Drugs of abuse

Eileen Wong and Jayendra K. Patel

4 (SED-14, 100; SEDA-23, 34; SEDA-24, 32; SEDA-25, 34) AMPHETAMINES

Amphetamine Cardiovascular Two new cases of myocardial infarction following use of amphetamine

Drugs of abuse have suggested that calcium channel blockers may play an important role in the treatment of myocardial infarction due to amphetamine use or abuse. In one patient, administration of betablockers caused anginal pain, suggesting that they should be avoided. All the patients except one had a good outcome.

have been reported (1 At, 2Ar).

Nervous system 9 A 34-year-old man who smoked a pack of cigarettes a day took amphetamine for mild obesity. He developed an acute myocardial infarction 1 week later. Echocardiography showed inferior left ventricular hypokinesia and a left ventricular ejection fraction of 50%. Coronary cineangiography showed normal coronary arteries, but confirmed the inferior left ventricular hypokinesia. Blood and urine toxicology were positive only for amphetamine. 9 A 31-year-old man developed generalized discomfort after injecting four doses of amphetamine and methamphetamine over 48 hours, but no chest pain or tightness or shortness of breath. Electrocardiograms showed inverted T waves and left bundle branch block. Echocardiography showed reduced anterior wall motion. The authors reviewed other reported cases of myocardial infarction associated with amphetamine. The patients were in their mid-thirties and most were men. The interval from the use of amphetamines to the onset of symptoms varied from a few minutes to years. No specific myocardial site was implicated. Coronary angiography in most cases showed non-occlusion. The cause of myocardial ischemia in these cases was uncertain, even though coronary artery spasm followed by thrombus formation was considered the most likely underlying mechanism. Some have suggested that electrocardiographic and biochemical cardiac marker testing should be considered in every patient, with or without symptoms suggesting acute coronary syndrome, after the use of amphetamines. Others 9 2003 Elsevier Science B.V. All rights reserved.

Side Effects of Drugs, Annual 26 J.K. Aronson, ed. 30

Vertebral artery dissection

has been reported in a patient taking amphetamine and methamphetamine (3Ar). A healthy 40-year-old right-handed man presented with a 3-day history of an occipital headache and imbalance. He had a 3-year history of daily oral amphetamine abuse with escalating quantities, the last occasion being 12 hours before the onset of the symptoms. He had a history of "speed" abuse and a 20-pack-year history of tobacco use. He had mild right ann dysmetria without ataxia. His brain CT scan without contrast was normal. He then developed nausea, vomiting, visual loss, and progressive obtundation. He had hypertension (160/90 mmHg), bilateral complete visual loss, right lower facial weakness, mild dysarthria without tongue deviation, divergent gaze attenuated by arousal, bilateral truncal and appendicular dysmetria with inability to stand and walk, and generalized symmetrical hyper-reflexia with extensor plantar reflexes. His urine screen was positive for methamphetamine. A brain MRI scan showed infarction of both medial temporal lobes, the left posteromedial thalamus, and the right superior and left inferior cerebellum. Magnetic resonance angiography and fat saturation MRI showed reduced flow in the left vertebral artery and a ring of increased signal within its lumen, consistent with hematoma and dissection. The authors suggested that there was a possible association between the use of amphetamines and vertebral artery dissection.

Methamphetamine Psychiatric

Methampbetamine is difficult to control legally, as it is easily manufactured

Drugs of abuse

Chapter4

in a small laboratory. Chronic methamphetamine use is associated with psychiatric symptoms, such as psychosis and anxiety. Methamphetamine increases the activity of dopamine, mainly by inhibiting the dopamine transporter. However, this does not explain why psychosis persists even when the methamphetamine is no longer present in the body (4R). Chronic methamphetamine use has been reported to reduce dopamine transporter density in the caudate/putamen and nucleus accumbens. However, previous studies have been criticized for not controlling for other drug use. Dopamine transporter density in the brain has been investigated during a period of abstinence in 11 methamphetamine monodrug users and nine healthy subjects, all men (5c). The dopamine transporter density of methamphetamine users was significantly lower in the caudate/putamen, nucleus accumbens, and prefrontal cortex than in the controls. The severity of psychiatric symptoms correlated with the duration of methamphetamine use. The reduction in dopamine transporter density in the caudate/putamen and nucleus accumbens was significantly associated with the duration of methamphetamine use and closely related to the severity of persistent psychiatric symptoms. The reduction in dopamine transporters may be long lasting, even if methamphetamine is withdrawn. Only some methamphetamine users develop psychosis, not all (4R). In laboratory animals, methamphetamine is toxic to dopamine terminals. In 15 subjects (six men and nine women, mean age 32 years), who met the criteria for methamphetamine abuse, and 18 healthy volunteers (12 men and six women), there was a significant reduction in the number of dopamine transporters in detoxified methamphetamine abusers compared with controls (mean values of 28% in the caudate and 21% in the putamen) (6c). This was associated with poor motor and memory performance. The reductions in dopamine transporters in the methamphetamine abusers were smaller than those found in patients with Parkinson's disease and occurred in subjects who had been abstinent for 11 months. Since significant reductions in dopamine transporters occur with both age and methamphetamine use, it is possible that methamphetamine will be associated with a higher risk of parkinsonian symptoms in abusers later in life.

31 Glucose metabolism in the brain has been studied using positron emission tomography, to look for evidence of functional changes in regions other than those innervated by dopamine neurons in 15 detoxified methamphetamine abusers and 21 controls (7c). Whole-brain metabolism in the methamphetamine abusers was 14% higher than in the controls. The difference was largest in the parietal cortex (20%), but there was significantly lower metabolism in the thalamus (17%) and striatum (12% caudate and 6% putamen). The authors suggested that methamphetamine, in doses abused by humans, causes long-lasting metabolic changes in brain regions connected with dopamine pathways, but also in areas that are not innervated by dopamine. The effects of protracted abstinence on loss of dopamine transporters in the striatum in 5 methamphetamine abusers has been evaluated during short-term abstinence and then retested during protracted abstinence (12-17 months) (8c). The dopamine transporters increased in number, providing hope for effective treatment; however, this regeneration was not sufficient to provide complete functional recovery, as measured by neuropsychological tests. Drug dependence The role of dopamine in the addictive process has been explored (9c). The authors raised the possibility that the orbitoprefrontal cortex is linked to compulsive drag abuse. They recruited 15 methamphetamine users and 20 non-drug user controls. The methamphetamine abusers had significantly fewer dopamine D2 receptors than the controls. There was an association between lower numbers of dopamine De receptors and metabolism in the orbitofrontal cortex in the methamphetamine users. These findings are similar to those observed in cocaine, alcohol, and heroin users. The authors suggested that De receptormediated dysregulation of the orbitofrontal cortex could be a common mechanism underlying loss of control and compulsive abuse of drugs.

Methylenedioxymethamphetamine (ecstasy, MDMA) Concern has been raised about the increasing use of ecstasy in Europe in the last 10

32 years (10Cr), particularly the U K and the Netherlands. M D M A and drugs such as its Ndemethylated derivative (MDA), 3,4-methylenedioxyethylamphetamine (MDEA), N-methylbenzodioxazolylbutamine (MBDB), and 4bromo-2,5-dimethoxyphenylethylamine (2-CB or Nexus) are often grouped together as "ecstasy". Some have used the term "enactogen", meaning "touching within", to describe MDMA. The patterns and trends of substance use among college students have been evaluated over a 30-year period ( l l C ) . Alcohol use remained stable, but illicit drug use peaked in 1978 and fell sharply over the next 20 years. M D M A was the exception: its use rose from 4.1% in 1989 to 10% in 1999. M D M A was the second most frequently tried illicit drug after marijuana.

Chapter 4

Eileen Wong and Jayendra K. Patel

Respiratory Pneumomediastinum

after

M D M A has been reported (13c). 9 A 16-year-old boy took six ecstasy tablets over 2 hours. A period of vomiting ensued and he developed chest pain and swelling in the neck. A chest X-ray showed pneumomediastinum. He was managed conservatively and his emphysema settled uneventfully within 2 days. The authors reported that five such cases have been reported in the past 4 years in the British literature; the respiratory complications were thought to be due to severe physical exercise or secondary to vomiting. It is therefore possible that this complication may not be due to a direct effect of M D M A , but rather a consequence of repeated Valsalva maneuvers associated with the dance habits of ecstasy users or vomiting induced by the drug.

C a r d i o v a s c u l a r Cardiotoxicity following ecstasy use has been reported (12Ar). 9 A 16-year-old boy took three tablets of ecstasy and amphetamine 0.3 g and several hours later had convulsions and a temperature of 40.9~ His heart rate was 210 and his blood pressure 100/75 mmHg. His creatine kinase activity was raised and he had myoglobinuria, renal impairment, hyperkalemia, and hypocalcemia. An electrocardiogram showed ventricular and supraventricular tachycardias but no myocardial ischemia. A diagnosis of serotonin syndrome due to ecstasy ingestion with associated hyperpyrexia and rhabdomyolysis was made. Following active treatment, his condition stabilized, with restoration of sinus rhythm and normal urine output. However, 12 hours later he developed jaundice, raised liver enzymes, and coagulopathy, suggesting acute liver failure due to ecstasy. With supportive treatment, his liver function improved. However, another 12 hours later, he developed shortness of breath associated with right-sided chest signs and X-ray changes compatible with aspiration pneumonia, and required emergency intubation 4 days later. He developed pulmonary edema, his pulmonary artery was occluded, and an echocardiogram showed globally impaired left ventricular function with an ejection fraction of 30-35%; there was electrocardiographic T wave inversion. Primary myocardial damage causing cardiac dysfunction was investigated using serial creatine kinase and troponin measurements. He recovered completely with treatment and an echocardiogram showed an ejection fraction of 60%. The authors reported that this was the first case report of clinical, radiological, biochemical, and echocardiographic evidence of myocardial damage and cardiac dysfunction following ecstasy and amphetamine use.

The cognitive effects of MDMA Recently, several studies have focused on the cognitive effects o f MDMA, and a review o f the adverse effects o f MDMA in animals has raised concerns about potential toxicity in humans (14R). MDMA can selectively damage brain serotonin (5-HT) neurons in animal brains, even at doses within the range o f those typically used recreationally. In many studies lasting reductions in various brain 5-HT markers have been reported in MDMA-treated animals. Axons Of 5-HT neurons were damaged in MDMA-treated animals, including monkeys, and neurotoxic effects o f MDMA have been observed in every animal species studied so far. In non-human primates, the toxic dose of MDMA closely approaches the dose used by humans. In 30 regular ecstasy users (drug use ten or more times per month) and 31 ecstasy-free controls, prospective memory--the process o f remembering to do things at some future time-was assessed using a self-report questionnaire (15c). Ecstasy users reported global impairment in prospective memory, even after controlling f o r the use o f other drugs. The authors observed that their finding o f impairment o f cognitive functions, especially memory, in regular ecstasy users is similar to findings in other recent studies. They postulated that serotonergic toxicity secondary to chronic MDMA exposure

Drugs of abuse

Chapter 4

can cause cognitive impairment, as serotonergic pathways are involved in memory function. More support f o r a relation between memory impairment, serotonin neurotoxicity, and chronic MDMA use has come from a study of cognitive performance and serotonin function in two groups of 21 men with moderate or heavy MDMA use and a control group of 20 men who had not used MDMA (16R). Ecstasy users had a broad spectrum of statistically significant but clinically subtle impairment of memory and prolonged reaction times. Heavy users had larger effects than moderate users. Serotonergic function was assessed in a double-blind crossover challenge with dexfenfluramine 30 mg or placebo. Release of cortisol, but not prolactin, after dexfenfluramine was significantly reduced in both groups of ecstasy users compared with controls. According to the authors, these neuroendocrine findings are similar to those observed in animals and humans. Recent exposure to ecstasy, psychosocial profiles, and the use of other drugs did not explain the differences. As mentioned above, animal studies have shown reductions in various serotonin markers in the brain. The density of serotonin transporters (SERTs) in humans can be measured by neuroimaging techniques, such as SPECT and PET. Two groups of ecstasy users (22 recent but abstinent and 16 ex-users) were compared with ecstasy-na~'ve controls (17c). In subjects who had stopped using MDMA more than 1 year before the study, cortical densities of SERTs did not differ from those of controls. However, recent MDMA users had global reductions in SERTs. In addition, individuals who had stopped using MDMA had a deficit in verbal memory similar to that in current MDMA users. Higher lifetime doses of MDMA were associated with greater impairment o f immediate verbal memory. The authors suggested that the absence of reductions in SERT densities in exMDMA users suggested reversibility of MDMAinduced changes in brain SERTs. Thus, MDMA use can lead to neurotoxic changes in human cortical 5-HT brain neurons, but these changes may be reversible. However, functional consequences of MDMA on cortical brain 5-HT neurons may not be reversible, as seen by impaired memory function in this group, similar to that in current MDMA users. The amino acid N-acetylaspartate is a robust, non-specific marker of neuronal loss or

33 brain dysfunction. It is detectable by proton magnetic resonance spectroscopy (MRS). The ratio of creatine to phosphocreatine, another marker that remains stable in many brain diseases, can also be assessed using MRS. In a recent study, the ratio of N-acetylaspartate to creatine/phosphocreatine was used to determine whether there are memory deficits in MDMA users and whether there are changes in specific brain regions (18c). Eight men with a history of MDMA use and seven MDMA-na~'ve male controls took part. The findings included a significant difference in delayed recall between MDMA users and MDMA-na~ve controls. There was a strong association between impaired memory function in MDMA users and neuronal pathology, specific to the prefrontal cortex. Poorer performance on verbal memory testing was associated with greater neuronal loss or dysfunction in MDMA users. These findings implicate MDMA as a cause of serotonergic neuronal damage and memory impairment. Another group has assessed cognitive function in 80 subjects who were non-users, novice users, regular users, or currently abstinent users of MDMA (19c). Compared with the nonusers, all three groups of MDMA users had significantly poorer verbal fuency and immediate and delayed prose recall. Days since last use and total lifetime consumption of MDMA made separate contributions to the variance in recall scores. Novice and currently abstinent users likewise had significantly poorer immediate recall than non-users. The novice users had milder impairment than the regular users, while those who were currently abstinent performed at a similar level to regular users. These deficits were not attributable either to differences in general reasoning ability or to impairment of working memory. The authors expressed concern that increased use of MDMA in large numbers of young people and its enduring effects on memory are under-appreciated consequences. However, cognitive impairment and MDMA use is a complex association to study, with difficult confounding variables. For example, MDMA users may consume cannabis to relieve the negative experience that occurs when MDMA-related euphoria diminishes. In a recent study the concurrent use of cannabis was controlled by the recruitment of 31 drug-na't've controls, 11 MDMA/cannabis users, and 18 cannabis users (20c). Users were instructed

34 to abstain from drug use f o r 48 hours before testing. The MDMA/cannabis user group had deficits in learning, memory, verbal word fluency, speed o f processing, and manual dexterity compared with the healthy controls. The authors suggested that the deficits in the drug group were not related to MDMA. They observed that the study group did not perform poorly compared with those who used cannabis only. Moreover, the finding that the MDMA/cannabis group was no different from the cannabis group suggested that MDMA does not cause significant cognitive deficits. The poorer performance o f the MDMA/cannabis users was very little affected by the frequency o f use or total MDMA consumption. However, co-varying f o r indices o f cannabis consumption removed most o f the significant differences between the groups. On the other hand, MDMA did affect the measures o f working memory, such as forward and backward digit span. The authors raised the question o f whether previous evaluations o f the effects o f MDMA on cognition had been confounded by the concomitant use o f cannabis. Risk factors Sex differences in subjective experiences o f MDMA use have been reported. Three previously published controlled studies o f the acute effects o f MDMA in healthy subjects with no or single previous MDMA experience have been summarized (21M). There were 74 subjects (54 men and 20 women), aged 2049 (mean 27) years, o f whom 69 were ecstasynaive and five had used it on one or two occasions before. All had been screened using a semi-structured interview, and anyone with a personal or family history o f mood disorders, schizophrenia, or other psychiatric disorders was excluded. The analysis included psychological and physiological effects o f MDMA in controlled settings. Generally, subjective effects o f MDMA were more intense in women then men. Women had especially higher scores f o r MDMA-induced perceptual changes, anxiety, and adverse effects. In contrast, men were slightly activated by MDMA compared with women and had significantly higher increases in systolic blood pressure. The authors suggested that women may be more sensitive to the effects o f MDMA. Many previous studies have suggested sex differences in markers f o r serotonergic activity in ecstasy users, with sugges-

Chapter 4

Eileen Wong and Jayendra K. Patel

tions that serotonergic function is relatively impaired in women compared with men. The authors, based on their findings coupled with data from previous reports, raised the question of whether women might be more susceptible to MDMA-induced depletion o f serotonin. Psychiatric Psychosis, both acute and chronic, has been reported following the use of ecstasy. A 26-year-old man without previous psychopathology (except social phobia) unknowingly consumed ecstasy with alcohol and developed an acute psychosis 12 hours later. The authors reported that 12 cases of acute psychosis have previously been reported after the use of ecstasy once or twice. Based on a previously suggested hypothesis, they proposed that the psychosis was probably due to the indirect effects of MDMA on the dopaminergic system, secondary to serotonergic deregulation. Most patients who went on to develop a chronic psychosis were either chronic ecstasy users or multiple substance users. However, in the case mentioned here, after 6 months the patient still had symptoms of psychosis. The authors further suggested that genetically slow metabolizers of ecstasy are probably more vulnerable to this adverse effect, even with a single exposure. Past reports have suggested that MDMA use is associated with increased scores on selfreport measures of depression. The long-term effects of M D M A consumption on depression have been examined in 29 individuals who had consumed large quantities of the drug in the past, but were ilow leading relatively drug-free lives (22c). They had taken an average of 1.5 ecstasy tablets in the last month, 8.4 in the last 6 months, and 23.3 in the last 12 months. None had taken it in the last 14 days. The former chronic ecstasy users had not taken ecstasy for an average of 26 weeks. The female former users had taken ecstasy more recently than the men (15 versus 31 weeks respectively). The levels of depression, as measured by Beck's depression inventory (BDI), were significantly increased compared with a matched non-drug using control group. The depression scores were independent of alcohol and cannabis use. Peak usage (maximum ecstasy usage in 12 hours) and current levels of perceived stress together significantly predicted depression scores. Thus, former chronic ecstasy users may be at a high risk of developing more severe depression.

Drugs of abuse Liver

Chapter4

A case of MDMA-associated hepato-

toxicity has been reported (23At). 9 A 17-year-old gift developed progressive jaundice and weight loss. Four months before, she had had malaise, anorexia, a sore throat, and tender cervical lymph nodes. Two months later she reported eating "hallucinogenic mushrooms". Five weeks before admission she observed blood clots in her stool. Three weeks later, she ate more mushrooms. She then developed progressive jaundice, with vomiting, dark urine, light colored stools, and raised aminotransferases. She drank alcohol in binges and reported marijuana use since the age of 15. She had used MDMA on several occasions during the previous 2 months. She had a minimally tender enlarged liver. Her viral hepatitis screen was negative. Genetic, metabolic, and autoimmune disorders were also ruled out. A urine screen for drugs was positive only for cannabinoids. Abdominal ultrasound showed periportal edema and contraction of the gall bladder, but no gallstones or dilated bile ducts. A C T scan showed moderate amounts of free fluid in the abdomen and pelvis and periportal hepatic edema. Percutaneous liver biopsy showed acute cholestatic hepatitis with cholangitis, eosinophils, and histiocytes, strongly suggesting a hypersensitivity reaction. There was no evidence of chronic liver disease. Within 24 hours after the liver biopsy, her liver enzymes and coagulopathy had begun to improve. Two cases of successful livel; transplantation after ecstasy-induced hepatotoxicity have been reported (24 At, 25Ar). 19-year-old man with no significant past history of medical problems took 1Y2 tablets of ecstasy and some alcohol. Within 2-4 days he developed tiredness, nausea, malaise, and vomiting and on the fifth day weakness and anorexia; 12 days later he was admitted to hospital with marked jaundice and weight loss. He deteriorated and developed hepatomegaly and an abnormal prothrombin time; his total bilirubin was 571 (reference range 5-17) txmol/1, AsT 213 (14-50) U/I, and A1T 336 (1160) U/1. By day 20, his condition had deteriorated, with increased jaundice, somnolence, mild disorientation, and altered glucose metabolism. His total bilirubin was 654 p.mol/1, AsT 1290 U/I, and A1T 1932 U/1. A liver biopsy showed swollen hepatocytes, patches of necrosis, and patchy cholestasis. Two days later, he developed a grade III encephalopathy and further disturbances of coagulation. Abdominal ultrasonography showed hepatic atrophy and a liver biopsy showed massive necrosis. Serological tests for viral infections were negative. The probable diagnosis was toxic hepatitis secondary to MDMA. On day 31, he had a right auxiliary liver transplantation, but there was no clinical and laboratory improvement during the next 48 hours. Histopathology of the transplanted liver showed massive liver necrosis consistent with

9 A

35 a "diagnosis of primary non-function'. A second liver transplant on day 33 was successful. A 17-year-old woman with no history of drug abuse took two tablets of ecstasy at a disco 10 days apart, and reported malaise, constipation, and icterus 6 days after taking the second. She had severe acute hepatic failure. Viral hepatitis was ruled out. Following rapid clinical and neurological deterioration (encephalopathy grade I-If), she had an urgent liver transplant and made a good recovery. In the affected liver there was submassive centrilobular hemorrhagic necrosis (75-80%) with massive periportal and lobular lymphocytic infiltration (CD 8+) and moderate fatty changes. Many cases of hepatotoxicity and some deaths have occurred in dmg-na'/ve subjects after the ingestion of relatively small amounts of M D M A . The authors reported that more than 70 deaths have been reported world wide between 1990 and 1998 after the onset of severe hepatic damage from ecstasy. Although many patients died after liver transplantation, a significant number recovered. The authors suggested that in emergency care the use of ecstasy should be suspected in young people who present with unexplained jaundice, hepatomegaly, or altered liver function, in the absence of other known substance exposure. Early referral for liver transplantation may be significantly beneficial. The prognosis may be better with grade I - I I encephalopathy than grade III-IV, which is usually associated with rapid deterioration and a poor prognosis. P r e g n a n c y Workers in Canada have tried to characterize women who reported gestational exposure to ecstasy (26c). The Motherisk Program is a large Teratogen Information Service based in Toronto and receives over 150 calls daily about exposure to various agents during pregnancy. The authors reviewed the data from 1998 to 2000. The study group consisted of all pregnant w o m e n who had been exposed to M D M A . The control group was randomly selected pregnant women who visited the Motherisk Clinic during the same w e e k as the subject who called about M D M A . The 132 M D M A exposed women were significantly younger, earlier in gestational age, and weighed less than the non-exposed controls. The M D M A users had had significantly fewer pregnancies and live births and had a higher rate of therapeutic abortions but not spontaneous abortions. Significantly more M D M A users reported unplanned

36 pregnancies and were more likely to be single and white. The M D M A users were more likely than controls to have had alcohol exposure in pregnancy, and significantly more drank heavily. The MDMA-exposed women were more likely to binge drink and smoke cigarettes during pregnancy, and more were significantly heavy smokers. M D M A users also had a greater tendency to use marijuana, cocaine, amphetamines, ketamine, gamma-hydroxybutyrate, and psilocybin. Of the 132 women who reported MDMA use, 129 had used it during pregnancy, of whom 101 reported previous use of M D M A before their pregnancy, but had discontinued it. The mean gestational age of last M D M A exposure was 5.0 weeks (range 1-24 weeks). All but three used tablets: two snorted and one used a liquid formulation. The mean dose taken on one occasion was 1.24 tablets. Of the 122 patients whose data were included in the analysis, most (57%) had only one exposure to MDMA during pregnancy; 10 women had more than five exposures. One 15-year-old girl did not realize she was pregnant until 24 weeks gestation and had used two tablets of M D M A four times a day. Only seven of the MDA group reported exposure to M D M A alone. M D M A associated adverse events were reported by 33 of 77 respondents. The physical adverse effect most commonly reported was vomiting (23%). The authors raised significant concerns about the potential teratogenic effects in these women, due to clustering of risk factors.

Drug contamination

It is not uncommon for people to be deceived into consuming other substances, believing them to be MDMA. At dance parties and "raves" for young adults compounds passed as ecstasy may be more lethal than MDMA, either because they contain more potent amphetamines than MDMA or because of adulteration with other substances. In three fatal cases reported in the USA the victims (two men aged 19 and 24 and a woman aged 18) believed that they were using MDMA but had in fact taken paramethoxyamphetamine (PMA), a more potent central stimulant with structural and pharmacological similarities to MDMA (27c). They became agitated and developed bruxism, severe hyperthermia, convulsions, and hemorrhages. The presence of PMA was confirmed by enzyme immunoassay, and

Chapter 4

Eileen Wong and Jayendra K. Patel

MDMA was not detected. PMA is not a contaminant of MDMA.

CANNABINOIDS

(SED-14, 95;

SEDA-23, 41; SEDA-24, 36; SEDA-25, 43) The adverse effects of cannabis are discussed in detail in the Side Effects of Drugs Essay in this volume (pp. xxxiii-xlviii), in the context of the question of whether cannabis should be made available for medical use. The essay contains many references to experimental data in animals, not usually a feature of these volumes.

Cardiovascular

Marijuana has several effects on the cardiovascular system, and can increase resting heart rate and supine blood pressure and cause postural hypotension. It is associated with an increase in myocardial oxygen demand and a decrease in oxygen supply. Marijuana use is most popular among young adults (I 8-25 years old). However, with a generation of post-1960s smokers growing older, the use of marijuana in the age group that is prone to coronary artery disease has increased. Nevertheless, it is not known whether marijuana can precipitate myocardial infarction. Investigators in the Determinants of Myocardial Infarction Onset Study recently reported that smoking marijuana is a r~re trigger of acute myocardial infarction (28c). Interviews of 3882 patients (1258 women) were conducted an average of 4 days after infarction. Reported use of marijuana in the hour preceding the first symptoms of myocardial infarction was compared with use in matched controls. Among the patients, 124 reported smoking marijuana in the previous year, 37 within 24 hours, and nine within 1 hour of cardiac symptoms. The risk of myocardial infarction was increased 4.8 times over baseline in the 60 minutes after marijuana use and then fell rapidly. The authors emphasized that in a majority of cases, the mechanism that triggered the onset of myocardial infarction involved a ruptured atherosclerotic plaque secondary to hemodynamic stress. It was not clear whether marijuana has direct or indirect hemodynamic effects sufficient to cause plaque rupture.

Drugs of abuse

Chapter4

Paroxysmal atrial fibrillation

has been reported in two cases after marijuana use (29A). 9 A healthy 32-year-old doctor, who smoked marijuana 1-2 times a month, had paroxysmal tachycardia for several months. An electrocardiogram was normal and a Holter recording showed sinus rhythm with isolated supraventricular extra beats. He was treated with propranolol. He later secretly smoked marijuana while undergoing another Holter recording, which showed numerous episodes of paroxysmal atrial tachycardia and atrial fibrillation lasting up to 2 minutes. He abstained from marijuana for 12 months and maintained stable sinus rhythm. 9 A 24-year-old woman briefly lost consciousness and had nausea and vomiting several minutes after smoking marijuana. She had hyporeflexia, atrial fibrillation (maximum 140 beats/min with a pulse deficit), and a blood pressure of 130/80 mmHg. Echocardiography was unremarkable. Within 12 hours, after metoprolol, propafenone, and intravenous hydration with electrolytes, sinus rhythm was restored. The authors discussed the possibility that delta-9-tetrahydrocannabinol, the active ingredient of marijuana, can cause intra-atrial reentry by several mechanisms and thereby precipitate atrial fibrillation. N e r v o u s system Marijuana can interact with the neurotransmitter dopamine, and the effects of marijuana on the brain in schizophrenia have been studied by single photon emission computerized tomography (SPECT) (30A). 9 A 38-year-old man with schizophrenia secretively smoked marijuana during a neuroimaging study. A comparison of two sets of images, before and after marijuana inhalation, showed a 20% reduction in the striatal dopamine D2 receptor binding ratio, suggestive of increased synaptic dopaminergic activity. On the basis of this in vivo S P E C T study, the authors speculated that marijuana may interact with dopaminergic systems in brain reward pathways.

(SED-14, 106; SEDA-23, 37; SEDA-24, 37; SEDA-25, 40) COCAINE

C a r d i o v a s c u l a r Chest pain is a frequent emergency presenting complaint of cocaine

37 users. Myocardial infarction is the most serious cause, but other causes for pain must be considered, including aortic rupture and dissection (SEDA-18, 36; SEDA-19, 26; SEDA-21, 29; SEDA-22, 31). A first case of intramural hematoma of the ascending aorta has been reported in a cocaine user (31A). 9 A healthy 39-year-old man developed retrosternal chest pain radiating to the back with nausea and sweating. About 10-15 minutes before he had inhaled cocaine for 2 hours and then smoked crack cocaine. He had an aortic dissection, which was repaired surgically. The authors identified hypertension secondary to the use of cocaine as the risk factor for this complication.

Coronary artery dissection associated with cocaine is rare. The first case was reported in 1994 (32A), and two new cases have been reported (33 A, 34A). A healthy 33-year-old man with prior cocaine use had a small myocardial infarction, and 36 hours later, having inhaled cocaine, developed a dissection of the left main coronary artery, extending distally to the left anterior descending and circumflex arteries. There was marked anterolateral and apical hypokinesis. A 23-year-old man with a history of intravenous drug abuse and hepatitis C was found unconscious, hypoxic, and hypotensive. A urine drug screen was positive for cocaine metabolites, benzodiazepines, and opiates. An electrocardiogram suggested a myocardial infarction, verified by raised troponin I and the MB fraction of creatine kinase. He had severe hypokinesia with a left ventricular ejection fraction of 10%, falling to less than 5%. He became septic, developed multiorgan system failure, and died. The post-mortem findings included dissection of the left anterior descending artery with complete occlusion of the true lumen and thrombosis of the false lumen. The left ventricle showed extensive transmural myocardial necrosis with adjacent contraction band necrosis. He also had deep vein thromboses in veins in the neck and abdomen and multiple pulmonary infarctions. Cocaine is associated with vascular complications, including pulmonary, musculoskeletal, intestinal, and placental. Cocaine-induced ischemic finger necrosis has been reported (35 A). 9 A healthy 36-year-old man, who had used intranasal crack cocaine dally in increasing doses for 2 weeks, developed pain, numbness, swelling, and cyanosis of the fingers and toes aggravated by cold and an ulcer on one finger. Ultrasound Doppler of

38 the hand confirmed ischemic finger necrosis. He was treated unsuccessfully with aspirin, diltiazem, and heparin, but responded to intravenous infusions of iloprost for 5 days. R e s p i r a t o r y P u l m o n a r y complications associated with cocaine use include exacerbation o f asthma, lung infiltrates, p u l m o n a r y infarction, pneumothorax, and end-stage lung disease (SEDA-20, 21; SEDA-21, 25; SEDA-22, 31; SEDA-23, 37; SEDA-25, 41). A case of severe bullous emphysema in a cocaine smoker has been described (36A), 40-year-old man with cough, shortness of breath, and fever progressed to respiratory failure. He had smoked cocaine for the past 17 years. His tobacco history was not known. His medical history included recurrent respiratory tract infections. A chest X-ray and CT scan showed findings consistent with bilateral bullous emphysema with a right lung abscess. He was ventilated and given antibiotics but died from respiratory failure secondary to pneumonia. Sputum cultures were positive for Enterobacter cloacae and Streptococcus species. Alpha-I antitrypsin deficiency was ruled out.

9 A

Spontaneous pneumomediastinum has been reported (37 R). 9 A 20-year-old obese Hispanic man awoke with severe, continuous retrostemal chest pain radiating to the neck and back. The pain was aggravated by deep breathing and local chest pressure. He denied substance abuse and gave a history of a flu-like illness 2 months before. His respiratory rate was 19/minute. He had a two-component pericardial rub. Laboratory blood testing ruled out myocardial infarction. His arterial blood gases and pH, electrocardiogram, chest X-ray, and echocardiogram were unremarkable. A later chest X-ray showed air in the mediastinum and chest CT confirmed the diagnosis of pneumomediastinum. Urine toxicology was positive for cocaine and cannabinoids. On further questioning, he admitted to substance use and performing a Valsalva maneuver during inhalation. E a r , nose, t h r o a t Intranasal cocaine can damage the sinonasal tract, causing acute and chronic inflammation, necrosis, and osteocartilaginous erosion (SEDA-17, 36). These conditions occur secondary to the c o m b i n e d effects o f direct t r a u m a from instrumentation, vasoconstriction of small blood vessels with resultant ischemic necrosis, and chemical irritation from adulterants. Intranasal cocaine users can develop septal perforation, saddle-nose deformities, and sinonasal structural damage (38A).

Chapter 4

EileenWongand Jayendra K. Patel

43-year-old woman with a past history of chronic heavy cocaine use and osteomyelitis of the hard palate and nasal cavity 10 years before had required continuous follow-up for recurrent ethmoid and sphenoid sinusitis. Endoscopy showed an absent nasal septum, middle turbinates, anterior twothirds of the inferior turbinates, and lateral nasal wall.

9 A

In another case there was progression of septal perforation to secondary bone infection in a chronic cocaine user (39A). A 56-year-old chronic intranasal cocaine abuser with a visible nasal defect presented with a hole in the roof of his mouth. He had been reportedly drug free for 2 weeks. He had an oronasal fistula with adjacent black necrotic areas and erosive destruction of the nasal septum, turbinates, and antrum, with mucoperiosteal thickening of the sphenoid and maxillary sinuses. Treatment included antibiotics and a prosthesis plate construction to cover the defect. Two years later, having continued to inhale cocaine, he had progressive destruction of his sinonasal tract, a fistula between his oral and nasal cavity, a saddle-nose deformity with total cartilage loss, and a complete palatal defect. Biopsy of the nasal septum showed acute osteomyelitis and extensive bacterial overgrowth (including anerobic Actinomyces-like organisms). He was given intravenous antibiotics for 6 weeks followed by longterm oral antibiotics. N e r v o u s s y s t e m Cocaine has been associated with m o v e m e n t disorders, such as acute dystonias, choreoathetosis, and akathisia. Chronic pancerebellar dysfunction occurred in a cocaine user with schizophrenia treated with risperidone (40A). A 38-year-old man was found comatose in a crack house. The ambient temperature was 13~ He had earlier abused cocaine. His temperature was 43~ heart rate 115, blood pressure 144189 rnmI-Ig, and oxygen saturation 97% on air. His general muscle tone was flaccid. He had a mild leukocytosis and hypophosphatemia. Urine toxicology was positive for benzoylecgonine, a cocaine metabolite. He was mechanically ventilated, cooled, and given intravenous fluids. His temperature fell to 38~ but he later developed acute disseminated intravascular coagulation and rhabdomyolysis. After 5 days he developed nystagrnus, intention tremor, truncal ataxia, dysarthria, ocular dysmetria, and dysmetria of the arms and legs. There were no sensory or motor deficits. Finger-to-nose and beelto-knee tests were slowed and uncoordinated. He could not stand. Brain imaging studies (CT and MRI scans) were unremarkable. He was given thiamine, propranolol, clonazepam, primidone, and baclofen every 8 hours without improvement. After 1 year he still had nystagmus, intention tremor,

Drugs of abuse

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ataxic gait, and dysmetria were. He could walk short distances slowly. Cocaine and neuroleptic drugs can both cause hyperthermia and the authors proposed that the combination of cocaine and risperidone may have caused this problem. Cocaine-induced delirium with severe acidosis has been reported (41A). 9 A 25-year-old man with agitation and paranoia

who had consumed a lot of alcohol with cocaine the night before had a clonic seizure lasting 1 minute. In the emergency room, he responded to pain and made incomprehensible sounds. His pulse rate was 116, blood pressure 100/40 mmHg, respiratory rate 28, and temperature 38.3~ He was acidotic (pH 6.53), with a PaCO2 of 13.1 kPa, a base deficit of 36 mmol/1, a serum potassium concentration of 7 mmol/1, and sodium 153 mmol/l. He was hyperventilated and given sodium bicarbonate, dantrolene, and passive cooling. His acidosis quickly corrected and his temperature fell to 37.6~ within 1 hour. The association between cocaine use and

aneurysmal subarachnoid hemorrhage has previously been reported (SEDA-18, 36; SEDA21, 26). New research has identified cocaine as a risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage (42M). In a retrospective analysis of the medical records of 440 patients who presented to a neurosurgery unit between 1992 and 1999 with aneurysmal subarachnoid hemorrhage, 27 patients (6.1%) had either a positive urine screen for cocaine metabolites (n = 20) or a history of cocaine use within 72 hours of subarachnoid hemorrhage (n = 7). Cocaine users were more likely to have cerebral vasospasm from 3 to 16 days after subarachnoid hemorrhage than non-exposed patients (63% versus 30%). They were also more likely to be younger and to have aneurysms of the anterior circulation than the control group (97% versus 84%). Cocaine use has been associated with a re-

duced inhibitory response of the P50 auditory evoked response, attributed to catecholaminergic neurotransmission secondary to cocaine (43A). In a double-blind, placebo-controlled study, 11 cocaine users in the first and third weeks of detoxification had electrophysiological testing 10 minutes before and 30 minutes after taking nicotine gum 6 rag. Nicotine briefly reversed the inhibitory deficit.

39 Chronic substance use has been associated with long-lasting changes in brain function (44c). Five brain regions that may be affected (the orbitofrontal gyms, rectal gyms, anterior cingulate gyms, basal ganglia, and thalamus) were selected for analyses of cerebral glucose metabolism by positron emission scanning in controls, cocaine users, and alcoholics (17 in each group), who performed the Stroop test, which assesses cognitive interference and response inhibition. In controls, higher brain glucose metabolism in the orbitofrontal gyms correlated with poorer performance. In contrast, in substance users, higher brain glucose metabolism was associated with better performance. Chronic abuse appears to be associated with altered function of the orbitofrontal gyms. Psychological

Urinary tract Cocaine can cause acute renal insufficiency (SEDA-21, 19, SEDA-24, 38). A recent study has suggested that it can also cause chronic renal insufficiency (45r Of hemodialysis patients from an urban center in California, 55 who reported a history of significant cocaine use were compared with 138 non-users. A diagnosis of hypertension-related end-stage renal disease was reported in 49 of the 55 cocaine users (89%) and 64 of the 138 non-users (46%). Of 113 patients with endstage renal disease, 49 had a history of cocaine use. The patients who had used cocaine had hypertension for a shorter duration (5.3 vs. 12.7 years). They were also younger (41 vs. 54 years). The authors proposed that this outcome had been caused by several mechanisms: renal vasoconstriction or stenosis, resulting in ischemic nephropathy and secondary hypertension, direct renal damage with progressive renal insufficiency, and recurrent episodes of accelerated hypertension, vasculitis, acute tubular necrosis, and rhabdomyolysis.

Renal infarction

is an uncommon adverse effect of cocaine (46A). 9 After using intranasal cocaine, a 25-year-old African man developed fever and progressive fight flank pain over 4 days. He had a temperature of 38.3~ a blood pressure of 106/54 mmHg, and severe tenderness in the fight flank and right lower quadrant of the abdomen. His urine contained cocaine. A C T scan showed reduced uptake in the lower pole of the kidney, confirming renal infarction. Other causes were mled out.

40 Sexual function Priapism has been reported in men who have used cocaine by inhalation or applied it topically to the glans penis or intraurethrally (SEDA-19, 26, SEDA-23, 24, SEDA24, 38). Priapism associated with intracavernosal injection of cocaine has now also been reported (47A). 9 A 43-year-old man developed persistent painful

erection after intracavernosal injection of cocaine. He had previously administered cocaine in this way to prolong erections. Cavernosal aspiration resulted in partial detumescence, but the condition recurred. Urine screen was positive for cocaine. Aspiration and irrigation fully alleviated the condition. During penile erection, nitric oxide is released from the endothelium of the cavernous spaces and from nerve endings (non-adrenergic and non-cholinergic). Nitric oxide stimulates guanylate cyclase, which is involved in the conversion of guanosine triphosphate to cyclic guanosine monophosphate (cGMP); the latter relaxes the smooth muscle in the corpora cavernosa, allowing influx of blood for erection. The authors suggested that cocaine directly applied to the cavernosal endothelium can cause nitric oxide production. Drug abuse A rare case of polysubstance abuse, which unmasked myasthenia and caused complete external ophthalmoplegia, has been reported (48A). 9 A 29-year-old woman, who used cocaine 2 g/day, heroin 1 g/day, and methadone 40 mg/day, developed abscesses caused by drug injection. She had had generalized weakness, difficulty in swallowing, and lagging eyelids for 1 week. There was bilateral ptosis, and a diagnosis of myasthenia was made. Edrophonium 10 mg relieved the ptosis and improved ocular movements. The prevalence rate of cocaine use during pregnancy is 10-45% in some centers in North America. As cocaine use is increasing and widespread, information on the possible adverse effects secondary to fetal cocaine exposure continue to amass in case reports and studies. Fetal microcephaly has been attributed to cocaine abuse during pregnancy (49A). Urine toxicology confirmed the presence of morphine, benzoylecgonine, barbiturates, paracetamol, and propoxyphene. Analyses of amniotic fluid, placenta, and fetal serum and urine Fetotoxicity

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EileenWongand Jayendra K. Patel

were also positive for these substances. The authors suggested that vascular disruption was the likely major mechanism of anomalies, both behavioral and malformative, due to prolonged exposure to cocaine in utero. However, in a prospective, large-scale, longitudinal study there was no association between prenatal cocaine exposure and congenital anomalies in 272 offspring of 154 cocaineusing mothers and 154 non-using matched controis (50 c). The cocaine-exposed group had significantly more premature infants, who were significantly smaller in birth weight, length, and head circumference than the control infants. However, there were no differences in the type or number of abnormalities. The impact of prenatal exposure to cocaine on fetal growth and fetal head circumference has been studied in 476 African-American neonates, including 253 full term infants prenatally exposed to cocaine (with or without alcohol, tobacco, or marijuana) and 223 noncocaine exposed infants (147 drug-free, 76 exposed to alcohol, tobacco, or marijuana) (51c). The cocaine-associated deficit in fetal growth was 0.63 standard deviations and for gestational age 0.33 standard deviations. There were also cocaine-associated deficits in birth weight and length, but no evidence of a disproportionate effect on head circumference. There have been two studies of the adverse effect of prenatal cocaine on behavior of the offspring. In the first, 31 cocaine-exposed, very low birth weight infants and matched very low birth weight controls followed longitudinally were assessed at 3 years (52c). The cocaineexposed children had delayed cognitive, motor, and language development compared with the controls. Of the exposed children 45% scored in the range of mental retardation compared with 16% of the controls. Infants in the exposed group during the neonatal period were less responsive in their interactions and their mothers were less nurturing and less emotionally available. In contrast, in a second study there were few differences in interactive behaviors between prenatally cocaine-exposed and non-exposed 12-month-old infants and their mothers (53c). Videotapes recorded African-American infants and their mothers engaged in interactions (49 cocaine-exposed, 63 non-exposed). Children

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who were prenatally exposed to cocaine ignored their mother's departure during separation significantly more often than controls. Mothers who abused cocaine used more verbal behavior with their children than non-abusers. The effects of prenatal cocaine exposure on later learning abilities, including language, have been further investigated in 265 infants aged 1 year (134 cocaine-exposed and 131 matched non-exposed), who were tested using the Preschool Language Scale-3 (PLS-3) by blinded examiners (54c). The infants were assigned to three cocaine exposure groups: (as defined by maternal self-report and infant meconium assay): non-exposure (n = 131), heavier exposure (n = 66), and lighter exposure (n = 68). Fetal cocaine exposure was associated with deficits in developmental precursors of speech/language skills. At 1 year of age, more heavily exposed infants had poorer auditory comprehension than the non-exposed infants and worse total language performance than lighter and non-exposed infants. The more heavily exposed infants were also more likely to be classified as mildly delayed than nonexposed infants. Moreover, the degree of cocaine exposure had an inverse relation to auditory comprehension. Prenatal cocaine exposure has been associated with subependymal hemorrhage and subependymal cyst formation in term neonates and more recently in preterm neonates (<36 weeks of gestation) (55M). Medical records and cranial sonograms obtained during 1 year on 122 premature infants showed an increased incidence of subependymal cysts in preterm cocaine-exposed infants (8 of 18) compared with non-exposed infants (8 of 99). There was no increase in the incidence of major structural abnormalities. All subependymal cysts resolved by 4 months of age. The authors noted that the neurodevelopmental implications of such cyst formation are unknown. Prenatal cocaine exposure appears to have short-term effects on respiratory function in very low birth weight infants. In a retrospective study of 149 such infants, 48 cocaine-exposed and 101 non-exposed, the cocaine-exposed infants had transiently improved respiratory status at time of delivery; they needed surfactant treatment in lower doses and at a lower frequency and intubation less often (56c). At 24 and 48 hours there was no significant difference

41 between the treatment requirements in the two groups. The development of bronchopulmonary dysplasia was also similar. The authors suggested that prenatal cocaine exposure affects the fetus by two mechanisms: indirectly through reduced uterine blood flow with placental insufficiency and directly through an adrenergic effect on the fetus. The fetus may experience cocaine as a stressor that leads to accelerated fetal lung maturity. The relation between prenatal cocaine exposure and early childhood outcome has been reviewed (57M). Prospective longitudinal studies of perinatal cocaine exposure and associated outcomes were studied in a survey of 36 of 74 reports, published from 1984 to October 2000, in which the examiners were blinded to cocaine exposure. Prenatal cocaine exposure did not alter physical growth, developmental test scores, or receptive and expressive language among children aged 6 years or less. The authors concluded that there is no convincing evidence that prenatal cocaine exposure is associated with effects on a child's physical or behavioral development, and that many findings once thought to be specific effects of in utero cocaine exposure instead correlated with factors such as the quality of the child's environment and prenatal exposure to tobacco, marijuana, or alcohol. This review generated responses from other authorities in the field. Some commented that the conclusions may be premature, given the age of the subjects, and drew attention to several studies that have shown subtle but consistent deficits in cognitive and attentional processes in 6- and 7-year-old children (58r). These effects may become more prominent as development continues and may persist into adulthood. Others criticized the attempt to isolate cocaine exposure from all other associated risk factors; from a public health perspective, prenatal cocaine exposure clusters with other risk factors, such as poor care-giving, child maltreatment, domestic violence, and prenatal exposure to other substances (59r). Furthermore, the selection criteria narrowed the total articles reviewed to under half of the 74 articles found. Others suggested that the study had been misinterpreted (60r).

Pregnancy In a attempt to replicate the conclusions of an earlier study, there was no association between cocaine use during preg-

Chapter 4

42 nancy and acute thrombocytopenia in 326 patients (61M). There were similar prevalences of thrombocytopenia in cocaine-using women (13/160) and non-using w o m e n (11 / 160) during pregnancy. Thrombocytopenia occurred more often in the third trimester in both groups.

OPIATES

(SED-14, 198; SEDA-24, 36;

SEDA-25, 37)

Diamorphine (heroin) Nervous system Reflex sympathetic dystrophy, in which there is an excessive or abnormal sympathetic nervous system response in a limb, has been associated with rhabdomyolysis secondary to heroin abuse (62A). 9 A 37-year-old male heroin smoker developed teacolored urine and pain, swelling, and tenderness in both feet. He had acute renal insufficiency and rhabdomyolysis and was treated with hemodialysis. Urine toxicology was negative. He also had persistent burning pain in both feet, with cool, pale, thin skin on both legs, a mild reduction in sensation on the lateral aspects of the lower legs and diminished bilateral knee and ankle reflexes. Walking was restricted, with limited range of movement owing to the severe pain. His feet would swell and redden after a 5 meter walk, suggesting loss of sympathetic regulation. Nerve conduction velocity studies of the tibial, peroneal, and sural nerves were abnormal. Radiographs showed mildly reduced bone mineralization in the legs. Three-phase bone scintigraphy showed diffusely increased radiotracer accumulation over both feet in all three phases, as found in reflex sympathetic dystrophy. The diagnosis was confirmed by local anesthetic sympathetic blockade. Nasal calcitonin spray led to pain relief 2 months later. A follow-up threephase bone scintigram showed less radiotracer uptake, consistent with a good response to calcitonin therapy. Profound reversible hearing loss and vestibular dysfunction has been at-

Sensory systems

tributed to heroin abuse (63A). 9 A 47-year-old man with a history of chronic heroin abuse (up to 1 g/day) and oral methadone maintenance (85 mg/day) relapsed after 3 weeks of full abstinence and injected 0.25 g of black tar heroin intravenously. He was unconscious for about 20 minutes and awoke with profound hearing loss and loud tinnitus. He had profound bilateral symmetrical sensorineural hearing loss and severe vestibulopathy. He recovered gradually over the next 3 weeks.

EileenWongand Jayendra K. Patel

The authors pointed out that bilateral deafness after heroin relapse after prolonged abstinence had been reported in two previous cases, suggesting resensitization of a tolerized opioid system or prolonged hypersensitization of a system in withdrawal. D r u g abuse Smoked heroin by heating the free base over tin foil and inhaling the vapors is known as "chasing the dragon", a method that probably originated in Southeast Asia. Some are using this to reverse the stimulant effects of ecstasy. In a study of 102 patients (55 men and 47 women, mean age 21 years) interviewed at four clinics in Dublin, Ireland, three subgroups of opiate users were identified: (a) those who had ever used opiates to come off ecstasy, who were compared with those who had never used opiates for this purpose, (b) those whose first use of opiates had been to c o m e off ecstasy, and (c) those who had started opiates by "chasing" and then did or did not move to injecting (64r O f the 102 patients, 92 reported having taken ecstasy, 68 of w h o m reported having taken opiates to come off it, and the remaining 24 of w h o m had not. The 68 patients who reported taking opiates to c o m e off ecstasy had significantly heavier ecstasy use, in terms of the number of nights per w e e k and number of tablets taken per night. O f 36 who reported that their first ever experience of using opiates was in the context of "chasing" to come off ecstasy, 28 reported this as their main reason for starting to use opiates and the other eight reported that they would probably have tried opiates independent of their ecstasy use. O f the 86 patients whose initial route of use of heroin was "chasing", 61 reported changing to injecting, 23 continued to smoke heroin, and two switched to an oral formulation of methadone or morphine. When those who came to inject heroin were compared with those who did not (61 vs. 23), the injectors had begun illicit drug use earlier, had started heroin at a younger age, were younger at the time of interview, and had been more likely to have a history of ecstasy use. Despite the younger age of onset of illicit drug use in those who came to inject, they had not been using illicit drugs for longer at the time of interview. This study confirmed the authors' previous findings that heroin smoking was associated with ecstasy use.

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43

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44 28. Mittleman MA, Lewis RA, Maclure M, Sherwood JB, Muller JE. Triggering myocardial infarction by marijuana. Circulation 2001; 103: 2805-9. 29. Kosior DA, Krzysztof J, Filipiak, Przemyslaw S, Grzegorz O. Paroxysmal atrial fibrillation following marijuana intoxication: a two-case report of possible association. Int J Cardiol 2001; 78: 183-4. 30. Voruganti LN, Slomka P, Zabel P, Mattar A, Awad AG. Cannabis induced dopamine release: an in-vivo SPECT study. Psychiatry Res 2001; 107: 173-7. 31. Neri E, Toscano T, Massetti M, Capannini G, Frati G, Sassi C. Cocaine-induced intramural hematoma of the ascending aorta. Tex Heart Inst J 2001; 28: 218-19. 32. Jaffe BD, Broderick TM, Leier CV. Cocaineinduced coronary-artery dissection. New Engl J Med 1994; 330: 5 1 0 - l l . 33. Eskander KE, Brass NS, Gelfand ET. Cocaine abuse and coronary artery dissection. Ann Thorac Surg 2001; 71: 340-1. 34. Steinhauer JR, Caulfield JB. Spontaneous coronary artery dissection associated with cocaine use: a case report and brief review. Cardiovasc Pathol 2001; 10: 141-5. 35. Balbir-Gurman A, Braun-Moscovici Y, Nahir AM. Cocaine-induced Raynaud's phenomenon and ischaemic finger necrosis. Clin Rheumatol 2001; 20: 376-8. 36. Van der Klooster JM, Grootendorst AF. Severe bullous emphysema associated with cocaine smoking. Thorax 2001; 56: 982-3. 37. Goel P, Flaker GC. Cardiovascular complications of cocaine use. New Engl J Med 2001; 22: 1575-6. 38. Gupta A, Hawrych A, Wilson W. Cocaineinduced sinonasal destruction. Otolaryngol Head Neck Surg 2001; 124: 480. 39. Taibott JE Gorti GK, Koch RJ. Midfacial osteomyelitis in a chronic cocaine abuser: a case report. Ear Nose Throat J 2001; 80: 738-43. 40. Tanvetyanon T, Dissin J, Selcer UM. Hyperthermia and chronic pancerebellar syndrome after cocaine abuse. Arch Intern Med 2001; 161: 608-10. 41. Allam S, Noble JS. Cocaine-excited delirium and severe acidosis. Anaesthesia 2001; 56: 385-6. 42. Conway JE, Tamargo RJ. Cocaine use is an independent risk factor for cerebral vasospasm after aneurysmal subarachnoid hemorrhage. Stroke 2001; 32: 233843. 43. Adler LE, Olincy A, Cawthra E, Hoffer M, Nagamoto HT, Amass L, Freedman R. Reversal of diminished inhibitory sensory gating in cocaine addicts by a nicotinic cholinergic mechanism. Neuropsychopharmacology 2001: 25: 796. 44. Goldstein RZ, Volkow ND, Wang G J, Fowler JS, Rajaram S. Addiction changes orbitofrontal gyrus function: involvement in response inhibition. NeuroReport 2001; 12: 2595-9. 45. Norris KC, Thornhill-Joynes M, Robinson C, Strickland T, Alperson BL, Witana SC, Ward HJ. Cocaine use, hypertension, and end-stage renal disease. Am J Kidney Dis 2001; 38: 523-8. 46. Saleem TM, Singh M, Murtaza M, Singh A, Kasubhai M, Gnanasekaran I. Renal infarction: a rare

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Eileen Wong and Jayendra K. Patet

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