Journal of Psychopharmacology 17(3) (2003) 342–345 2003 British Association for Psychopharmacology (ISSN 0269-8811) 0269–8811[200309]17:3;342–345; 033061 Case Reports
Neuropsychiatric consequences (atypical psychosis and complex-partial seizures) of ecstasy use: possible evidence for toxicity–vulnerability predictors and implications for preventative and clinical care Psychiatric University Hospital Zurich, Zürich, Switzerland.
Two case reports of ecstasy abuse and its serious neuropsychiatric complications are presented. The first patient developed a florid paranoid psychosis resembling schizophrenia after repeated long-term recreational ecstasy abuse, and significant alterations with intermittent paroxysmal discharges were found in his electroencephalogram. The second patient showed an atypical paranoid psychosis with Fregoli syndrome and a series of complex-partial epileptic seizures with secondary generalization after a first single ecstasy dose. Both subjects presented considerable vulnerability; the first a minimal brain dysfunction after perinatal asphyxia and a persisting attention deficit/hyperactivity disorder, the second a long-lasting opioid addiction. In vulnerable individuals, dose-independent ecstasy abuse can lead to unpredictable and potentially dangerous neuropsychiatric sequelae which require proper initial Key words: case report, complex-partial epilepsy, ecstasy, Fregoli syndrome, MDMA, 3,4-methylenedioxyamphetamine,paranoid psychosis, prevention, side-effects animals (Curran, 2000) and emerging evidence of neurotoxicity inhumans (Boot et al., 2000). There are pronounced interindividual MDMA or ecstasy (3,4-methylenedioxymethamphetamine) is a differences with regard to the sensitivity to the MDMA toxic synthetic amphetamine analogue stimulant, broadly used effects. Life-threatening or lethal outcomes have been seen with ‘recreationally’ (Franken, 2001). In Switzerland, life prevalence of concentrations between 0.11 and 7 mg/l (Theune et al., 1999).
ecstasy-consume is 5.3% (BAG, 1998). Biochemically, it depletes We report two cases of MDMA abuse with unusual stocks and thus induces an acute increase in levels of the neuropsychiatric complications. In both cases, predisposing factors neurotransmitters serotonin (5-hydroxytryptamine, 5-HT) as well were identified. We discuss assessment in cases with unusual as dopamine (Rattray, 1991). The immediate psychological effects syndromes and consider implications for clinical practice.
of its use include a sense of well being, elation, enhancedsubjective arousal and reduction in social anxiety (Curran andTravill, 1997).
Adverse reactions were reported even after the ingestion of a single dose, and they may include symptoms of sympathomimetic toxicity, trismus and bruxism (Greer and Tolbert, 1986). MDMA The patient was a 24-year-old man who suffered perinatal asphyxia has also been implicated with serious physical disturbances and there was a slight delay in his psychomotor development. At including rhabdomyolysis, disseminated intravascular coagulation, the age of 3–4 years, attention deficit/hyperactivity disorder intracranial haemorrhage, coma, and even death in some cases (ADHD) became evident with ensuing school and relational (Henry et al., 1992). Serious mental disorders such as chronic difficulties persisting until adulthood. He succeeded in completing paranoid psychosis, recurrent paranoid psychosis, panic attacks an apprenticeship as a salesclerk; however, he could not maintain and depression with suicidal ideation have been described (Bailly, his job because of uncontrollable behaviour problems. Since the age of 21 years, there was a history of recreational use of ecstasy The usual recreational oral dose is 1–2 tablets (each containing and cannabis. After the additional intake of LSD at age 23 years, approximately 60–120 mg of MDMA) and the drug is typically the patient suffered a ‘horror trip’ with symptoms of panic attack, used once fortnightly, or less, because of rapid tolerance including intense fears of dying. He abstained from further LSD development. The perceived relative safety of MDMA is at odds use; however, he intensified his abuse of ecstasy and cannabis.
with evidence of MDMA destruction of serotonergic neurones in Three months later, he was referred for psychiatric hospitalization M. VECELLIO ET AL.: NEUROPSYCHIATRIC CONSEQUENCES OF ECSTASY USE because of a psychotic condition: He was anxious, expressed ideas continued. The seizures became clinically milder and gradually of reference and of persecution (unknown people would shoot him disappeared. During the following days, phenobarbital was stopped dead) and bizarre fears (his eyes would fall out of his eye-sockets).
and clonazepam therapy continued. The EEG abnormalities He had acoustic (voices conveying him different messages) and disappeared, whereas individual psychotic symptoms persisted for visual (birds that would devour him) hallucinations.
several weeks in spite of the initiated neuroleptic treatment with There were no abnormalities on general medical and haloperidol, 10 mg (later reduced to 5 mg/day).
neurological examination and all laboratory parameters werewithin normal limits. Brain computerized tomography (CT) wasnormal. An electroencephalogram (EEG) showed normal basic activity; however, intermittent paroxysmal discharges wereregistered in both temporal regions with a tendency towards After ecstasy ingestion, both patients experienced a florid generalization, without any clinical evidence of seizures.
psychotic condition necessitating hospitalization. Even though Following treatment with olanzapine up to 40 mg/day, a slow paranoid schizophrenia was suspected in the first case, it had some amelioration over 6 weeks was observed with stepwise regression features of toxic delirium (i.e. vivid perceptual disturbances).
of hallucinatory experiences and delusional ideas. He was given a Subsequently, the patient experienced short-lasting prepsychotic diagnosis of probable paranoid schizophrenia.
decompensations after sporadic ecstasy and cannabis abuse.
After discharge, the patient stopped his medication and restarted Moderate thought disorder has been observed after taking MDMA sporadic ecstasy and cannabis abuse. Drug intake was frequently even in healthy volunteers (Vollenweider et al., 1998). In the followed by a short-lasting condition of prepsychotic decompensa- second case, an atypical psychosis with high anxiety level and tion with increased impulsivity and hyperactivity, loosening of florid paranoid hallucinatory experiences was diagnosed, with associations and volatile paranoid ideas. However, he always Fregoli syndrome (identification of a familiar person in a stranger recovered after such episodes within 2–3 days without using anti- who is perceived to be physically different but psychologically psychotic medication. Unfortunately, the patient refused control identical to the familiar person), a variant of misidentification syndrome (Ellis et al., 1994), being a part of patient’spsychopathology. In both patients, a diagnosis of acute exogenic psychotic reaction could have been given. Cases of acute and The patient was a 23-year-old female who was referred for chronic exogenic psychosis and delirium after ecstasy intake are psychiatric emergency hospitalization. There was no history of well known (Bailly, 1999) and toxic psychosis is a recognized psychotic disorder, epilepsy and organic brain disorder, but the complication of amphetamine abuse, where schizophrenia-like patient had been heroin-dependent for several years and was psychotic reactions are described (Bell, 1965).
currently under methadone substitution (45 mg/day). Also, there Both patients also presented significant EEG-alterations with was a history of recreational use of cannabis and benzodiazepines.
lower threshold neuronal activity. The first patient showed On admission, approximately 3 h after she had taken a single, irritative foci in both temporal lobes without clinical signs of probably high dose of ecstasy for the first time, the patient seizures. The second patient had an irritative temporo-pariental presented a wide range of sympathomimetic symptoms, including focus in EEG and presented clinically with several series of tachycardia, tremor, mydriasis and headache. She felt extremely complex-partial epileptic seizures. Both clinical semiology and anxious, was psychomotorically agitated, incoherent in thinking EEG findings were compatible with the diagnosis of temporal lobe and disoriented in time and place. She experienced vivid visual and epilepsy, which has been characterized, among others, by visceral auditory hallucinations along with feelings of bodily change, sensations, derealization and panic feelings (Niedermeyer, 1984), alienation and strangeness. Furthermore, she expressed ideas of and which may generalize to include tonic-clonic seizures. The reference (people staring and ridiculing her) and considered the occurrence of complex-partial seizures after ecstasy intake is exceptional and was not mentioned by Bailly (1999) in his survey Except for slightly increased liver enzymes (history of hepatitis of neuropsychiatric disturbances following ecstasy intake. To our C), all laboratory parameters and electrocardiogram were within knowledge, such a complex clinical picture including Fregoli normal limits. Urine drug screening was positive for MDMA, syndrome, as observed in our second patient, has not been benzodiazepines, cannabis and methadone, and it was negative for described in association with the use of MDMA before. A positive other substances of abuse. Blood screening for dextromethorphane correlation between level of previous ecstasy use and EEG changes and psilocine was negative. Brain CT showed no intracerebral has been reported (Dafters et al., 1999).
anomalies. EEG revealed discrete general alteration with an In both patients, toxic reactions appeared for the first time after increase of beta-waves and a significant irritative focus in the right ingestion of ecstasy; in the first patient, after increased abuse and, in temporal and parietal region, consistent with the diagnosis of the second patient, after the first abuse. In the first case, there was repeated ecstasy abuse over several years until the toxic reaction During the initial hours of her hospital stay, the patient appeared; in the second patient, it appeared after a single ecstasy presented with two series of four and five complex-partial epileptic dose. Whereas in the latter case, abuse could be substantiated by seizures, two of them with secondary generalization (grand mal).
identification of MDMA in urine, we had to rely on the patient’s Initial treatment consisted of valium 10 mg and phenobarbital 100 statement in the first case and we cannot be sure that he really always mg. After the second episode, she received clonazepam (1 mg took MDMA; the conception of ecstasy sometimes encompasses the i.m). Medication with phenobarbital (100 mg/day), clonazepam (3 whole group of amphetamine derivatives with enactogenic effects mg/day) and valium (as needed to prevent seizure repetition) was (Enderlin et al., 1999). Therefore, we cannot be sure that there is a true causal relationship between the drug ingested and the toxic Implications for clinical care
reactions observed. Admittedly, the time relationship between ecstasy intake and epileptic seizures in the second patients is appealing, but There is a need for integrated school- and community-based drug seizures due to a reduced level of benzodiazepines must be prevention programs that capture the full spectrum of patterns of considered. Nevertheless, epileptic grand maux seizures in the first use and levels of risk among those populations at risk (Poulin and hours following ecstasy intake were described (Theune et al., Elliott, 1997). Because adolescence is associated with an increased 1999) and the seizures in our patient occurred within hours after risk of developing drug abuse/dependence, young people should be drug ingestion and, in two of them, generalization was observed.
addressed. During adolescence, brain and hormonal systems arestill undergoing crucial maturational rearrangements, which take Predisposing toxicity-vulnerability factors
place together with significant modifications in psychosocial The pathogenesis of ecstasy-induced neuropsychiatric complica- development. Novelty-seeking, a personality trait that is typical of tions in general, and of psychotic reactions and seizures in this age period, might substantially contribute to psychobiological particular, still remains unclear. Because only a minority of vulnerability to drugs (Laviola et al., 2000).
MDMA abusing individuals suffer such complications, andbecause there is a lack of relationship between ecstasy dose and seriousness of the complications (Thomasius et al., 1997), Drug intake is high among those referred for psychiatric individual vulnerability must play a role. There are different assessment and hospitalization (Modestin et al., 1997) and it must potential toxicity–vulnerability factors: always be considered, especially in the young. Good history taking Genetic vulnerability has been suggested to precipitate serious is crucial but often hindered because of abnormal psychic states mental disorders for psychotomimetic drugs (Bowers, 1977) and with cognitive impairment, and those claiming to have ingested MDMA (Thomasius et al., 1997). In our patients, there was no ecstasy may actually have taken other agents. Prodromi often evidence of a personal or family history of mental illness.
include sympathomimetic signs and complaints of restlessness, However, genetic factors could influence the MDMA metabolism.
tremor and visual hallucinations. A quick determination of MDMA MDMA is demethylenated by the polymorphic cytochrome P450 in urine or serum should be mandatory in all unclear cases of CYP2D6. Individuals possessing CYP2D6, 2, 17 and, particularly, psychotic decompensation and epileptic seizures. Initial monitoring of liver and renal functions, complete blood count, consequently, higher MDMA toxicity (Ramamoorthy et al., 2002).
electrolytes, etc., helps to rule out other potential organic causes.
A past history of neurodevelopmental disorder may have been of importance in the first patient. ADHA following perinatal hypoxia may have predisposed him to acute psychosis after Seizures due to ecstasy intoxication generally need aggressive increased ecstasy intake. Correspondingly, perinatal hypoxia is treatment with benzodiazepines whereas, in our experience, considered a vulnerability factor for schizophrenic disorder ecstasy-induced psychotic conditions respond to neuroleptics.
(Davies et al., 1998). Incidentally, ADHA patients tend to abuse MDMA releases serotonin and, to a lesser extent, dopamine and selectively psychostimulants such as cocaine, perhaps as a form of norepinephrine. The release of serotonin could be blocked by self-medication (Carroll and Rounsaville, 1993).
serotonin uptake inhibitors such as citalopram which should reduce Multiple substance abuse may end in higher pharmacodynamic all MDMA effects except for body temperature (Liechti and and phamacokinetic vulnerability. Indeed, ecstasy abuse may not Vollenweider, 2000). However, the clinical evidence of its efficacy be the main and sole responsible factor for psychiatric in this indication is lacking. Somatic emergencies must be manifestations (Bango et al., 1998), and some 70–100% of ecstasy addressed as needed. In the case of hyperthermia, active cooling, users also consume other psychoactive substances (Bilke, 1998).
rehydratation and treatment of acidosis and other metabolic Both our patients abused cannabis. In addition, the second patient problems, and the use of a benzodiazepine in large doses, may had a long history of heroin abuse and she was under methadone form part of the initial intervention.
substitution. It has been suggested that delta-9-tetrahydrocanna- In summary, our case reports confirm that clinically important binol, the psychoactive principle of cannabis, facilitates mesolimbic and unpredictable effects (such as complex-partial epileptic dopamine neurotransmission (Sakurei Yamashita et al., 1989) and seizures) may occur after MDMA ingestion, possibly when that the repeated use of cannabis may increase dopamine intra- combined with other drugs such as cannabis. They remind us of the synaptic levels, thus leading to agitation, delirium and convulsive potential danger associated with ecstasy and other ‘social drugs’ states (Hollister, 1988). On the other hand, according to Vaiva et al. (2001), 13 cases of acute psychotic episode after ecstasy ingestionhave been reported, three of them after a single ecstasy dose, andthe serotonergic dysregulation due to ecstasy, which is independent of cannabis use (Croft et al., 2001), may also lead to mesolimbichyperdopaminergic state. According to Solowij (1993), MDMA J. ModestinPsychiatric University Hospital Zürich possesses not only stimulant, but also mild hallucinogenic properties.
Other accidental dispositional factors have been reported. For example, MDMA seizures can occur in the absence of any metabolic abnormality but, in other cases, they were precipitated by other ecstasy complications such as hyponatraemia and cerebraloedema (Holmes et al., 1999).
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