. Med., 315, 1438. 26. RoUingher IM, Beizberg AS, Macdonald IL (1986) Cocaine-induced myocardial infarction. Can. Med. Assoc. J., 135, 45. 27. Simpson RW, Edwards WD (1986) Pathogenesis of cocaine-induced ischemic heart disease. Arch. Pathol. Lab. Med., li0, 479. 28. Weiss ILl (1986) Recurrent myocardial infarction caused by cocaine abuse. Am. HeartJ., 111,793. 29. Mathias DW (1986) Cocaine-associated myocardial ischemia. Am. J. Med., 81,675. 30. Loghmanee F, Tobak M (1986) Fatal malignant hyperthermia associated with recreational cocaine and ethanol abuse. Am. J. Forens. Med. Pathol.. 7, 246.

39 31. Kosten TR, Kleber HD (1987) Sudden death in cocaine abusers: relation to neuroleptic malignant syndrome. Lancet, 1, 1198. 32. Barth CW, Bray M, Roberts WC (1986) Rupture of the ascending aorta during cocaine intoxication. Am. J. Cardiol., 57, 496. 33. CocoresJA, Dackis CA, Gold MS (1986) Sexual dysfunction secondary to cocaine abuse in two patients. J. Clin. Psychiatry, 47, 384. 34. Schwartz JG, McAfee RD (1987) Cocaine and rhabdomyolysis. J. Fam. Pract., 24, 209. 35. Tames SM, Goldenring JM (1986) Madarosis from cocaine use. N. Engl. J. Med., 314, 1324. 36. Bingol, Fuehs M, Diaz V e t al (1987) Teratogenicity of cocaine in humans. J. Pediatr., 110, 93. 37. Isenberg SJ, Spierer A, Inkelis SH (1987) Ocular signs of cocaine intoxication in neonates. Am. J. Ophthalmol., 103, 211. 38. Feldman MD, Behar M (1986) A case ofmassive diphenhydramine abuse and withdrawal from use of the drug. J. Am. Med. Assoc., 255, 3119. 39. Westermeyer J (1987) The psychiatrist and solvent-inhalant abuse: .recognition, assessment, and treatment. Am. J. Psychiatry, 144, 903. 40. Hormes JT, Filley CM, Rosenberg NL (1986) Neurologic sequelae of chronic solvent vapor abuse. Neurology, 36, 698. 41. Run MA (1986) Volatile substance abuse: a review of possible long-term neurological, intellectual and psychiatric sequelae. Br. J. Psychiatry, 148, 235. 42. Fornazzari L, Riley D, Wu P etal (1987) Toluene abuse and neurologic impairment. Neurology, 37, 356. 43. Heyer El, Simpson DM, Bodis-Wollner I e t al (1986) Nitrous oxide: clinical and electrophysiologic investigation of neurologic complications. Neurology, 36, 1618. 44. May DC, Heiderman H, Eigenbrodt EH et al (1986) Chronic sclerosing glomerulopathy (heroinassociated nephropathy) in intravenous T's and Blues abusers. Am. J. Kidney Dis., 8, 404. 45. Von Almen WF, Miller JM (1986) ffs and Blues' in pregnancy. J. Reprod. Med., 31,236. 46. Patel R, Connor G (1985-86) A review of thirty cases of rhabdomyolysis-associated acute renal failure among phencyclidine users. J. Toxicol. Clin. ToxicoL, 23, 547. 47. MeCarron MM (1986) Phencyelidine intoxication. In: Clouct DH (Ed), Phencyclidine: An Update, p 209. NIDA Res. Monogr. No. 64, DHHS, ADAMHA, Rockville, MD. 48. Foster HM, Narasimhaehari N (1986) Phencyclidine in CSF and serum: a ease of attempted filicide by a mother without a history of substance abuse. J. Clin. Psychiatry, 47, 428. 49. Grover D, Yeragani VK, Keshavan MS (1986) Improvement ofphencyclidine-assoeiated psyehosis with ECT. J. Clin. Psychiatry, 47, 477.