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REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003

ECSTASY INTOXICATION: THE TOXICOLOGICAL BASIS FOR TREATMENT

Maristela Ferigolo, Adriana G. da S. Machado, Niara B. Oliveira and Helena M. T. Barros

FERIGOLO M et al. - Ecstasy intoxication: the toxicological basis for treatment. Rev. Hosp. Clín. Fac. Med. S. Paulo 58(6):332-341, 2003.

Youngsters are increasingly using 3,4 methylenedioxymethamphetamine, known as ecstasy, because it is wrongly believed that it does not induce harm. However, there are many reports of adverse effects, including acute intoxication, abuse potential, and possible neurotoxic effects. Therefore, health care providers need to promptly recognize the symptoms of systemic intoxication in order to initiate early treatment. The drug is used by the oral route for long hours during crowded dance parties. Acutely, ecstasy increases the release of serotonin and decreases its reuptake, leading to hypertension, hyperthermia, trismus, and vomiting. There is debate on whether recreational doses of ecstasy cause permanent damage to human serotonergic neurons. Ecstasy users showed a high risk of developing psychopathological disturbances. The prolonged use of ecstasy might induce dependence, characterized by tolerance and hangover. Acute ecstasy intoxication needs emergency-type treatment to avoid the dose-dependent increase in adverse reactions and in severity of complications. There are no specific antidotes to be used during acute intoxication. Supportive measures and medical treatment for each one of the complications should be implemented, keeping in mind that symptoms originate mainly from the central nervous system and the cardiovascular system.

DESCRIPTORS: 3,4 methylenedioxymethamphetamine. Adverse effects. Substance-related disorders. Cognition. Hyperthermia.

In 2001, an estimated 8.1 million also known as XTC, E, Adam, MDM subjective effects of MDMA in hu- (3.6%) Americans aged 12 or older had or “ drug of love”7. The behavioral ef- mans are not the same as those pro- tried ecstasy at least once in their life- fects of increased self-confidence, un- duced by LSD and because the drug times. This is more than the estimated derstanding and empathy, and an in- does not have a similar structure or 6.5 million (2.9 %) lifetime users in creased sensation of proximity and in- pharmacological activity to hallucino- 20001. The Brazilian National House- timacy with other people are described gens or psychedelic drugs, the term hold Survey on Use mainly in uncontrolled studies. Com- “entactogens” meaning “entering in detected that 0.6% of respondents munication and personal relationship contact with yourself”10,11 was pro- aged 12 or older used ecstasy or other skills were also described to improve. posed to define a new pharmacologi- , meaning that 295,000 Euphoria and increased emotional and cal class. Also, a never-proven sexual Brazilians used this group of drugs at physical energy are presumed to occur enhancement action was cited by ex- least once in their lifetimes2. with this psychostimulant8-11. Since the perimental consumers12,13. However, Ecstasy or 3,4 methylene- ecstasy does not increase the excite- dioxymethamphetamine (MDMA) is a ment or the sexual desire in most of the 3-5 From the Psychoactive Substances synthetic , the wide- Information Service, Division of users, and orgasms may be delayed due spread use of which since the 1980s Pharmacology, “Fundação Faculdade to higher awareness of sensory input, might be related to the exaggerated Federal de Ciências Médicas de Porto especially in men; it cannot be classi- Alegre”- Porto Alegre/RS, Brazil. declaration of possible therapeutic ef- Received for publication on fied as an agent to treat sexual fects by some authors6. This drug is June 16, 2003. dysfuctions12. Ecstasy can be more

332 REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003 Ecstasy intoxication: the toxicological basis for treatment Ferigolo M et al. easily classified as a psychostimulant, In Northern Hemisphere countries, PATTERNS OF ECSTASY USE since it has chemical and action simi- adolescents with a polydrug-use pat- larities with and ampheta- tern also consume ecstasy. The sub- Ecstasy was synthesized and pat- mines. According to the American Psy- stance is introduced later in a drug-use ented in Germany by Merck in 1914 chiatric Association, ecstasy may be sequence of legal and illegal sub- for appetite control. However, it was classified as a , due to its stances. The pattern of ecstasy use dif- never released in the market22, and the potential to occasionally induce hal- fers from the use of ; it scientific community ignored it until lucinations and “flashbacks” if used in is strongly associated with subcultural 1970. At that time, ecstasy was re- extremely high doses14. Certainly, in music preferences and house-party go- ported to produce “a controllable state the coming years, a better understand- ing and weakly associated with smok- of alteration of conscience with sen- ing of the drug’s effects will allow its ing and conduct problems19. Its use is sual and emotional harmony”, suggest- accurate classification. increasing in college students who also ing that it could be used as an Nowadays, MDMA is becoming the use marijuana, alcohol, have multiple adjuvant in psychotherapy8,9,25. In the center of discussion in both lay and sex partners, and spend more time so- beginning of the 1980s, MDMA be- scientific press for its abuse potential cializing than studying20. Gay/bi- came popular as a recreational drug26,27. and possible neurotoxic effects. In the sexual men who are MDMA users Around 1985, the USA Drug Enforce- beginning of the 1990s, it was banned (13% of the group) were found to be ment Administration (DEA) restricted as a therapeutic drug by the World younger, less educated, to have had the therapeutic use of MDMA, placing Health Organization15. Ecstasy was in- more male partners, more one night it on the list of forbidden substances troduced in Brazil around 1994. Since stands with men, to have unprotected and without clinical use due to its fre- 1997, ecstasy has been a topic of ques- anal sex with males, to have more gay/ quent abuse and to central nervous tioning for drug hot lines in Brazil16. In bisexual friends, and to have higher system serotonergic degenera- Brazil, ecstasy is sold at all-night dance levels of gay community participation tion22,24,28,29. Due to the expansion of parties attended by hundreds of thou- and affiliation than nonusers21. the illegal drug market and the belief sands of youngsters where loud techno Ecstasy has a reputation of being that the use of ecstasy for recreational music is played, and bright and pulsat- a safe drug; however, there are many purpose is safe, the number of cases of ing lights fill the environment. There is reports of adverse reactions associated toxicity related to ecstasy or to a mix- evidence that until now, the use of ec- with the drug, as described in other re- ture of substances sold as ecstasy has stasy has been limited to middle-class views3,22,16,23,24. The increasing popular- been increasing6. However, several sci- or upper-middle-class individuals in ity of ecstasy among youngsters entific reports confirm that ecstasy is Brazil, so that most people, including prompts the need for health care pro- potentially fatal, and therefore, precau- health care professionals, are unfamil- viders to quickly recognize the symp- tions should be taken to avoid the be- iar with the drug. However, ecstasy may toms of severe systemic intoxication ginning of its use by children and ado- be becoming more popular in Latin in order to initiate early treatment, with lescents30,31. America, following the pattern seen in rehydration and cooling in cases of Ecstasy is used orally and is sold as North America and Europe. The fact hyperthermia, for seizures, cardiac ar- tablets or capsules of several colors, that ecstasy is sold as a pill and is thus rhythmia, and for metabolic and elec- shapes, and sizes, containing from 50 extremely easy to use is a possible con- trolyte abnormalities. The need for to 150 mg of the drug. Sometimes it is tributing factor to the drug’s popular- more information on ecstasy seems to sold as a powdered substance to be ity17. In a recent survey in the city of be growing due to its increased use, mixed with beverages6,32,33. There are São Paulo, most ecstasy users were detectable by the higher number of re- descriptions of rectal use and intrana- shown to have attended universities ports of intoxication with ecstasy. sal use of the powdered MDMA34. The and use dance party events and the Therefore, the objective of this review street preparations are up to 90% pure34 Internet for entertainment. These indi- is to give a recent picture of the clini- and may also contain MDA, , viduals are equally distributed in het- cal effects of the drug and the conse- LSD, amphetamine, , erosexual and homosexual groups, with quences of drug use. We also reviewed mixture of amphetamines, paracetamol, respect to sexual orientation, and most some preclinical studies performed or and other nonidentified of them use piercing and tattoos. Ac- with experimental animals to elucidate substances34,35. Therefore, since quality cording to these individuals, the ex- clinical problem mechanisms and dis- control does not exist in the illicit drug perimental use of the drug occurred due cuss future prevention methods for market, consumers are subject to addi- to its easy acquisition18. long-term adverse outcomes of ecstasy. tional risk. When the typical recrea-

333 Ecstasy intoxication: the toxicological basis for treatment REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003 Ferigolo M et al. tional doses are used, MDMA is not wives, merchants, health professionals, mg and last from 2 to 4 hours3,26. Peak frankly hallucinogenic24,26. Changes in and writers, as well as unemployed in- ecstasy plasma levels occur 2 hours af- perception and hallucinations occur in dividuals have been motivated by cu- ter oral administration, and residual big gatherings. The typical dose for riosity to start ecstasy use34. The in- levels of 0.005 mg/L are found after 24 recreational purpose is 70 to 150 mg, crease of the recreational use of hours from the last dose42,43. The oral corresponding to 1 or 2 capsules or tab- MDMA by youth is well documented; dose of 50 mg of ecstasy produces a lets. Dose supplements of 50 to 100 mg however, reports about ecstasy effects maximum plasma level of 0.11 mg/L, may be taken every 30 minutes18,24 due in children do not exist30. Accurate es- 75 mg produces a level of 0.13 mg/L, to the expectation of increasing the in- timates of the prevalence and inci- and 125 mg produces a level of 0.23 tensity of the experience34. In Brazil, dence of ecstasy use are still under mg/L. There is lack of data on the per- most individuals use up to 1 tablet per scrutiny in several countries. cent of oral absorption of MDMA22. night chronically, however a few of The pattern of ecstasy use is rather The area under the curve (AUC) of them reported the use of more than 3 uncommon when compared to the use plasma concentrations of ecstasy is tablets per night18. The recreational use pattern of other substances. The recrea- 0.99 mg/L after 50 mg and may reach of ecstasy is done more frequently dur- tional use is frequently spaced by 2 to 2.2 mg/L after 125 mg. The consump- ing weekends in dance clubs or parties 3 weeks. One of the reasons for this tion of several capsules of ecstasy where crowds dance vigorously. Raves, pattern might be that the pleasant ef- causes drug plasma levels up to around meaning delirium or fury, are all-night fects of the drug seem to decrease at 7.72 mg/L. More than 40 tablets of ec- dance parties attended by a large the same time as the “negative effects stasy are described to have been used number of people, sometimes exceed- “ increase if 5 or more doses of the in some of the overdose cases and pro- ing 20,000. The rave scene is interna- drug are used frequently. In the 1980s, duced plasma levels 6 to 70 times tional and may be accompanied by MDMA was used less than twice per higher than this37. The AUC describes clandestine activities, hypnotic elec- month, and most individuals had lower the concentration of the drug in tronic music, and the liberal use of than 10 drug experiences in their en- plasma as a function of time and sug- drugs (marijuana, alcohol, cocaine, tire lifetime34. More recently, higher gests that MDMA has a non-linear , gamma-hydroxybutyrate, and frequency of drug use is already being pharmacokinetic profile; consumption ketamine) in addition to ecstasy20,21,36- described with individual cases of of elevated doses of the substance may 39. Therefore, raves accumulate condi- daily and intense use of ecstasy18,24. produce disproportional elevation of tions that induce or increase the number This can be seen in the Brazilian popu- plasma levels of ecstasy5,42. of toxic or lethal cases induced by ec- lation, since half of the ecstasy users MDMA or ecstasy is widely distrib- stasy because they are crowded, very in São Paulo report the use of ecstasy uted in the mammalian organism, eas- noisy, and may develop high environ- on 5 to 50 different occasions, while ily crossing membranes and the blood- mental temperatures23,33. Most of the around one-third of the interviewees brain barrier. The amount of drug bind- patients with serious ecstasy intoxica- reported the use of ecstasy on 50 to ing to plasma proteins is unknown22. tion present dehydration, fainting, or 500 occasions18 . Its clearance depends partially on liver convulsions, and they frequently need metabolism, 3% to 7% become the ac- treatment at hospital emergency depart- tive substance MDA, and 28% is ments37. Because of that, in some places TOXICOKINETICS biotransformed to other metabolites. where youngsters go to get the drug and Around 65% of the dose is eliminated to party, the “drug agencies” are spe- There is incomplete knowledge without being metabolized through cially prepared to assist ecstasy users about the pharmacological properties the kidneys42,43. As with all amines, uri- and to minimize the adverse effects ac- of MDMA in humans, since the stud- nary excretion depends on the urinary companying drug use16. ies are difficult to perform because of pH. Acidification of urine increases The recreational use of ecstasy be- ethical issues22,42. Only case reports43 drug elimination, which could be ap- gan among North American students, and small randomized double-blind plied to speed drug clearance during and its consumption has been increas- clinical studies42 among healthy peo- intoxication22. However, acidification ing in Spain, Italy, England, and in ple using small to moderate doses of is rarely recommended due to the risk countries of Latin America6,16,40. It is ecstasy are reported. The psychosti- of worsening nephrotoxicity by my- used in environments where the con- mulant effects of MDMA are observed oglobinuria44. sumption of cocaine and alcohol is 20 to 60 minutes after the ingestion of The plasma half-life of ecstasy is also prevalent34,41. Students, house- moderate doses of ecstasy, 75 to 100 7.6 hours. This information is very rel-

334 REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003 Ecstasy intoxication: the toxicological basis for treatment Ferigolo M et al. evant when treating intoxication, be- When the typical recreational doses episodes, impulse control disorders, cause 6 to 8 half-lives are necessary to are used, MDMA is not frankly hallu- panic disorders, and social pho- complete depuration of the drug; cinogenic24,26. Changes in perception bia48,49,52. The cases of paranoid psy- therefore, about 48 hours would be and hallucinations occur in cases of chosis after abuse of MDMA show that necessary for the complete elimination intoxication with higher doses of 300 there is an organic disorder secondary of ecstasy. It can also be foreseen that mg or more34. These hallucinations are to the neurotoxic effect of MDMA for a plasma level of 8 mg/L, which is similar to those produced by mesca- rather than a temporary functional considered to be the severe intoxica- line. Initially, visual hallucinations are mental disorder53. Depression in ec- tion level, about 24 hours would be in black and white and later become stasy patients could be related to necessary to decrease to a plasma level colorful. Modification of body percep- serotonergic function as measured lower than 1 mg/L, which produces tion with sensation of depersonaliza- through PET scans54. In fact, weekend much less clinical effects. Therefore, tion, confusion, illusions, and sensa- use of MDMA may lead to mid-week this would be the estimated time of in- tion of lightness or flotation may oc- depressed mood, and the possible tensive care needed by intoxicated pa- cur34. In addition to these behavioral mechanism underlying the behavioral tients who used a few ecstasy capsules. effects, symptoms include trismus, changes includes temporary depletion However, this time would be longer bruxism, nystagmus, motor tics, rest- of serotonin, due to serotonergic when a higher number of tablets are lessness, headaches, and anxiety45. The neurotoxity55. consumed, since drug depuration is most frequently perceived adverse ef- For 10 years, ecstasy has been rec- not linear. fects are decreased desire to execute ognized as inducing psychological physical and mental tasks (70%), de- dependence after daily use of high creased appetite (65%), and trismus doses for prolonged time34. Physiologi- ACUTE AND CHRONIC (50%)15. It must be assumed that the cal dependence is not yet recognized BEHAVIORAL EFFECTS risk of being involved in traffic acci- because “craving” or withdrawal syn- dents during MDMA use is increased. drome was not described34. However, The neuropsychiatric effects in- The prevalence of detectable MDMA based on the diagnostic criteria for duced by ecstasy may be classified blood levels indicate an increased risk substance dependence by the Ameri- into different categories. The acute of reckless driving comparable to that can Psychiatric Association14, physi- subjective effects are altered perception observed after the use of ampheta- ological dependence by ecstasy should of time and changes in visual percep- mine46. be kept in mind. Actually, the pro- tion, increased self-confidence, under- Psychopathologies associated with longed use of ecstasy fulfills 4 depend- standing and empathy with decreased the use of MDMA are classified as ence criteria: it is used in larger doses defensiveness and aggression, and in- acute, when occurring in the first 24 than the ones initially planned56; it is creased social interactions. Communi- hours after drug use, subacute when used in spite of the knowledge of the cation and personal relationship skills occurring 24 hours to 1 month after adverse effects, it produces a hangover were also described to improve. In- drug ingestion, and chronic if they oc- characterized by insomnia and fa- creased emotional and physical “en- cur after a month of drug use24,45. The tigue57; and it may induce tolerance48. ergy” is presumed to occur with this most frequent acute complications in- Tolerance to the psychoactive proper- psychostimulant; however, there is de- clude anxiety, insomnia, flashbacks, ties of MDMA develops rapidly, and creased ability and less desire to per- panic attacks, and psychotic there are some individuals who use in- form mental or physical tasks. Eupho- spells48,49,50. Those who have acute creasing amounts of ecstasy to rein- ria, decreased sleep, appetite, fatigue, paranoid psychotic reactions after tak- force the psychoactive effect18,48. In depressed mood, and decreased anxi- ing MDMA may become violent and some individuals, tolerance occurs to ety are described as short-term ef- are likely to react in the same way some of the pleasant psychoactive ef- fects10,11,15,25,28. Other central nervous when taking the drug again51. The su- fects of ecstasy but not to the physi- system effects range from euphoria, bacute complications include depres- cal effects, and the dose increase may central nervous stimulation, and feel- sion, dizziness, anxiety, and irritabil- produce dysphoria26. In this group of ings of closeness to mild hallucina- ity. MDMA consumers are found to be individuals, MDMA does not cause tions, impairment of cognition and co- at high risk of developing psycho- dependence, and the use of very large ordination, and more serious reactions pathological disturbances, mainly amounts of ecstasy, for a long period like agitation, disturbed and bizarre flashbacks, depression, psychotic dis- is rare56. It is still necessary to define behavior, and possibly psychosis. orders, cognitive disturbances, bulimic which are the social, genetic, cultural,

335 Ecstasy intoxication: the toxicological basis for treatment REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003 Ferigolo M et al. environmental, and hormonal factors ability59. Users processed information porter was significantly reduced in the involved in these long-term individual as quickly as nonusers but less accu- mesencephalon and the thalamus of differences in ecstasy’s effects. rately60. Ecstasy users were unimpaired ecstasy users when compared with Perhaps the most disturbing aspect in simple tests of attention (alertness), drug-naive subjects. The distribution of ecstasy effects is the risk of irrevers- but performed worse than nonusers in volume ratios of the serotonin trans- ible long-term neuropsychiatric ef- more complex attention tests, in porter in former ecstasy users were very fects33. MDMA is neurotoxic to sero- memory and learning tasks, and in similar to drug-naive subjects in all tonergic neurons of different animal tasks reflecting aspects of general in- brain regions, indicating protracted species13, although there is debate on telligence. Heavy ecstasy use and but reversible lesions of the serotonin whether recreational doses of ecstasy combination with cannabis is associ- transporter by PET68. may cause permanent damage to the ated with poorer performance by the human brain33,56. In very recent publi- group of ecstasy users61. cations, several authors presented evi- There is ecstasy-related 5-HT neu- DIAGNOSIS AND TREATMENT dence that ecstasy might be neurotoxic ral injury associated with the func- OF ACUTE INTOXICATION to humans58, 59, 60, 61, 62. tional sequelae of ecstasy users de- WITH ECSTASY Cognitive performance may be af- scribed above. In particular, ecstasy fected in drug-free recreational ecstasy users have selective decrements in cer- The well-known risks of adverse users, with reduced memory for new ebrospinal fluid 5-hydroxyindo- reactions to ecstasy and their probable information, impaired higher execu- leacetic acid and a decreased number mechanisms are summarized in table 1. tive processing, and heightened impul- of brain serotonin transporters, similar The intensity of the adverse events de- sivity. Some ecstasy users also com- to nonhuman primates with docu- pends on the dose, the frequency of plain of poor memory and/or concen- mented MDMA-induced neurotoxic- use, and on individual variation. It is tration difficulties, which they at- ity62. Therefore, the neurochemical still not clear why some people use the tribute to the previous MDMA use. data provide evidence that MDMA is drug regularly without adverse out- This particular pattern of cognitive neurotoxic to brain serotonin neurons comes, while others present severe decrement in humans is consistent in humans, and the behavioral data toxic responses35. One of the possibili- with the animal data showing seroto- suggests that brain serotonin injury is ties is that there might be differences nergic damage following MDMA ad- associated with subtle, but significant, in effects at the first experience with ministration, accompanied by impul- cognitive deficits64. the drug or at a new acute episode fol- sivity, higher cognitive impairment, lowing previous experiences with the and memory deficit58. drug. These adverse events may be In fact, ecstasy users showed a MECHANISMS OF TOXICITY acute, residual, or persistent. The acute broad pattern of statistically signifi- adverse effect may occur after the use cant, but clinically small, impairment Probably, a sole mechanism of ac- of low doses and may disappear in 24 of memory as measured by direct re- tion is insufficient to explain all ef- hours. Overdose acute reactions occur call and recognition and prolonged re- fects induced by ecstasy. Due to its at indeterminate dosages, and have action times that are accompanied by complex activity spectrum, its effects been described to occur after the in- changes in cortisol plasma levels. on human behavior can be related to take of 1 to 42 capsules of ecstasy. Re- Heavy users were more affected than several neurochemical processes in- sidual effects have a hangover time moderate users63. Significant impair- volving serotonin, , and course, while persistent effects last for ment was found on measures of verbal norepinephrine8,10, similarly to what is up to 2 weeks. Gender differences in memory and of delayed memory in ec- seen with other amphetamines13. How- effects are expected to be described, stasy users. However performance was ever, serotonin plays the main role in because it is recognized that there are similar across all parameters for visual ecstasy effects22,65,66 . more neurochemical effects of ecstasy reaction time, auditory reaction time, There is an extensive body of data on females69, but epidemiological stud- complex reaction time, visual memory, demonstrating that ecstasy produces ies still do not provide evidence that and attention and concentration. There toxic effects on brain serotonin neu- they are at higher risk than males when is, therefore, evidence for long-term rons in animals within the dose range using similar ecstasy doses. neuropsychological sequelae associ- of recreational MDMA users due to Symptoms to be treated originate ated with the use of ecstasy, particu- type 2 vesicular monoamine trans- mainly from the central nervous sys- larly with regard to delayed memory porter reduction67. The serotonin trans- tem and the cardiovascular system.

336 REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003 Ecstasy intoxication: the toxicological basis for treatment Ferigolo M et al.

Table 1 - Ecstasy behavioral effects after use of moderate doses or after repetitive intake and their probable neurotransmitter mechanisms.

Patterns of use Acute doses Repetitive intake Acute (low doses) effects tachycardia1, hypertension1, decreased appetite, trismus1,2, vomiting2, ataxia, nystagmus visual bruxism1,2, nausea1, headaches1, insomnia1, tremor1, sudoresis1 allucination2, paresis/ paresthesia of extremities, increased cold sensitivity (may also occur in the first experience with high dose)

Overdose reactions cardiac arrhythmias1, tachycardia1, palpitations1, hypertension screams3 and subsequent hypotension1, hyperthermia2,increased toxic hepatites4 muscular tonus, visual allucinations2, hepatotoxicity4, acute renal failure, disseminated intravascular coagulation1, rhabdomyolysis, death

Residual effects insomnia1, muscle aches, fatigue5, lightheadedness

Persistent effects fatigue5, depression5, nausea2, flashback2 panic and anxiety attacks2, persistent insomnia1, psychosis3, loss of weight1,2, irritability3 Noradrenergic effects 1; Serotonergic stimulation 2; Serotonergic deficiency 3; Idiosyncrasy 4; Noradrenergic/Serotonergic deficiency5.

Death due to ecstasy overdose is asso- sessment to evaluate the degree of response to MDMA in a hot, crowded ciated with arrhythmia or hyperten- dehydratation70. dance environment74. Thermoregula- sion8,32,37 and may be associated with Acute severe ecstasy intoxication tion of individuals on ecstasy is labile acute bronchospasm, allergic reac- requires effective and quick treatment and much more dependent on environ- tions, malignant hyperthermia, convul- to avoid the dose-dependent increase mental conditions. Serotonergic an- sions, disseminated intravascular co- in frequency of adverse reactions and tagonists, such as ketanserin or methy- agulation, rhabdomyolysis, and acute to prevent severe complications. It still sergide, or may be needed renal failure32,71,72 or hepatotoxicity73. must be determined whether antagonist to stabilize body temperature; however, The estimated interval between drug agents acting at serotonergic, noradre- neuroleptics must be used with extreme use and death varies between 2 and 60 nergic, or dopaminergic sites will have care, because they may also cause hours6,30,73. beneficial effects if used to reverse the hyperthermia23. Selective or not selec- When treating an intoxicated pa- drug effects. Currently, specific anti- tive reuptake inhibitors of serotonin, tient, confirmation of the agent in- dotes against ecstasy are not avail- such as tricyclic antidepressants, volved should be sought. The analy- able33, and similar treatment protocols fluoxetine, or citalopram are formally sis of suspicious substances (powder to the ones used for amphetamine or contraindicated because they enhance samples) or of corporal fluids (serum, cocaine intoxication are proposed. Ba- the effects of serotonin release and de- urinates, aspired gastric) can be accom- sically, ventilatory and cardiovascular crease the seizure threshold23. plished by thin layer chromatography, support and appropriate treatment for Rehydration might be necessary gaseous chromatography, ultraviolet each one of the complications should and should be done with caution due and infrared spectrophotometry or be implemented. to the risk of water intoxication. To flame ionization32,57. Based on the half- Ventilatory support to maintain the decrease muscular activity and for sei- life of the drug and time of renal elimi- airway and evaluation of body tem- zure treatment and decrease of agita- nation of ecstasy, the biological mate- perature and decrease of body tempera- tion or anxiety, midazolam, diazepam, rial should be collected at least in the ture if necessary are the first measures or lorazepam should be given through first 72 hours from the beginning of to be implemented in ecstasy intoxi- IV administration. The use of dantro- the intoxication disorder. Among the cation. Hyperthermia may be pre- lene as a muscular relaxant may be general laboratory tests needed for pa- vented33. Heavy and frequent recrea- necessary33,71. Clomethiazole is used in tients intoxicated with ecstasy are tional users of MDMA may have im- England in the treatment of the acute hematological assessment, because paired thermoregulation as demon- toxicity of the drug because of its ac- MDMA is involved in the suppression strated in preclinical studies, and thus tion at GABA receptors, with further of bone marrow, and electrolytic as- may be at greater risk for acute adverse antagonism of the serotonergic syn-

337 Ecstasy intoxication: the toxicological basis for treatment REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003 Ferigolo M et al. drome and antiseizure activity23. How- avoid paradoxical hypertension or coro- eral Council of Narcotics did not de- ever, it is not available worldwide. Ha- nary insufficiency, labetalol might be tect the local production of the drug, loperidol also attenuates ecstasy-in- preferred. Hypotensive patients need and the responsible organizations are duced mania but has no reducing ef- fluid reposition or vasoconstrictors44. still determining the best approach for fect on other subjective changes or on combating its trafficking. cardiovascular effects4. This review was sought with the in- Emesis is contraindicated, due to CONCLUSION creasing use of ecstasy in mind. It might the risk of inducing seizures in these be expected that with the increase in fre- patients, but gastric lavage and admin- It is known that primary and sec- quency of ecstasy use worldwide, ecstasy istration of activated coal and a cathar- ondary prevention of drug abuse is intoxication will become a frequent tic may be indicated44. Chewing gum fundamentally based on information. emergency even in pediatric and inter- counteracts jaw-clenching33. As already Knowing about the dangerous effects nal medicine clinical practice. The re- pointed out, acidification of urine to of a drug is the first step in avoiding view on ecstasy intoxication treatment increase drug excretion is rarely recom- drug abuse. Recognizing and discloses the need to find specific anti- mended due to the risk of worsening the promptly treating acute intoxication dotes instead of only having sympto- nephrotoxicity induced by myoglob- prevents further damage. In spite of it matic treatment, which would be ex- inuria44. Hypertension and tachycardia not being a new drug, the great major- pected to enhance the quality of health may be temporary in mild cases. For ity of health professionals do not know care provided to these patients. moderate intoxications, sedatives or the effects and possible complications oral nifedipine will be needed44. Other- of ecstasy use. There is international wise, patients may be treated with concern that ecstasy has the potential ACKNOWLEGMENT vasodilators, phentolamine, or nitro- to be the worst drug of the 21st cen- prusside44. Arrhythmias are treated with tury, according to the Organization of H.M.T.B is the recipient of a CNPq propranolol or esmolol; however, to the United Nation. In Brazil, the Fed- 1C productivity grant.

RESUMO

MARISTELA F e col. - Intoxicação intoxicação a fim de iniciar o tratamen- mento de emergência, para se evitar re- por êxtase: bases toxicológicas to o mais breve possível. A droga é ações adversas e complicações graves. para o tratamento. Rev. Hosp. Clín. usada via oral durante várias horas de Não há antidotos específicos para tra- Fac. Med. S. Paulo 58(6):332-341, festas com danças. Agudamente, o êx- tar a intoxicação aguda. Medidas de 2003. tase aumenta a liberação do serotonina suporte e tratamento médico para cada e diminui sua recaptação, levando a uma das complicações devem ser exe- Os jovens estão cada vez mais hipertensão, hipertermia, trismo e vô- cutados, mantendo-se em mente que usando o 3,4-metilenodioximetan- mitos. Há discussão se as doses recrea- os sintomas a serem tratados originam- fetamina, conhecido como êxtase, pois cionais causam danos permanentes aos se principalmente do sistema nervoso acreditam que não causa danos. Entre- neurônios serotonérgicos em humanos. central e do sistema cardiovascular. tanto, existem muitos relatos de efei- Os usuários apresentam risco elevado tos adversos, incluindo a intoxicação de desenvolver distúrbios psicopato- DESCRITORES: 3,4-metileno- aguda, abuso potencial e possíveis lógicos, além disso, o uso prolongado dioximetanfetamina. Efeitos adver- efeitos neurotóxicos. Portanto, profis- pode induzir a dependência, caracte- sos. Desordens relacionadas a subs- sionais da área da saúde necessitam re- rizada pela tolerância e ressaca. A in- tância. Cognição. Hipertermia. conhecer prontamente os sintomas da toxicação aguda necessita de trata-

338 REV. HOSP. CLÍN. FAC. MED. S. PAULO 58(6):332-341, 2003 Ecstasy intoxication: the toxicological basis for treatment Ferigolo M et al.

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