Drugs of abuse

Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

4 CANNABINOIDS (SED-15, 614; SEDA-28, 36; SEDA-29, 35; SEDA-30, 31; for dronabinol see Chapter 36)

In research on the effects of cannabinoids the routes of administration include smoking a plant-derived cigarette, oral dronabinol (synthetic delta-9-tetrahydro­ cannabinol, THC), or intravenous THC. Each method has specific characteristics: cigarettes deliver a wide range of dosages, dronabinol has a slower onset of action and lower potency, and intravenous THC offers precise dose and timing (1r). Careful screening of subjects’ medical backgrounds and status and close monitoring during research participation are essential. Cardiovascular Cannabis smoking is associated with an increased risk of cardiovascular events (SEDA-30, 31). In one case acute myocardial infarction was an outcome of inherited thrombophilia and cannabis smoking (2A).
A 24-year-old man developed severe chest

pain, which radiated to the arms and back for 4 hours. He had a 16 cigarette pack-year habit. There was ST segment elevation in leads V2–6, with reciprocal ST segment depression in II, III, and aVF. Troponin-T (18.0 ng/ml) and creatine kinase activity (7266 IU/l) were both raised. An anterolateral myocardial infarction was diagnosed. He was given clopidogrel, aspirin, heparin, and streptoki­ nase. A stent was inserted at coronary angiography. Drug screening was positive for THC. Genetic testing revealed a hypercoagul­ able state with a combination of factor V

Side Effects of Drugs, Annual 31 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(09)03104-3 r 2009 Elsevier B.V. All rights reserved.

Drugs of abuse Leiden mutation and the methylenetetrahy­ drofolate reductase (MTHFR) C677T and A1298C polymorphism.

In this case, the increased risk of coronary artery thrombosis was inherited and smok­ ing may have predisposed to coronary spasm and subsequent thrombosis. Activation of cannabinoid CB1 receptors by cannabis or THC is associated with reduced blood pressure. The effects of rimo­ nabant, a CB1 receptor antagonist, on blood pressure have been reported in 63 male cannabis smokers (3C). The smokers were assigned to eight groups and were pretreated with oral rimonabant (1, 3, 10, 30, 90 mg) or placebo. They smoked active (2.64% THC) or placebo marijuana cigarettes 2 and 6 hours after rimonabant. Cannabis alone had no consistent effect on blood pressure but 22% reported hypotensive symptoms (dizziness, lightheadedness) as did 20–33% of rimona­ bant recipients (1, 3, or 10 mg). Subjects who had symptomatic hypotension had higher mean peak plasma THC concentrations than those who did not. Rimonabant had a dosedependent effect on the hypotensive response to cannabis. Subjects receiving the two highest doses, 30 and 90 mg, did not have symptomatic hypotension. Respiratory Cannabis smoking can cause serious injury to the lungs (SEDA-30, 33). “Bong lung” involves histological changes characteristic of irregular emphysema (4A).
A 39-year-old man developed weight loss,

fever, dry cough, and pleuritic chest pain. His cannabis and cigarette smoking history had started at age 12 and his current habit was 3 g of cannabis daily and 50 cigarette packs per year. A CT scan of the lung showed a pattern of large peripheral paraseptal bullae.

The authors compared this patient’s CT scan with one from a cigarette smoker. The

33

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

second scan illustrated a strikingly different pattern of emphysema, with smaller pana­ cinar bullae in a uniformly distributed centrilobular pattern. An explanation of the differences in lung findings due to cannabis and cigarettes would take into account a number of variables. Cannabis smoking requires longer inhalation and breath-holding time. Inhaled cannabis through a bong is at a higher temperature. A cannabis joint, which lacks a filter, also has a greater delivery of the drug. Psychological Memory Cannabis has acute effects on memory, specifically tran­ sient deficits in immediate and delayed free recall of information presented after expo­ sure. Recognition recall is not affected and neither is recall of information learned before exposure. These findings emerged from a literature review of 35 studies of varied populations (occasional to heavy cannabis users) and varied doses of cannabis (5M). The authors concluded that cannabi­ noids have significant acute effects on processes of encoding, retrieval, and con­ solidation of memory, but they pointed to several limitations of the studies they reviewed, including small sample sizes, sample selection, and the effects of tolerance and dependence. Driving skills In a double-blind, placebocontrolled study to define the concentrations of THC needed to cause significantly impaired driving, 20 recreational cannabis users were given a series of performance tests at between 15 minutes and 6 hours after smoking 0, 250, or 500 mg/kg of THC (6c). The tests included measures of perceptualmotor control, motor impulsivity, and cog­ nitive function. THC concentrations in saliva and blood were monitored throughout. At higher THC concentrations, there was impairment in an increasing proportion of trials, becoming significant at concentrations of 2–5 ng/ml, and for the perceptual-motor control task, at 5–10 ng/ml. The authors suggested that concentrations of THC, rather than positive versus negative drug screens, should be used to set legal standards for driving under the influence.

Motor control To assess how highpotency (13%) THC affects motor control, 20 recreational marijuana users were given single doses of placebo, low-dose THC (250 mg/kg), or high-dose THC (500 mg/kg) in a double-blind crossover study (7c). Participants were aged 19–29 years, had no medical or psychiatric problems, and used marijuana on average 3.4 times per month. Impairments in object tracking, executive function and planning, and response inhibition were greatest at 15– 75 minutes after smoking and persisted for up to 6 hours. The authors suggested that high-potency cannabis, rather than the less commonly used low potency THC, should be assessed in future studies. Psychiatric Cannabis has been implicated as having a neurodevelopmental role in conditions such as schizophrenia, substance abuse, mood and anxiety disorders, and impaired cognitive function. Exposure of the developing brain to cannabis can occur at several key periods: in utero, by crossing the placenta from mother to fetus; after birth through breast milk; and in adoles­ cence by smoking. This topic has been reviewed, along with relevant animal stu­ dies (8R). Co-morbid substance use, beyond canna­ bis, may account for the increased positive symptoms observed in chronic schizophre­ nic cannabis users. When lifetime positive and negative symptoms were compared for those with (n ¼ 66) or without (n ¼ 139) cannabis abuse and dependence, there was no difference in positive symptoms between the two groups, after controlling for use of other substances; cannabis users also had fewer negative symptoms than non-canna­ bis users (9C). The reduction in avolition and apathy was more pronounced when the analysis was restricted to those chronic schizophrenics who used cannabis and no other substances. The authors offered several hypotheses for these findings: can­ nabis use may be a susceptibility factor for schizophrenia in those who have a genetic predisposition for a lower severity of negative symptoms; alternatively, cannabis itself may reduce negative symptoms; lastly, those who have fewer negative symptoms

Drugs of abuse

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Chapter 4

may have a greater social ability to acquire the drug. Research suggests that a functional poly­ morphism of the catechol-O-methyltransfer­ ase gene (COMT Val158Met) may mediate an increased risk of psychosis in response to cannabis exposure. In a double-blind, pla­ cebo-controlled, crossover study, individuals with a psychotic disorder (n ¼ 30), healthy controls (n ¼ 32), and relatives of indivi­ duals with a psychotic disorder (n ¼ 12) were exposed to either cannabis or placebo (10C). All underwent assessments of psycho­ tic symptoms (Positive and Negative Syn­ drome Scale (PANSS)) and susceptibility to psychosis (Community Assessment of Psy­ chic Experiences (CAPE)), a cognitive battery (including measures of attention and memory, and genotyping). Cannabis expo­ sure most significantly increased psychotic symptoms, memory, and attention deficits among those with the Val allele compared with those with the Met allele. Susceptibility to psychosis among the Val carriers was increased most among those with CAPE scores suggesting susceptibility. The authors suggested that the increased risk of psychosis associated with the Val allele may be mediated through an additional pre-existing susceptibility. Sensory systems Eyes There has been a pilot evaluation of the effect of sublingual cannabinoids (THC and cannabidiol) on intraocular pressure in a randomized, dou­ ble-masked four-way, crossover study in six patients with ocular hypertension or early primary open-angle glaucoma (11c). A single dose of THC 5 mg was well tolerated but temporarily reduced intraocular pres­ sure. Intraocular pressure was unaffected by cannabidiol 20 mg, but 40 mg resulted in a transient increase. Gastrointestinal Cannabinoids stimulate appetite and relieve nausea in patients with cancer. These effects are mediated by cannabinoid receptors in the gut, nervous system, and immune system (CB1 receptors in the colon and ileum, inhibiting smooth muscle, and CB2 receptors in the colon, where they are involved in hypermotility, inflammation, and pain (12R)).

The effects of stimulating cannabinoid receptors with dronabinol on gastrointest­ inal transit and postprandial satiation have been studied in 30 healthy volunteers who were given either dronabinol 5 mg bd or placebo (13c). Each subject received three doses of medication and underwent non­ invasive physiological tests 1 hour after the first and third doses. Dronabinol delayed gastric emptying, with a more pronounced effect in women. Men who received drona­ binol had higher fasting gastric volumes, a finding that is associated with reduced postprandial symptoms and satiation after a meal and possibly greater appetite. Skin An unusual case of cannabis-related contact dermatitis has been reported (14A).
A

29-year-old otherwise healthy female worker for the Forensic Science Service in the UK developed urticarial wheals, headaches, and rhinitis within minutes after contact with cannabis plants. For 6 years she had grown, stripped, and ground cannabis plants; her symptoms started after 2 years and were gradually worsening, with a quicker onset after exposure. Patch tests to dried and fresh cannabis leaf, flower, and resin were positive.

This was a type I hypersensitivity reaction to cannabis, with a wheal-and-flare reaction due to urticaria. Reproductive system Cannabis is the most widely used illegal recreational drug among men and women of reproductive age. The effects of cannabis on in vitro fertilization (IVF) and gamete intrafallo­ pian transfer (GIFT) outcomes have been reported in 221 couples undergoing IVF or GIFT at fertility centers in California (15C). Outcomes for a single cycle per couple were included. Data collection included three questionnaires for women and two for men and the medical records were accessed for information on sperm characteristics (num­ bers, motility, and morphology). Both the amount of cannabis use and the timing had negative effects. Women who had lifetime heavy cannabis use had 27% fewer oocytes retrieved and fewer embryos transferred. Moderate cannabis use in men and women was associated with 15% and 17%

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

falls in infant birth weight respectively. As to timing, women who used cannabis for 1 year before IVF/GIFT had 25% fewer oocytes retrieved and couples had 28% fewer oocytes fertilized. Teratogenicity Findings from two long­ itudinal studies of children exposed to cannabis in utero have been included in a review of neurodevelopmental effects (8R). Cannabis exposure resulted in small reduc­ tions in length, head circumference, and birth weight (about 100 g), but did not increase rates of prematurity or miscar­ riage. The children in these studies also had deficits in visuospatial reasoning and memory at ages 9–12 and 13–16 respectively. Fetotoxicity Exposure to cannabis during pregnancy and its adverse effects on the fetus are difficult to assess, for several reasons. Concentrations of the psychoactive agents in cannabis sold on the street vary widely, from a trace of THC to as much as 20%. The amount of drug use by expectant mothers and duration of use are also difficult to determine. A study of altered neurobehavior in term neonates with prenatal cannabis exposure within 24–72 hours of life has been reported (16C). Between July 2001 and November 2002, 928 (25%) of 3685 infants at a hospital in Brazil were born to adolescent mothers; 26 infants (4.6%) of 561 infants who met the study criteria had marijuana exposure detected by maternal hair and neonatal meconium analysis for marijuana and cocaine metabolites. Neo­ nates who had prenatal exposure to tobacco, alcohol, or cocaine were excluded. The infants were assessed with the Neona­ tal Intensive Care Unit Network Neurobe­ havioral Scale (NNNS). Infants exposed to marijuana scored significantly higher in variables of arousal, regulation, and excit­ ability than non-exposed infants. Only one of 26 mothers who used cannabis during pregnancy revealed this during the inter­ view. Research on cannabis use in adolescent pregnancy is complicated by a number of variables (17r). Adolescent mothers

frequently have poor nutrition, use other substances, and have poor mental health. The parenting environment of an infant born to an adolescent mother is likely to have a number of psychosocial stressors. A systematic review of studies on neuro­ behavioral and cognitive outcomes asso­ ciated with cannabis in utero exposure has been published (18M). To date, there have been only two longitudinal studies, the Ottawa Prenatal Prospective study (2002) and the Maternal Health Practices and Child Development Study (1998). The consequences of heavy prenatal exposure to cannabis appear to be subtle, with the prefrontal brain region negatively affected by prenatal cannabis use. There have been no studies focused on moderate or low cannabis use during pregnancy. A small fMRI study has suggested that prenatal cannabis exposure may have effects on neural activity during tasks involving visuospatial working memory in young adults (19c). In this study, 16 prenatally exposed and 15 unexposed indi­ viduals (aged 18–22) performed a task involving visuospatial working memory while being imaged by fMRI. While there was no difference in performance between the two groups, there were differences in the neural networks that were activated during the task. Those exposed to cannabis had more activity in the left inferior and left middle frontal gyri, the left parahippocam­ pal gyrus, the left middle occipital gyrus, and the left cerebellum, whereas they had less activity in the right inferior and right middle frontal gyri. Tumorigenicity Cannabis smoking is asso­ ciated with an increased risk of some of the traditional tobacco-related cancers. Cannabis smoke contains tar, which has many of the same carcinogens as tobacco tar, such as vinyl chlorides, nitrosamines, phenols, and reactive oxygen species. The smokingassociated cancers affect organs such as the lungs, upper airways, and bladder, which have long-term exposure to these carcinogens. Transitional cell carcinoma of the blad­ der has been reported in a smoker of marijuana (20A).

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A 45-year-old man who had a 30+ year habit

of smoking of up to five marijuana cigarettes a day developed macroscopic painless hema­ turia. He had no history of tobacco use, chemical exposure, or family history of transi­ tional cell carcinoma. There was a 7-cm bladder mass on CT scan and cystoscopy showed papillary lesions along the right lateral wall. The bladder tumor was resected and was a high-grade stage T1 transitional cell carci­ noma. He received intravesical BCG for 6 weeks. After 3 months cytology was normal. He stopped using cannabis.

The association between cannabis and transitional cell carcinoma has been investi­ gated in 156 men aged less than 60 years in a US Veterans Association Hospital, 52 with a transitional cell carcinoma and 104 agematched controls, who completed selfadministered questionnaires (21C). Detailed questions on tobacco and cannabis use and duration and exposure to other potential carcinogens, including radiation, Agent Orange, smoked or processed meats and dyes, were included. There was significantly higher habitual cannabis use by 46 of the 52 patients with transitional cell carcinomas compared with 72 of the 104 age-matched controls. The former had engaged in greater cannabis use as measured in joint-years (the product of joints per day and years smoked), with a mean of 48 joint-years compared with 29 joint-years in controls. In both groups, there was high tobacco use, with rates greater than 90%. The association between cannabis smoking and the development of lung cancer has been the subject of a systematic review of research studies written in English on adult subjects for the period 1966 to 1995; 19 articles out of 186 abstracts were identified and categorized (22M). There was an association between marijuana smoking and increased tar expo­ sure, alveolar macrophage tumoricidal dys­ function, increased oxidative stress, and bronchial mucosal histopathological abnorm­ alities compared with tobacco smokers and non-smoking controls. However, there were no significant associations between marijuana smoking and lung cancer after adjusting for use of tobacco, although the age of the participants was too young to allow conclu­ sions based on long-term exposure.

COCAINE (SED-15, 848; SEDA-28, 38; SEDA-30, 31; see also Chapter 11) Cardiovascular The prevalence of coronary atherosclerosis (SEDA-29, 38) has been described in 51 patients (49 men) aged under 50 years with an acute persistent STsegment elevation myocardial infarction with and without cocaine exposure who were admitted to a US hospital; 17 patients (16 men) self-reported cocaine use more than 10 times in a lifetime and 35 were noncocaine controls (23c). Coronary angio­ graphy showed that cocaine users had a higher prevalence of atherosclerosis (65%) and a higher number of coronary artery lesions (2.3 per patient) compared with controls (32% and 1.6 per patient). Cocaine users had a lower mean age and a lower mean number of cardiac risk factors. The authors challenged a popular explanation that spasm in otherwise normal coronary arteries is the main cause of myocardial infarction in young cocaine users. Their findings strongly support a proatherosclerotic effect of cocaine. The effect of cocaine on the QT interval (SEDA-29, 39) has been further studied. The effect of cocaine on QT variability (a measure of cardiac repolarization), has been assessed in 29 healthy volunteers with past cocaine exposure, who received ran­ domized sequential intravenous infusions of cocaine 20 mg and 40 mg or placebo; 17 repeated the course 1 week later (24c). Cocaine significantly and dose-dependently increased QT variability; the results were reproducible 1 week later. In 14 habitual cocaine users, who smoked cocaine 25 mg during closely monitored 12­ minute sessions with electrocardiographic recording, the heart rate increased by a mean of 22/minute; there was significant QTc prolongation, reduced T wave ampli­ tude, and increased U wave amplitude (25c). One patient developed an accelerated junc­ tional rhythm and five had non-specific ST­ T wave abnormalities. The authors of these papers discussed how cocaine has a destabilizing effect on cardiac repolarization, which contributes to cardiac dysrhythmias. Like other sympatho­ mimetic agents, cocaine is an alpha1, beta1,

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

and beta2 adrenoceptor agonist with sodium channel blocking properties. Fatal vasoconstriction of the aorta has been attributed to cocaine (26A).
After a 5-day crack cocaine binge, a 32-year­

old woman developed severe bilateral leg pain and inability to walk. She drank several cans of beer to try to relieve the pain. She had a history of “speed balling”, or injecting a mix of heroin and cocaine. She was lethargic, with a systolic blood pressure of 70 mmHg, a heart rate of 172/minute, and a respiratory rate of 22/ minute. Her truncal skin was mottled below the umbilicus. The abdomen was diffusely tender and no bowel sounds were detectable. Her limbs were mottled, pale, and cold to the touch. The femoral pulses were faintly audible with Doppler. There were no pulses distally. Sensation was markedly reduced in the legs. She was given oxygen, intravenous isotonic saline, and glyceryl trinitrate infusion. Her systolic blood pressure rose to 110 mmHg and her pulse rate to 110/minute. Abdominal ultrasound showed severe vasoconstriction of the abdominal aorta above the renal arteries. She had a raised creatinine kinase activity (56 mg/l), blood urea nitrogen of 156 mg/dl, creatinine of 6.2 mg/dl, and potassium of 4.0 mmol/l. On day 3, she had fever, acute septic shock, and disseminated intravascular coagulopathy and died.

Myocarditis has cocaine (27A).

been

attributed

to


A 42-year-old healthy occasional user of

cocaine developed fatigue, fever, cough, mus­ cle aches, and abdominal pain after using cocaine 3 days before, and collapsed and died. Autopsy showed a mottled enlarged heart weighing 585 g and 50 ml of serous pericardial fluid. Histology of the myocardium showed a mononuclear inflammatory cell infiltrate with lymphocytes in and around the sinoatrial node and the bundle of His and the left bundle branch. Prominent contraction band necrosis, some coagulative necrosis, and myocyte loss were also present, and there was evidence of myocyte apoptosis. There were cocaine meta­ bolites in the blood.

Before this report, cocaine-induced myo­ carditis has been associated solely with chronic use. The authors also pointed out that this is a first report of involvement of the bundle of His and left bundle branch. The mechanism of damage may include myocardial adrenergic stress and cardiac myocyte apoptosis.

Nervous system Neuroimaging research has significantly improved our understand­ ing of the neurobiological effects of acute cocaine on the brain. Brain regions such as the basal forebrain, caudate, nucleus accumbens, thalamus, ventral tegmentum, cingulate, and prefrontal cortex are acti­ vated during cocaine use. Electroencepha­ lographic measurements have elucidated the acute effects of cocaine on brain neurophysiology. Quantitative electroen­ cephalographic profiles were obtained from 13 crack cocaine-dependent users who self-administered single-blinded doses of smoked cocaine base 50 mg versus placebo in monitored sessions (28c). Cocaine rapidly increased the absolute theta, alpha, and beta power of the prefrontal cortex for up to 25 minutes. Increased theta power was associated with reported “good drug effect” and increased alpha power with reported “nervousness”. Increased delta power was positively associated with plasma cortisol concentra­ tion and negatively with reported nervous­ ness. Placebo increased alpha power in the prefrontal cortex. The authors propose that slow wave delta and theta activity are involved in the rewarding properties of cocaine. Cocaine also affects cerebral blood flow. Hypoperfusion of the orbitofrontal cortex and possible differences among male and female cocaine users has been reported in 35 abstinent cocaine-dependent subjects and 37 healthy controls, using single photon emission computed tomography for regio­ nal cerebral blood flow after infusion of cocaine or saline (29c). There were sexspecific anatomical differences: regional blood flow was reduced bilaterally in the orbitofrontal cortex in male cocaine users and in the medial orbitofrontal cortex in female cocaine users compared with con­ trols. The authors explained that the orbitofrontal cortex is involved in assessing prospective rewards and making decisions. When it is injured, a person tends to make impulsive impaired decisions. They sug­ gested that these sex differences may be important in developing methods for treat­ ing relapses.

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Fatal cocaine-related encephalopathy has been reported (30c).
A 21-year-old man with a history of depres­

sion and no prior cocaine use was found comatose in a hotel room with injection marks in the left cubital fossa. A syringe, empty packets with traces of white powder, later identified as cocaine, and a farewell letter were also found. He was unresponsive, with intact brain stem reflexes, bilateral hyper-reflexia, and moderately increased muscle tone. There was a mild metabolic acidosis (pH 7.30), raised liver enzymes, rhabdomyolysis, leukocytosis, and increased creatinine and hyperkalemia. There was cocaine in the urine. Electroence­ phalography after 3 and 12 days showed diffuse 2–4 Hz activity, with 2–30 seconds episodes of flattening and lack of response to visual or tactile stimulation. An MRI scan of the brain on day 21 showed diffuse symme­ trical white matter lesions in the cerebrum, with preservation of U fibers. Proton nuclear magnetic resonance spectroscopy (1H-MRS) on day 21 in the occipitoparietal white matter and mid-occipital gray matter showed signifi­ cant reductions in N-acetylaspartate, myoino­ sitol, and creatine, with increased lactate, lipids, and macromolecules, consistent with major neuroaxonal injury and white matter demyelination. He died at 24th day. Autopsy showed severe leukoencephalopathy, with demyelination and liquefaction of the central cerebral white matter. The cortex, subcortical white matter and U fibers, brain stem, cerebellum, and hippocampus appeared rela­ tively intact.

The authors pointed out that the clinical presentation may vary, whereas the radi­ ological and histological findings in toxic leukoencephalopathy due to cocaine or other drugs of abuse are fairly characteristic. Sleep There has been a longitudinal study of maternal substance use and child sleep behavior in 65 cocaine-exposed and 53 non-exposed infants and their primary care-givers, recruited at the time of deliv­ ery (31c). By 7 months 18 of the cocaineexposed infants had been removed from parental care, compared with only one of the non-cocaine group. At 7 months the care-givers’ psychopathology was assessed with the Brief Symptom Inventory (BSI) and the Maternal Cognitions about Infant Sleep questionnaire, a measure of mothers’ awareness about their infants sleep

pattern, was administered. Infant physio­ logical assessment during rest was done at both 4–8 weeks and 7 months. The severity of sleep difficulties significantly related to the severity of prenatal cocaine exposure, and maternal anxiety had a key role in this association. Altered sleep regulation in 7-month-old infants was strongly influ­ enced by the care-givers’ environment. Non-maternal care-givers had fewer mental health problems than cocaine-using mothers. Infants who were in non-parental care had milder sleep problems than those who remained in parental care. Dysregulation of sleep with impairment of cognition and learning associated with cocaine has been studied (32c). In a 23-day in-patient study, 12 abstinent chronic cocaine users self-administered blinded dosages of either intravenous cocaine (8, 16, and 32 mg per 70 kg at 30-minute intervals) or placebo on each of study days 4, 5, 6, 18, 19, and 20 in 2-hour sessions. Six took cocaine on days 4–6 (early bingers) and the other six on days 18–20 (late bingers). There was a marked discrepancy between recorded sleep and self-reports. Over the period of controlled abstinence (up to 17 days), sleep deterioration as measured objectively (total sleep time, sleep latency, and times awake after sleep onset) was timed to the sleep that chronic cocaine users reported as “at its best”. Spectral activity showed increased slow wave sleep, suggestive of chronic insomnia. Vigilance and procedural learning were also impaired. The authors suggested that chronic cocaine users are unaware of “occult insomnia”, which relates to dysre­ gulation of homeostatic sleep drive. In this proposed mechanism, increased time awake is not recognized and translated into a drive to sleep. Sensory systems Eye Corneal distur­ bances have been reported with crack cocaine, including ulcerative keratitis (33A).
A

42-year-old African–American woman developed blurred vision and a mucopurulent discharge and progressive pain in her left eye. She had a history of polysubstance

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

abuse, but no history of contact lens use, trauma, or surgery. She had injected heroin the evening before and again several hours later. The left cornea had a deep paracentral stromal ulcer with an overlying epithelial defect. Toxicology screen was positive for cocaine and heroin. Corneal cultures grew Candida albicans. With topical therapy the lesion regressed in size and her symptoms abated.

Ulcerative keratitis is a sight-threatening condition. Crack-cocaine vapors can have a direct toxic effect, which impairs the pro­ tective capacity of the corneal epithelium and predisposes the corneal tissue to blemishes and infection. They also have anesthetic properties, which may increase the risk of mechanical trauma from exces­ sive eye rubbing. Psychiatric One of the common psy­ chiatric manifestations of cocaine use is paranoia, an intense, irrational suspicion of others or a fear of being harmed. Cocaine-induced paranoia is usually brief and reversible, as it is associated with acute intoxication. However, some cases are protracted or even chronic. Of 420 cocaine-dependent full-sibling pairs (n ¼ 840) who participated in a SemiStructured Assessment for Drug Depen­ dence and Alcoholism (SSADDA) interview, 273 (65%) reported cocaineinduced paranoia (34C). Factors associated with sibling cocaine-induced paranoia were analysed by logistic regression, with alcohol dependence as a positive control. No familial component was identified as a possible susceptibility factor. However, members of the subject’s family had more severe cocaine dependence (as measured by Diagnostic Manual IV symptom count) and an earlier age of onset. They were more likely to smoke cocaine and also to have reduced their amount of cocaine use in the preceding year. Whereas probands with cocaine-induced paranoia had a higher proportion of siblings with the trait, the difference was not statistically significant (66% versus 59%). Endocrine Stress, drug cues, and drug craving are the principal influences on

substance users’ behaviors of use and relapse. The combined neuroendocrine and cardiovascular responses to stress has been studied in relation to sex differences in 25 abstinent female cocaine users and 25 abstinent male cocaine users (35c). Subjects were instructed to imagine a recent personal stressful experience, a personal drug-related one, and a neutral-relaxing one. Subjective craving and anxiety, cardi­ ovascular measures, and plasma ACTH, cortisol, and prolactin were measured. Both men and women reported increased cocaine craving and anxiety in response to the stress and drug-cue exercises, but there were significant sex differences. Men had higher ACTH and cortisol concentrations at base­ line and more robust response measures after all three exercises. Women had lower ACTH and cortisol with higher heart rates and prolactin at baseline and less marked responses to the exercises. The authors proposed that clarification of sex differ­ ences in sensitivity and responses in the hypothalamus–pituitary–adrenal axis and in cardiovascular responses may be useful in developing treatments.

Pregnancy Cocaine body packing during pregnancy has been reported (36A).
A 26-year-old woman at 32 weeks gestation

was detained in customs at the Miami Inter­ national Airport for possessing cocaine pack­ ets. She confessed to swallowing packets for concealment. She was admitted to hospital and Golytely was administered to facilitate passage of the packets. A few hours later she had generalized seizures and became apneic and unresponsive. Ventricular tachycardia ensued. Ultrasound showed a singleton fetus with a bradycardia of 80/minute. A 2800 g boy was delivered by cesarean section, with Apgar scores of 2, 4, and 5 at 1, 5, and 10 minutes respectively. The mother died. Autopsy showed an ischemic uterus and 157 latex packets containing about 830 g of cocaine in the stomach and small and large intestines. One condom had ruptured. The maternal serum cocaine concentration was 4.6 mg/l and serum benzoylecgonine 12 mg/l. At 1 year the child had neurodevelopmental delay.

The authors reported that in pregnancy the activity of plasma esterase, which degrades cocaine, is reduced and that progesterone,

Drugs of abuse

Chapter 4

which may slow the metabolism of cocaine, is increased. Fetotoxicity (SEDA-29, 41; SEDA-30, 35) Adverse morphological and craniofacial outcomes in 154 children aged 6 years with in utero cocaine exposure and 131 high-risk controls (matched for race and social class) have been described (37C). Prenatal cocaine exposure was associated with lower standardized height and weight for height at age 6 years. No pattern of craniofacial or structural abnormalities was found. Drug–drug interactions Methylphenidate Attention-deficit/hyperactivity disorder (ADHD) is diagnosed in up to 30% of cocaine users. Methylphenidate, used to treat ADHD, is, like cocaine, a stimulant with potential cardiovascular and central nervous system toxicity. The concomitant use of cocaine and methylphenidate has been described (38c). Seven subjects who were cocaine users completed a placebocontrolled, crossover study with methyl­ phenidate 60 and 90 mg and cocaine 20 and 40 mg. Methylphenidate and cocaine were well tolerated in combination. Methylphe­ nidate had no significant effects on vital signs, electrocardiography, or the phar­ macokinetics of cocaine. However, this conclusion cannot be generalized; the maximum dose of cocaine was 40 mg, and cocaine users on the street are likely to use more than that.

Ecstasy (3,4-methylenedioxymetamfetamine, MDMA) (SED-15, 180; SEDA-28, 4, 28; SEDA-29, 1; SEDA-30, 37; for other amphetamines see Chapter 1) Drugs that are often used in dance clubs or at rave parties, also known as “club drugs”, are commonly used by populations at high risk of HIV infection. According to the 2004 National Survey on Drug Abuse and Health, 1.9 million persons aged 12 years and over used MDMA in the USA (39R). Use of club drugs is more prevalent among

41 men who have sex with men than in the general population. Its use is also more common among populations with and at high risk of HIV infection. Most epidemio­ logical data show that club drugs increase sexual risk behavior. Their use may interact with certain antiretroviral medications and has been associated with reduced adher­ ence. The authors suggested that clinicians should ask all patients about patterns of club drug use, counsel patients about the risks associated with club drugs, and refer patients to appropriate behavioral treat­ ment programs for substance use when clinically indicated. Nervous system Acute myelopathy after intranasal insufflation of amphetamines and heroin has been reported (40A).
A 17-year-old woman became drowsy and

unable to walk after an overdose of intranasal insufflated heroin and amphetamines. Within a few hours she became stuporose, with weakness in all four limbs, especially the legs. She had massive rhabdomyolysis (creatine kinase 368 mg/l), acute renal failure, and hepatic failure. She had habitually used ecstasy and cannabinoids since age 12, and in the previous week had insufflated heroin about once a day; the previous night she had used twice the dose of heroin along with 1 g of amfetamine. The next day she was alert and cooperative, but complained of diffuse muscle pain and tenderness, especially in the legs, where weakness rapidly worsened to flaccid areflexic paralysis. Urinary MDMA was 7.68 mg/l, 3,4-methylenedioxyamfetamine 2.0 mg/l, and opiates over 2.0 mg/l. The acute renal failure resolved by day 10. Muscle weakness resolved in the arms but flaccid paralysis persisted in the legs. There were no sensory symptoms or signs and no sphincter abnormalities. Electromyography showed complete non-excitability of the leg motor nerves innervated by L3–S1. MRI after 1 month showed selective T2 hyperintensity of the anterior horns and signal alteration in the lumbar nerve roots associated with volume increase and intense gadolinium enhancement. Intravenous high-dose steroid therapy had no effect, and 4 months later she was still paraplegic.

According to the authors, the neurophysio­ logical and neuroradiological evidence in this case suggested selective lumbar motor neuron involvement. The pathological pro­ cess primarily affected spinal anterior horn

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Eileen Wong, Jayendra K. Patel, and Sarah Langenfeld

cells conditioning motor neuron cell death, and then nerve roots and the lumbar plexus as a consequence of Wallerian degenera­ tion. They suggested that this presentation was probably due to the combined effect of heroin and ecstasy. Ecstasy use has spread from the clubs to urban and rural areas, and young whites are not the only group using club drugs (41A). This is illustrated by a case report of an African–American who had a stroke after using ecstasy.
A 20-year-old African–American man was

seen to drink beer, smoke marijuana, and take ecstasy before performing at a rap concert, during which he suddenly stopped rapping, started vomiting, and became aphasic. An hour later he was awake, non-verbal, and was able to follow verbal instructions. He did not have any signs of trauma and the strength in his limbs was 5+/5 bilaterally. It was difficult to complete the examination as he was comba­ tive. His cardiac examination was normal. His white blood cell count was raised without a shift or bands. His creatine kinase activity was 692 U/l. His ethanol concentration was 1130 mg/l and his urine drugs screen was positive only for cannabinoids. His head CT scan was negative. After about 18 hours he developed new right-sided weakness, a leftsided facial droop, and bilateral hyper-reflexia in the legs. An MRI scan showed complete infarction of the left middle cerebral artery and mild-to-moderate stenosis of the distal left internal carotid artery.

The authors speculated that ecstasy causes massive synaptic release of serotonin, resulting in down-regulation of 5HT recep­ tors, which can lead to low cerebral blood vessel volume, thereby increasing the risk of stroke through vasoconstriction. How­ ever, this report was criticized for assigning causality to the event in absence of a positive drug screen; other forms of amphe­ tamines could have been used or passed as ecstasy and there was no past history of drug abuse (42r). One of the authors of the original report expressed frustration at not being able to confirm the toxin, but explained that owing to the devastation caused by hurricane Katrina they had been unable to review or obtain any additional information about this case, and concurred with the criticism that ecstasy ingestion by the patient was purely speculative, despite a

reliable witness (43r). However, there had been no doubt about the stroke and the temporal connection to the abuse of street drugs. Other drugs are sold as ecstasy and could have been used, but they were not picked up by the toxicology screen, which was done at least 12 hours after ingestion, by which time drugs could have cleared the system.

Psychological Behavior The acute effects of ecstasy on driving performance or drivingrelated psychomotor performance have been assessed in 18 recreational ecstasy users aged 21–39 years in a double-blind, pla­ cebo-controlled, three-way, crossover study (44A). Ecstasy 75 mg, methylphenidate 20 mg, and placebo were administered on day 1 and driving tests were conducted 3 and 5 hours later. The test was repeated at 27– 29 hours during withdrawal. On-the-road driving tests consisted of a road-tracking test and a car-following test in a specially instrumented vehicle over a 100-km primary highway circuit. Standard Deviation of Lateral Position (SDLP) is a composite index of allowed weaving, swerving, and overcorrecting during the test duration of 1 hour. In the second test, time to speed adaptation, brake reaction time, and gain were assessed. Gain is the amplification factor between the speed signals collected from both the leading and following cars and indicates the magnitude of overshoot in reaction. Ecstasy and methylphenidate both reduced SDLP relative to placebo but not during withdrawal. Mean gain differed sig­ nificantly between treatments during intox­ ication but not withdrawal. Ecstasy and not methylphenidate significantly increased the modulus or gain of the subjects’ response to speed decelerations of the leading vehicle. Time to speed adaptation and brake reac­ tion time were not significantly affected. Thus, ecstasy not only improved road-track­ ing performance but also reduced carfollowing performance. The authors reported that these and other data suggest that ecstasy has activating or stimulating properties that may improve performance in certain aspects of the driving tasks but impair others.

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Chapter 4

In another study, the acute effects of ecstasy and alcohol, alone and in combina­ tion, on behavioral measures of impulsivity and risk-taking behavior were measured in 18 recreational users in a double-blind, placebo-controlled, six-way, crossover study (45C). The treatments consisted of ecstasy 0, 75, and 100 mg with and without alcohol (0.6 g/l peak blood concentration). The tests were conducted 1.5–2 hours after the dose of ecstasy and included a stopsignal task, a go/no-go task, and a gambling task. Ecstasy impaired stop reaction time, suggesting increased impulse control. Alcohol increased the proportion of com­ mission errors in the stop-signal task and the go/no-go task. The gambling task performance was not affected by either. None of the behavioral measures of impulsivity showed an interaction with ecstasy or alcohol. The authors speculated that the possible mechanism underlying the effect of ecstasy in improving impulse control may be related to acute serotoner­ gic or dopaminergic mechanisms after a single dose. However, ecstasy did not affect measures of impulsivity in every behavioral task. Decision-making pro­ cesses in the gambling task were not affected, which seems to indicate that the effects of ecstasy on stop reaction time in the stop-signal task were selective. The authors further distinguished between cog­ nitive impulsivity and motor impulsivity and suggested that they are probably controlled by different centers in the brain. Ecstasy selectively improved control over motor impulsivity while leaving cognitive impulsivity intact. Thus, pharmacological manipulations may affect these controls independently and selectively. With alco­ hol, on the other hand, the commission errors may reflect impairment of percep­ tual or attentive processing, rather than increased motor impulsivity. The gambling task performance tended to improve after alcohol, with more cautious decision-mak­ ing. This suggests that alcohol does not increase cognitive impulsivity in this type of decision-making task. According to the authors, absence of an alcohol effect on decision-making tasks versus the presence of a detrimental effect of alcohol on motor

43 inhibition tasks demonstrates that impul­ sivity is not a unitary concept, but com­ prises several independent psychological domains or brain regions that can respond very selectively to a pharmacological manipulation. They further observed that the CNS stimulant effects of ecstasy were never sufficient to overcome alcohol­ induced impairment on measures of impul­ sivity or risk taking and may be of particular importance in terms of road safety, especially crashes. Subjective effects Acute subjective effects following use of ecstasy have been studied. The authors of a meta-analyses searched for published articles that provided data on self-reported acute effects associated with use of ecstasy while intoxicated or within 24 hours after consumption (46M). The study criteria were met by 24 studies in 3074 ecstasy users. There was a slight preponderance of men; ages were 14–74, the largest proportion being 21–36 years.
Somatic effects were more frequent than any other effects, and 80% or more participants in one or more studies had bruxism/teeth problems, body tempera­ ture changes, fatigue or mental fatigue, accelerated heart rate or heart beat, sweaty palms, dry mouth/thirst, and increased energy. A few subjects com­ plained of stomach and/or intestinal pain, inability to urinate, shortness of breath, motor tics/shakiness, nausea and/or vomiting, headache, dizziness and/or ver­ tigo, and muscle aches or tightness.
For emotional effects, 80% or more participants in three or more studies reported feeling tenderness/affection, peaceful/calm, euphoria or improved mood, and reduced defensiveness. A few subjects reported anxiety or nervous­ ness, fear/paranoia, omnipotence, greater self-confidence or self-acceptance, and insecurity.
Cognitive effects reported in three or more investigations were confused thoughts (3–50%), loss of memory/ forgetfulness (3–28%) and increased alertness/attention focused on the hereand-now (7–100%).

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Sexual effects, especially arousal/ increased sensual awareness (7–100% in 8 studies) and decreased sexual desire (3– 45% in 4 studies) were also reported.
Sensory perceptions reported in three or more studies were visual effects/changes in visual perception (14–85%), sound hallucinations/altered sound perception (13–100%), enhanced sense of touch/ tactile illusions (3–95%), and hallucina­ tions not otherwise specified (2–60%).
Sleepiness was the only sleep effect recorded by more than one investigator (9–85%).
Decreased appetite was reported by 14– 100% subjects in 9 studies. Factors that affected ecstasy experience as reported in some studies were women having more negative physical and psycho­ logical effects than men. Larger doses were reported to be associated with more hallu­ cinatory experiences, disorientation, loss of control, and increased adverse effects. Acute subjective experiences usually peaked at 45–90 minutes and lasted 4.5– 9 hours. Desirable acute subjective experi­ ences were experienced more often than non-desirable ones. The authors suggested that acute subjective experiences may motivate or restrain ecstasy use, and that educators and researchers could use these data to develop credible prevention messages. The subjective experiences of ecstasy use have been explored in 305 unpaid volun­ teers (268 ecstasy users and 37 abstainers; mean age 26. range 18–72, years; 63% men) (47C). Lifetime use of ecstasy significantly correlated with estimated consumption of other drugs, including alcohol, cannabis, cocaine, and LSD; heavy use of ecstasy was associated with heavy use of all substances. Of the 262 individuals who specified their usual location of ecstasy use, 110 (41%) reported usually taking it at entertainment venues, 52% reported usually taking it in private houses, and 5% reported usually taking it outside. A heterogeneous sample of polysubstance misusers revealed six main components of acute ecstasy effects. These components were perceptual alterations, entactogenesis, pro-social effects, esthetic

and mood effects, negative intoxication effects, and sexual effects. More experienced ecstasy users reported fewer negative, perceptual, and esthetic effects. Naïve individuals expected greater perceptual alterations, esthetic and mood effects, negative intoxication, and sexual effects than those who reported frequent use of ecstasy. Respondents reported using ecstasy for a variety of reasons, most often for raves, dancing, enjoyment of music, to be sociable, to produce altered states of consciousness, and for self-defined psy­ chotherapy. There were no sex differences, in contrast to previous studies. The authors suggested that expectations may be primed by media reference to the negative effects of ecstasy and that those using the drug for other purposes, for example for spirituality, may adopt strategies to counteract negative effects or withdraw from social interactions as part of their drug use practice. They suggested that drug intervention strategies would be more effective if targeted to the particular user groups defined by the reasons given for substance use. Thus, people using ecstasy while dancing or to be social may be more interested in hearing harm reduction information focusing on ways to reduce negative effects. However, people who are not as attentive to negative effects, as those using ecstasy in self-defined therapeutic or spiritual context may be less interested in this information. A drawback of this study was that as many of the respondents were frequent polysubstance users, it would be difficult to differentiate the effects of ecstasy from those of other drugs. It has been suggested that lowering of serotonin for a period after ecstasy use could account for increases in both selfrated and objective measures of aggression previously found in ecstasy users several days after taking the drug (48c). A total of 46 participants were tested, 19 were ecstasy users and 27 controls. They were compared on the night of drug use and 4 days later. On day 4, a task designed to tap cognitive bias toward material with aggressive con­ tent was administered. To investigate sex differences, another data set from a pre­ vious study with similar study design was

Drugs of abuse

Chapter 4

combined, resulting in 107 participants. Ecstasy users recognized more aggressive sentences than controls. They rated them­ selves as being more aggressive and depressed than controls on day 4, but there were no sex differences on any measure of aggression in the combined data set. Neurocognition Chronic ecstasy use has been associated with memory deficits in abstinent users. Memory deficits were evaluated in 19 ecstasy-abstinent men, 19 cannabis-abstinent men, and 19 drug-naïve male controls (49C). The aim of this study was to investigate whether memory deficits in ecstasy users arose from temporal lobe dysfunction or whether the frontal lobes were also involved. Ecstasy users had widespread marked verbal memory deficits compared with drug-naïve controls and cannabis users. Cannabis users did not differ from the control subjects in memory performance. Ecstasy users had impair­ ments in learning, consolidation, recall, and recognition. There was a significant correla­ tion between memory performance and the amount of ecstasy taken, supporting the authors’ view that the memory deficits were caused by a selective neurotoxic effect of ecstasy, possibly on the serotonergic sys­ tem, as seen in animal studies. Moreover, these patients had worse recall consistency and strong retroactive interference. The authors suggested that these measures have been previously associated with frontal lobe function, implying that memory deficits in ecstasy users are related not only to temporal or hippocampal dysfunction but also to the frontal lobes. The postulated negative effects of ecstasy on brain serotonin neurons, which may underlie cognitive dysfunction (especially memory), may be associated with serotonin transporters. Some have suggested that the serotonin transporter promoter gene region may be involved in ecstasy dose and cognition. The effects of moderate and heavy ecstasy use on cognitive function and the effects of long-term abstention from ecstasy have been related to the serotonin transporter promoter gene region genotype (5-HTTLPR) (50C). There were 15 moder­ ate ecstasy users (under 55 lifetime tablets),

45 22 heavy MDMA users (over 55 lifetime tablets), 16 ex-ecstasy users (last tablet over 1 year ago), and 13 controls. There was a significant group effect only on memory function tasks, not on reaction times or attention/executive functioning. Heavy and ex-ecstasy users performed significantly poorly on memory tasks compared with controls. In contrast, there was no evidence of memory impairment in moderate ecstasy users. There were no significant effects of 5-HTTLPR or sex on memory impairment and ecstasy use. The persistent effect of memory problems in the ex-ecstasy users may suggest irreversibility of ecstasyinduced serotonin neurotoxic changes in the brain. Thus, there was a dose-dependent increase in memory dysfunction in ecstasy users, which may not be reversible. Transient persistent sequelae associated with an unusual amount of ecstasy con­ sumption have been reported (51Ar).
A 37-year-old man estimated that he had

used more than 40000 ecstasy tablets between the ages of 21 and 30. He concurrently consumed cannabis and had previously used other drugs. After three episodes of collapse at parties, he stopped using ecstasy. For a few months he felt as if he was still under the influence of ecstasy and had several episodes of tunnel vision. He eventually developed severe panic attacks, recurrent anxiety, depression, muscle rigidity (particularly in the neck and jaw), hallucinations, and para­ noid ideation. He was disoriented in time and had poor concentration and short-term mem­ ory difficulties. He reduced his cannabis intake, and his paranoid ideas and hallucina­ tions disappeared and his panic attacks reduced but his other symptoms remained. The Wechsler Memory Scale showed global memory impairment. There were major behavioral consequences of his memory loss (i.e., repeating activities several times). He fully understood instructions, but his concen­ tration and attention were so impaired that he was unable to follow the sequence of tasks required. A brain MRI scan was normal. He was given olanzapine 10 mg/day and his memory skills improved through the use of compensatory strategies.

The authors thought that this was the largest amount of ecstasy lifetime consump­ tion ever described. The “tunnel vision” effect observed in the first few months after withdrawal has never been reported before.

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The neurocognitive profile was very similar to that shown by current heavy ecstasy users, suggesting that the extent of memory impairment correlates positively with the intensity or frequency of ecstasy consump­ tion. Furthermore, selective impairment of neuropsychological performance associated with regular ecstasy use is not reversed by prolonged abstinence. Cognitive performance and extrapyrami­ dal function have been evaluated in 13 ecstasy users 10–15 hours after exposure and in controls (52c). Ecstasy subjects had impairment of executive functions and pro­ blems with short-delay free recall but they did not have any extrapyramidal motor effects. Contrary to expectations, the authors found minimal memory impairment and no frontal lobe dysfunction. The deficits in executive functions (probably transient) were thought to represent more global than frontal lobe dysfunction. The authors specu­ lated that these effects were more probably related to noradrenergic function. Cognitive function has been evaluated in 11 users of ecstasy and cannabis (THC), 15 THC users, and 15 non-drug controls matched for age and intellect, in order to test the hypothesis that feelings of depres­ sion and anxiety and cognitive impairment are more severe in combined ecstasy/THC users than in THC users alone (53c). Memory function was impaired in both groups of drug users. Ecstasy/THC users had slower psychomotor speed and less mental flexibility than non-drug users. THC users had less mental flexibility and per­ formed worse on the decision-making task than non-drug users, but these functions were similar to those in ecstasy/THC users. Ecstasy users had more feelings of depres­ sion and anxiety than THC users and controls. THC users had impairment of some cognitive abilities to the same degree as ecstasy/THC users, suggesting that some cognitive impairment attributed to ecstasy is more probably due to concurrent THC use. “Stereotype threat” has been the subject of studies of cognitive function in ecstasy users (54CR). According to the authors, “stereotype threat occurs when individuals, believed to be intellectually inferior, perform

badly on cognitive tests they perceive to confirm stereotypes about them.” They suggested that stereotype threat creates an additional burden that interferes with cog­ nitive ability, resulting in a higher mental workload, and that stereotype threats may be created by wide discussion of the negative cognitive effects of ecstasy in the media, by government sponsored drug education campaigns, by websites supported by NIDA, etc. They studied 68 unpaid volunteers (aged 18–36 years) recruited by traditional means. Polysubstance users who reported lifetime use of ecstasy were classi­ fied as ecstasy users. The controls were subjects who used alcohol and other illicit drugs but did not report lifetime use of ecstasy. People were excluded if they were currently using heroin or crack cocaine, had a lifetime diagnosis of a psychological disorder, or had an immediate family mem­ ber with a lifetime diagnosis of a psycholo­ gical disorder. Half of the subjects in both groups received a study information sheet that stated that there was strong evidence linking ecstasy use to mnemonic dysfunction (primed group). The other half did not receive the sheet, were told that there was no conclusive evidence supporting the link, and were verbally reinforced by the investi­ gators (non-primed group). Of all the participants, 84% believed that drug use caused memory loss and 77% believed that drug use caused psychiatric problems. Ecstasy users who were primed recalled fewer items in the delay component of the prose recall task compared with the nonprimed group. To the authors, this suggested that individuals using ecstasy may experi­ ence stereotype threat, raising the concern that stereotype threat may be an important variable in these types of studies. The nonprimed ecstasy users had better memory performance than the other three groups. A higher proportion of ecstasy users reported lifetime use of amfetamine, cannabis, cocaine, ecstasy, and LSD than controls, but there were no differences between the primed and unprimed subjects. Clearly there are limitations to such studies: for instance, controlled drug use was not quantified and it was possible that some subjects may have been recently intoxicated. Cognitive

Drugs of abuse

Chapter 4

functioning in ecstasy users was comparable to that of their non-ecstasy using peer group. None of them self-reported that they had memory loss. The authors interpreted this to mean that ecstasy users believe what they are told about the negative effects of ecstasy use on memory but do not experience these problems themselves. They further sug­ gested that these users may believe that the probability of negative things happening to them is very low, despite the fact that these problems exist. Thus, they suggested that media reports about the short- and longterm effects of ecstasy may actually be counterproductive. They suggested that researchers should take extra precautions to guard against inducing or amplifying stereotype threat in their studies. Liver Acute hepatitis after ecstasy expo­ sure has again been reported (55A).
A 19-year-old man developed jaundice. There

was no history of surgical procedures, blood transfusion, or ingestion of paracetamol or other medications. He had taken two tablets of ecstasy 2 weeks before, and biochemical confirmation of exposure was not possible. His mother had a history of chronic viral hepatitis B. He was afebrile with an enlarged liver and spleen and no signs of chronic liver disease. Histopathology showed macrovesicu­ lar fatty changes, foci of cell necrosis, and portal tracts expanded by edema and inflam­ matory cells. All other investigations were negative. His serum alanine transaminase and aspartate transaminase activities and bilirubin were markedly raised, with evidence of intrahepatic cholestasis.

Liver damage from ecstasy ranges from being asymptomatic to acute hepatic fail­ ure, and the occurrence and severity of hepatocellular toxicity are unpredictable. Moreover, the severity of symptoms is not related to the magnitude of use or the length of exposure to ecstasy. Although the exact mechanism of liver damage is unclear, the clinical course is the most reliable prognostic factor in ecstasy-induced hepati­ tis. The authors performed HLA typing to rule out a trait of idiosyncrasy and found that the patient had A11 molecules. HLA­ A11 has been reported in 50% of patients with hepatitis caused by tricyclic antide­ pressants and 75% of patients with

47 diclofenac, compared with 12% of controls. The authors suggested that the possibility of an association of specific HLA phenotypes with ecstasy-induced hepatotoxicity should be further investigated. If established, it would offer strong evidence for an immune pathogenetic mechanism. Drug overdose Accidental ecstasy poison­ ing has been reported in a toddler (56A).
While playing, a 17-month-old girl had picked

up a cigarette packet that contained a single ecstasy tablet; an older child had seen her place the tablet in her mouth and immediately alerted her mother, who saw the tablet under the tongue and removed it. About 5 minutes later she developed generalized tonic–clonic seizures. Her rectal temperature was 38.51C. When rectal diazepam 5 mg and paracetamol 180 mg failed, she was given lorazepam 1 mg intravenously, repeated 10 minutes later. She was than sedated with a midazolam infusion and given a single bolus dose of atracurium 10 mg. Her brain CT scan was normal. The serum MDMA concentration was 0.30 mg/l; no other toxins were detected. Her temperature rapidly normalized with tepid sponging and a fan. She was discharged within 48 hours and made a full recovery without sequelae.

The authors cautioned that with widespread use of ecstasy there is increased risk of accidental poisoning in children. This may be exacerbated by a false perception that ecstasy is safe, which may lead to lax supervision. Ecstasy tablets are often very colorful and therefore particularly attrac­ tive to young children. The authors were surprised that there were very few case reports of such poisoning. It appeared that children present with symptoms sooner (within 20 minutes) than adults and that convulsions are the initial manifestation. Other common features are hypertension, tachycardia, and moderate hyperthermia. However, in this case, the symptoms started within 5 minutes, suggesting that sublingual absorption is rapid. MDMA serum concen­ trations were higher than reported for recreational use (below 0.25 mg/l). Hyperthermia in infants is likely to be due to seizures. The authors suggested that termination of seizures combined with cool­ ing measures may be sufficient to restore core temperature. This suggests that

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hyperthermia in children may be from a different etiology than in adults and may not warrant the use of dantrolene. As the contents of ecstasy tablets tend to be variable, the authors suggested performing a full toxicological screen, even with a clear history of ecstasy use.

Khat

(SEDA-30, 43)

Khat is a stimulant commonly used in East Africa, Yemen, and southern Saudi Arabia. Because the major active component, cath­ inone, degrades to norpseudoephedrine and norephedrine within days of leaf picking, its use was initially limited to this region. However, with air travel and more sophisti­ cated distribution, khat is now also used in North America and Western Europe. Tra­ ditionally, it is ingested as a part of khat “sessions”, which may begin in the late afternoon and last for many hours. The social and economic impact of khat is significant and has been investigated in a small interview study. Among 50 subjects in Northeast Kenya, 88% of whom had a history of khat use, more than half reported spending over 50% of their household income on khat and 40% felt that it contributed to low productivity in the work­ place (57c). Cardiovascular Khat can cause cardiovas­ cular complications and has been associated with myocardial infarction (58A).
A 33-year-old man had an acute anterior

myocardial infarction after using khat con­ tinuously over the course of 2–3 days. After recovery, he used khat daily and 27 months later presented with shortness of breath and chest pain. He had biventricular heart failure (ejection fraction 15%).

The authors commented that while myo­ cardial infarction is a known complication of khat, guidelines specific to khat-induced cardiac events have not been established. Stroke has been attributed to khat (59A).
A 41-year-old Somali man had an acute left

hemiplegia 2 hours after chewing khat. He was hypertensive (190/95 mmHg) and a CT scan

showed a right middle cerebral artery infarct. He had used khat regularly, but used no other drugs and had no known medical problems. His carotid arteries were normal and there was no hypercoagulability. He was given aspirin and amlodipine and recovered over the course of several months. He resumed using khat and 18 months after the initial event had a left hemiplegia with a larger right middle cerebral artery infarction and white matter changes. After another full recovery, he stopped using khat and 3 years later had had no further ischemic events.

Psychiatric Two further cases of khatinduced psychosis have been described (60A).
Two young Somali men, aged 25 and 35, with

no known psychiatric co-morbidities, had brief self-limiting episodes of psychosis in the context of khat use. The episodes were characterized by paranoia and aggression, necessitating hospitalization; in both cases the episodes resolved over the course of weeks without specific treatment. The 35-year-old man was also given venlafaxine 75 mg/day for a depressed, dysphoric, anxious mood.

The authors pointed out the severe func­ tional impairments associated with khat use; both patients were withdrawn and unemployed. Liver Hepatitis has been attributed to khat (61A).
A 35-year-old East African with no known

medical problems developed hepatitis, with jaundice, dark urine, and pruritus, soon after he began chewing khat daily. He had no recent travel history, no history of transfusions, no infectious contacts, no medications, no family history of hepatitis, and no heavy alcohol or other recreational drug use. Hepatitis virology and autoimmune tests were negative. The symptoms resolved and liver function tests normalized with supportive care alone.

OPIOID ANALGESICS See Chapter 8, in which both therapeutic and abuse aspects of the opioids are covered.

Drugs of abuse

Chapter 4

Psilocybin Psilocybin-containing mushrooms, also called “magic mushrooms”, are used recrea­ tionally, with an expanding worldwide dis­ tribution. They are sold in “smart shops” and over the internet. Psilocybin is showing up in the nightclub scene, although its use is not as popular as “club drugs” such as ecstasy or amphetamines. In 1957, psilocy­ bin was isolated from the Psilocybe mex­ icana mushroom and it has since been identified as a component of over 75 distinct mushroom species (62R). Psilocybin and psilocin are listed as Schedule I drugs under the United Nations 1971 Convention on Psychotropic Sub­ stances. Spore prints, which are distributed in home-growing kits, are currently legal in several states of the USA and can be purchased over the internet (63r). Psilocybin content varies based on such factors as species and preparation. The most commonly used mushroom is Psilocybe cubensis, which contains 10–12 mg of psilo­ cybin per gram of dried mushrooms; effec­ tive oral doses range from 6 to 20 mg and about 40 mg/kg is considered the threshold level for intoxication (64R). Structure Psilocybin (N-phosphoryloxy-N, N-dimethyltryptamine), a simple tryptamine, is dephosphorylated to psilocin (4-hydroxy­ N,N-dimethyltryptamine) by alkaline phos­ phatase in the gastrointestinal tract and kidneys during first-pass metabolism. Psilo­ cin, the pharmacologically active compound, is an indole derivative with structural simila­ rities to serotonin. Psilocybin is detectable by high performance liquid chromatography, but this is not available in most clinical settings. Action Psilocin is a high-affinity agonist at serotonin 5-HT2A receptors, which are espe­ cially prominent in the prefrontal cortex. The net result of 5-HT2A agonism is increased cortical activity secondary to down-stream postsynaptic glutamate effects. Psilocin is also active at 5-HT1A, 5-HT1D, and 5-HT2C receptors, although these are thought to play a lesser role in its effects.

49 Additional evidence about the mechanism of action comes from studies of receptor antagonists. In the presence of the 5-HT2A antagonist ketanserin, the mental status changes typical of psilocybin do not occur, supporting the notion that primary effects are due to action at presynaptic 5-HT2A receptors (65R). Although psilocybin has no affinity for dopamine D2 receptors, a PET study using the D2 receptor ligand raclopride showed that psilocybin increases dopamine transmission in the striatum, probably through secondary increases in dopamine (66c, 67R). Some psilocybin-containing mushrooms contain phenylethylamine, which may contribute to sympathomimetic effects. Psilocybin like other serotonergic hallu­ cinogens, such as lysergic acid diethyla­ mide (LSD) and N,N-dimethyltryptamine (DMT), alters mood, perception, and cognition. In healthy volunteers, changes in emotion, consciousness, perception, and thought begin within 20–30 minutes of ingestion and peak in 30–50 minutes. Peak effects persist for 2 hours, with resolution of effect within 6 hours. Lower doses may produce shorter lasting effects of 1–2 hours. Moderate oral doses (12–30 mg) alter consciousness, increase introspection, and induce derealiza­ tion, dream-like states, illusions, complex hallucinations, synesthesia, and altered per­ ceptions of time and space. Muscle relaxation is also experienced with intoxication. Disrup­ tions in attention, such as difficulty in disen­ gaging from prior stimuli and impairment in monitoring several simultaneous visual sti­ muli, have been described (68c). Euphoria, grandiosity, and other amplifications of affec­ tive experience are common. The majority of psilocybin users experience a pleasant altera­ tion in mood, but some experience panic or dysphoria. A user’s expectations and envir­ onment very strongly influence the hallucino­ genic effects. Settings with more interpersonal support reduce panic and paranoia and increase positive experiences (69c). Psilocybin and psilocin are renally excreted, and about two-thirds of excretion occurs in the first 3 hours. The half-life is about 50 minutes (67R). After 24 hours, the compound is undetectable in the urine (70c).

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Uses Psilocybin has been used in obsessivecompulsive disorder (OCD) and some studies support its efficacy in this disorder. In a double-blind study, nine subjects received four doses, low (100 mg/kg), medium (200 mg/kg), and high (300 mg/kg), in a series of 8-hour sessions with a very low dose (25 mg/kg) inserted randomly in a doubleblind manner. All the subjects had a reduc­ tion in their symptoms (measured by the Yale-Brown Obsessive Compulsive Scale) during at least one of the sessions, and improvement lasted at least 24 hours. No dose effect was noted. With the exception of one subject who had transient hypertension, psilocybin was well tolerated and without adverse effects (71c, 72R). Synthetic psilocybin (Indocybin) was used for investigational and psychotherapeutic purposes in the 1960s. The serotonin hypoth­ esis of schizophrenia grew in part from the psychotomimetic effects of psilocybin seen in these investigations, as well as similar obser­ vations in studies of LSD. Psilocybin impairs thalamic sensory gating, resulting in an inability to screen out extraneous stimuli and difficulties attending to appropriate stimuli, which overwhelms frontal organizational capacities and is thought to result in the observed psychotomimetic effects (67R, 73R).

Adverse effects Cardiovascular An 18-year-old man devel­ oped Wolff–Parkinson–White syndrome and had a myocardial infarction during psilocy­ bin intoxication (74A). The mechanism for myocardial infarction is not known, although it is theorized that serotonin-induced changes in platelet aggregation and sympatheticallyinduced vasospasm may play a role (75R). In a study of the dose-dependent effects of psilocybin 45–315 mg/kg in eight subjects, there was no effect on the electrocardiogram or heart rate (76c). At the highest doses, mean arterial blood pressure rose signifi­ cantly in the 60 minutes after psilocybin ingestion, leading the authors to recommend that those with untreated hypertension should abstain from psilocybin. Nervous system In an interview study of 53 subjects with cluster headaches who were

using psilocybin or LSD to treat their symptoms, 32 had episodic cluster headache and 21 had chronic cluster headaches; 17 of 19 who tried sublingual psilocybin reported that it terminated the headache within 20 min­ utes (77c). Of the 29 who used psilocybin as prophylaxis, 15 described it as completely effective in avoiding headaches and 12 (42%) reported that it reduced the frequency or intensity of headaches. Of the 21 subjects with chronic cluster headaches, seven tried psilo­ cybin to abort a headache and five felt that it was effective; 20 tried psilocybin as prophy­ laxis and 10 reported a complete response, while eight reported partial efficacy. This small study used a retrospective design and may have been affected by recall bias, selection bias, and by its unblinded and uncontrolled design. Psychiatric Two cases of exacerbation of pre-existing psychosis have been reported (60A).
A 35-year-old man with a history of schizo­

phrenia developed anxiety, irritability, agitation, and aggression while using “a handful” of psilocybin-containing mushrooms plus cannabis twice daily. He also reported delusions of external control and persecution as well as auditory, olfactory, and gustatory hallucinations. He was given risperidone 3 mg/day and his symptoms gradually improved over 2 weeks.
A 35-year-old man with a 10-year history of paranoid schizophrenia experienced mood ele­ vation, anxiety, and psychomotor agitation as well as illusions, hallucinations, “sensory dys­ perceptions”, paranoia, compulsive thinking, and poor attention after taking psilocybin (amount and duration of exposure not speci­ fied). The symptoms resolved within days without pharmacologic treatment.

While these case studies suggest a possible role for psilocybin in exacerbating psychosis, the small number of cases and factors such as the simultaneous use of cannabis in the first case make it difficult to draw a more definitive conclusion. Hallucinogen persisting perceptual disor­ der (HPDD) has been reported after psilocybin (78A).
An 18-year-old man with no prior psychiatric

history who smoked cannabis weekly and took a single dose of 40 psilocybin-containing mushrooms, after which he experienced visual

Drugs of abuse

Chapter 4

distortions, temporal and spatial distortions, depersonalization, and derealization. These symptoms remitted, but recurred the next day in conjunction with cannabis use and continued daily thereafter. His symptoms, including hal­ lucinations, depersonalization, derealization, and dysphoric mood, remitted 8 months later, after discontinuation of cannabis and treatment with sertraline 150 mg/day and risperidone 2 mg/day.

The authors commented that both canna­ bis and psilocybin may play a role in triggering HPDD. Previous anecdotal reports that hallucino­ gens induce religious experiences and heigh­ tened spirituality have been investigated in a double-blind study in 36 healthy hallucinogennaïve volunteers, who were assigned to either psilocybin (30 mg per 70 kg) or methylphe­ nidate (40 mg per 70 kg) in an 8-hour drug session, returning at a later date for a session with the other drug (69c). Monitors were assigned to provide support throughout the sessions and a comfortable environment was maintained. Based on criteria from the Mysticism Scale and the States of Conscious­ ness Questionnaire, 22 of 36 volunteers had a “complete” mystical experience with psilo­ cybin, compared with four of 36 in response to methylphenidate. The authors noted that 33% of participants described the psilocybin experience as their most significant spiritual experience in life and another 38% rated the experience within their top 10 most signifi­ cant experiences. Dysphoria or anxiety in the 6 hours after psilocybin was reported by eight of the 36 participants; these reactions responded to reassurance and did not persist beyond the duration of the session. Of these healthy volunteers without a history of psychosis, 17% reported transient ideas of reference or paranoia in response to psilocybin; there were no lasting adverse effects. Endocrine In a double-blind, placebocontrolled study of psilocybin in 32 healthy volunteers, drug exposure did not affect prolactin, cortisol, or growth hormone concentrations (79c). In a study of the dose-dependent effects of psilocybin 45–315 mg/kg in eight subjects, there were transient rises in thyroid stimulat­ ing hormone, prolactin, ACTH, and cortisol

51 (76c). These effects were unlikely to be clinically relevant, since all values returned to baseline by 300 minutes after ingestion. The authors noted that only the prolactin concen­ trations fell outside the reference range. Electrolyte balance Psilocybin has no effect on electrolyte balance (measured at 105 and 300 minutes after exposure to 45–315 mg/kg) (76c). Liver Psilocybin has no clinically relevant effects on liver function (76c). Brief, statis­ tically significant increases in gamma-gluta­ myltransferase and aspartate transaminase activity resolved within 300 minutes of exposure. Body temperature Psilocybin has no effect on axillary body temperature (76c). Trauma Hallucinogen intoxication can result in traumatic injury if people believe that they have superhuman powers (80R). Death Psilocybin mushrooms are not known to cause major organ toxicity or death, but mis-identification can lead to the ingestion of toxic species with potentially fatal outcomes. For example, there have been reports of renal failure after ingestion of Cortinarius mushrooms that were mis­ taken for Psilocybe species (81A, 82A). Drug abuse and tolerance Psilocybin and other hallucinogens are not considered classic drugs of abuse because they do not have reinforcing properties and do not produce drug-seeking behaviors (69c). Use tends to be episodic and is generally shortterm and experimental (80R). Tolerance occurs with repeated dosing and is thought to be due to down-regulation of 5HT2A receptors (80R). There may also be crosstolerance between LSD and psilocybin (67R, 64R). Psilocybin, like other hallucinogens, is not known to cause dependence, craving, or withdrawal. Interference with diagnostic tests Urine toxicology may be falsely positive for amphe­ tamines because of the phenylethylamine in psilocybin-containing mushrooms (62R).

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Management of adverse drug reactions Treatment should begin with reassurance and observation in a low-stimulation envir­ onment. Benzodiazepines are considered first line for agitation. Most symptoms of

intoxication resolve within 6 hours of inges­ tion (64R, 83c). If it is suspected that another, potentially toxic, type of mushroom was ingested, activated charcoal should be admi­ nistered (62R).

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