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Moritz Haager PGY-2, Emergency Medicine February 13, 2003 Isn’t ecstasy safe? “I read this article about ecstasy being safer than aspirin….I now take 2-3 in the course of an evening…” Anon MDMA user from Parrott & Lasky. 1998. Psychopharmacology 139: 261-268 What makes MDMA dangerous? Several variables Factors related to the user Susceptibility, Polydrug use, dose Factors related to the drug Purity, MDMA content, intrinsic toxicity Factors related to the environment Rave venues, access to water Objectives Epidemiology: What is rave culture, and how is it relevant? What is the impact internationally? Locally? Pharmacology: What are the characteristics of club drugs? Toxicology: What are the acute effects? Long-term effects? Are there any therapies we need to know about? Rave Culture All-night dance parties in non-traditional venues popularized in Europe in mid 1980’s PLUR philosophy Various genres of non-commercial electronic music Alternative fashions Low EtOH use, but high prevalence of designer drug use to achieve “synesthesia” Street Sense Trivia What is synesthesia? A: the desired drug-induced state where colors are “heard” and sound is “seen”, hence the use of glowsticks Designer Drugs Made by combining the desired properties of two drugs into one new one Fentanyl analogues China white (α-methyl fentanyl) New heroin (MPPP) Hallucinogenic amphetamines ring-substituted amphetamines Blend of mescaline-like and amphetamine-like effects Drugs used at Raves Cannabis MDMA (ecstasy) MDEA (eve) MDA Methamphetamine PMA Ketamine GHB (gammahydroxybutyrate) Cocaine LSD PCP (phencyclidine) Others The Dawn of Ecstasy 6000 5000 4000 MDMA GHB Ketamine 3000 2000 1000 0 1994 1995 1996 1997 1998 1999 2000 2001 DAWN statistics of the number of ED mentions of MDMA & GHB Global Trends Use of club drugs is increasing MDMA use amongst students in the US : Grade 8 Grade 10 Grade 12 1996 3.4% 5.6% 6.1% 2001 5.2% 8.0% 11.7% By 1997 the UK had 53 deaths due to acute MDMA toxicity Worldwide >87 ecstasy related deaths reported Canadian Data Minimal data sources Estimates for ecstasy use in school age children are 3% & 5% for girls & boys Prevalence of MDMA use increased from 0.6% in 1993 to 4.4% in 1999 among Ontario adolescents 2.4% of university students report prior MDMA use 14 deaths between 1998 – 2000 in Ontario At least 3 fatalities in Vancouver area The Calgary Scene Increasing prevalence of ecstasy Drugs seen: Cannabis Crack cocaine Powder cocaine MDA MDMA LSD Ketamine Opiates Clandestine labs in Vancouver and USA 53 labs raided in western Canada b/w ’91-’99 60% produced MDA 15% produced MDMA Calgary data: 90% of “E” contains no MDMA at all Usually MDA or ketamine + PCP Street Purity & Doses Tremendous variation in content & dose 70-fold variation in MDMA content b/w brands 7-fold variation in MDMA content in same brand Virtually none contained solely MDMA Ephedrine, ketamine, tylenol, caffeine common Sherlock et al. J Accid Emerg Med 1999. 16: 194-97 Pharmaceutical Grade Ecstasy Lab Chemical composition of “ecstasy” tablets in Vancouver: 53% MDMA 17% MDA 15% ephedrine 12% Nethamphetamine 10% caffeine 5% PCP 4% ketamine 3% cocaine 3% dextromethorphan 3% codeine 2% amphetamine Rintoul & MacKillican. 2001. Designer Drugs and Raves. RCMP Drug Awareness Service Hallucinogenic Amphetamines Phenethylamines: derived from amphetamine + methamphetamine Chemically & biologically similar to epinephrine, dopamine, & serotonin Chemical Structures MDMA (Ecstasy, E, XTC, Adam, Hug Drug, Love Drug, Clarity E-bombs) 3, 4-methylenedioxy-methamphetamine Ring-substituted form of methamphetamine methylenedioxy group addition makes it structurally similar to mescaline and conveys hallucinogenic properties new class of compounds: “enactogens” chemically & biologically similar to MDA, MDEA MDMA 1912: 1st synthesized by Merck as appetite suppressant but never marketed 1970’s: Thought to be beneficial in psychotherapy due to its ability to break down barriers and improve communication 1976: Classified as schedule III under CDSA in Canada 1985: Classified as schedule 1 drug by DEA CDSA Schedule III It is illegal to posses, produce, import or export MDMA Possession is a criminal offence punishable for up to 3 years jail, $1000.00 fine or both. Trafficking carries jail sentence up to 10 years Legal for medical or scientific purposes MDMA Taken PO, but can be used IV, PN, PR Comes as tabs with logos, or capsules Typical dose is 50-150 mg but varies widely Onset within 20-40 min Duration 3-8 hours 60% stimulant, 40% hallucinogen Price is $20-40 Cdn per hit MDMA: Mechanism of Action Indirect Sympathomimetic: Increases serotonin, noradrenaline, and dopamine Serotonin & dopamine mental effects Noradrenaline physical effects Increases release, and blocks serotonin reuptake by binding SERT Direct agonism at 5-HT2, 5-HT1, and D2 receptors Serotonin release can be blocked by SSRI’s attenuates drug effects Also blocks MAO MDMA Metabolism MDMA N-demethylation MDA CYP2D6 Demethylation glutathione DHMA Toxic metabolites CYP2D6 Demethylation O-methylation DHA HMMA N-demethylation O-methylation HMA MDMA Pharmacokinetics Rapid absorption via GI tract Tmax is reached within 2 hours T1/2 ~8-9 hrs Metabolism appears to be non-linear; higher doses cause disproportionately greater increases in plasma levels Elimination is via hepatic metabolism and direct renal excretion Tolerance develops rapidly polydrug use Mas et al. 1999. J Pharm Exp Ther. 290: 136-45 Street Sense Trivia Why do ravers suck on lollipops or pacifiers? To alleviate bruxism which is jaw clenching and teeth grinding associated with MDMA use and which can cause significant dental damage MDMA Acute Effects 3 stages: 1. Initial disorientation 2. Tingling and spasmodic jerking 3. Happy sociability Euphoria, inc’d energy, confidence & insight Empathy, tolerance, & closeness towards others Sexual arousal, heightened sensory perception Tachycardia, bruxism, trismus, mydriasis, anorexia, nausea, ataxia, psychomotor agitation Acute CVS Effects 2 Double-blind RCT’s: Avg HR increased by 28-30 bpm Systolic BP increased by 25-44 mm Hg Diastolic BP increased by 7-25 mm Hg CO increased by 2 L/min No measurable inotropicity Lester et al. 2000. Ann Int Med. 133: 969-973 Mas et al. 1999. J Pharm Exp Ther. 290: 136-45 Street Sense Trivia What’s “hammerheading”? A: Combining ecstasy and viagra (also known as “sextasy”), called so for the resultant H/A and priapism MDMA: Aphrodisiac or OCP? Retrospective study of 20 male and 15 female users: all had mod-profound increase in sexual desire most felt enhanced sensuality 90% M / 93% F had mod-profound satisfaction 80% M / 40% F had delayed orgasm 40% M reported erectile difficulty 80% F had improved lubrication Zemishlany et al. 2001. Eur Psych. 16: 127-30 MDMA Subacute Effects “Crash” phenomenon Less pronounced than parent amphetamines Occurs 24-48 hrs post-ingestion Myalgias, fatigue, depression, irritability, concentration deficits, memory deficits, headache, akisthesia MDMA Serious Adverse Effects Appears to be NO relationship between dose, serum levels, and severity of reactions CVS: increased BP & HR -- CVA’s, ICH Endocrine: increases prolactin, cortisol, & ADH hyponatremia, hypoglycemia CNS: hyperthermia, neurotoxicity GI: hepatoxicity MSK: rhabdomyolysis GU: ARF Psychiatric: acute psychosis, panic reactions, depression, cognitive deficits Street Sense Trivia: What’s a “Vicks hit”? A: inhaling Vicks VapoRub, or applying it and having someone blow on it while on ecstasy. Done for the amplified sensation of cooling experienced on “E”. Hyperpyrexia Likely combined direct drug (class) effect and environment in which drug is used Most dangerous toxic pattern Felt to precipitate further injury cascade: Rhabdomyolysis ARF Hepatotoxicity DIC Hyperpyrexia: Possible Mechanisms Postulated serotonin effect in hypothalamus Loss of thermoregulation MDMA-treated rats are both hypo- and hyperpyrexic depending on ambient temp Malberg & Seiden. 1998. J Neurosci. 18:5086-5094 Cutaneous Vasoconstriction Rabbits exposed to MDMA exhibit sympathetically-mediated vasoconstriction Pedersen & Blessing. 2001. J Neurosci. 21: 8648-8654 Dopamine D1 agonism Hyperthermia is not attenuated by 5-HT uptake inhibitors or 5-HT receptor antagonists in rats D1 (but not D2) antagonism dec’s hyperthermia Mechan et al. 2002. Br J Pharm 135: 170-180 Hyperpyrexia: Possible Mechanisms Increased adrenergic drive Increased metabolism Muscle hyperactivity Environment Crowded & hot rave venues Vigorous physical activity Is there a link to serotonin syndrome? MH? NMS? MDMA & Malignant Hyperthermia Both appear to be idiosyncratic effects MDMA toxicity case reports similar to MH Dantrolene used “successfully” in several MDMA elevates myoplasmic Ca2+ in vitro, and potentiates halothane- and caffeineinduced muscle contracture Denborough and Hopkinson. 1997. MJA. 16:165-166 Serotonin Syndrome vs. NMS Differentiation important b/c different therapies – using wrong drug may be fatal At least 12 case reports of pts presenting with MDMA –related hyperpyrexia that fit diagnostic criteria for Serotonin syndrome Several have overlapping clinical features Symptom Serotonin Syndrome Malignant Hyperthermia Neuroleptic Malignant Syndrome Onset hrs minutes 3-9 days Fever ++ +++ ++ Rigidity + +++ +++ Rhabdomyolysis ++ +++ ++ Myoglobinuria + +++ ++ Tachycardia + +++ ++ BP changes + ++ + Hypercarbia + +++ ++ Behaviour changes +++ + ++ Altered LOC +++ + +++ Leukocytosis +++ - + Clonus +++ - - Shivering +++ - - Tremor +++ - - Hyper-reflexia +++ - - Hyperpyrexia: Treatment Hyperthermia from ANY cause MOF Peak temp & duration appear correlated with mortality & morbidity in MDMA Dar & McBrien. Int Care Med 1996. 22: 995-96 Approach essentially as per heat stroke: General cooling measures Consider more specific interventions Hyperpyrexia: Treatment General Measures: Ice packs to groin, axillae, neck Makka Body Cooling technique Iced peritoneal lavage Cold humidified O2 & IV fluids Cardiopulmonary bypass Hyperpyrexia: Treatment Specific treatment: Serotonin Antagonists Cyproheptadine & methysergide shown to block SS in animal studies No human studies looking at serotonin antagonists in MDMA-induced hyperthermia Needs further evaluation Hyperpyrexia: Treatment Specific Treatments: Dantrolene Evidence for Dantrolene in MDMA anecdotal Dec’d mortality in MH from 70-80% to <10% Used “successfully” in multiple MDMA cases Inhibits Ca2+ release for sarcoplasmic reticulum 1-2.5 mg/kg up to 20 mg/kg max If successful start infusion of 10 mg/kg/24h Hyperpyrexia: Treatment BDZ’s / Neuromuscular blockade: Decrease agitation Decrease neuromuscular activity & metabolism Non-depolarizing agents preferred Evidence is anecdotal only Hyperpyrexia: Treatment Relatively contraindicated: Bromocriptine dopamine agonist worsens NMS Succinylcholine Risk of malignant hyperthermia Haloperidol Risk of NMS + anticholinergic effects Hepatotoxicity Exact mechanism unknown Idiosyncratic reaction Usually mild hepatitis-like, but can be severe with liver failure requiring transplant Over 70 fatalities described after developing MDMA-induced hepatitis b/w ’90 -’98 Hepatotoxicity: Mechanism Postulated mechanisms: indirect hyperthermic and direct toxic effects of reactive metabolites Metabolites react with, and deplete, glutathione oxidative damage Toxic effects of unknown contaminants Immune-mediated damage May have metabolic predispositon related to CYP2D6 sub-types Hepatotoxicity: Classification Very early onset: Liver injury with hyperthermia Delayed onset: Acute liver failure in absence of hyperthermia Late onset: Hepatitis in absence of other detectable causes other than MDMA exposure Ellis et al. 1996. Gut. 38: 454 Hepatotoxicity: Treatment Conservative vs. transplant Indications for liver transplant: Core temp > 41oC and: Acidosis Renal failure Grade III encephalopathy Coagulopathy w/ INR >7+ Normal temp and: Malaise, GI sx Hyperbilirubinemia Rising AST / ALT Worsening coagulopathy Worsening encephalopathy Prognosis: 10-50% survival De Carlis et al. 2001. Transpl Proceed 33: 2743-44 Cardiovascular Toxicity Related to noradrenaline and dopamine release Manifests as tachycardia, HTN, & arrythmias Intracranial hemorrhage Cerebral infarct Arrythmias Retinal hemorrhages CHF & pulmonary edema High rate of underlying structural abnormalities McEvoy et al. 1998. Lancet. 351: 1029 CNS Toxicity Hyponatremia Develop seizures, cerebral edema, tentorial herniation, and/or respiratory arrest Females appear to be at increased risk ?estrogen effect Hyponatremia: Mechanism Profuse sweating & free water intake dilutional hyponatremia ADH release SIADH 8 volunteers given 47.5 mg MDMA or placebo Serum ADH increased in relation to MDMA levels w/o concomitant increase in cortisol Henry et al. 1998. Lancet. 351: 1784 Hyponatremia: Treatment NS infusion Fluid restriction <1 L/day IV mannitol or lasix if cerebral edema ?hypertonic saline Education regarding rehydration at raves Acute Renal Failure Mechanisms: Rhabdomyolysis DIC microvascular obstruction Direct toxic effect Report of CRF due to MDMA-induced necrotizing angiitis Bingham et al. 1998. Nephrol Dial Transplant. 13: 2654-2655 Street Sense Trivia What is “hooping”? A: using MDMA in suppository form. Neurotoxicity Most controversial research topic FDA refusal to investigate medicinal uses of MDMA based on potential neurotoxicity Overall good animal data supporting a detrimental effect on serotonergic system Human studies more limited and hampered by methodological weaknessess No clear evidence, but “highly suggestive” What’s the big deal with 5-HT? Implicated functions of serotonin: Regulation of: Mood Aggression Impulsivity Sexual activity Appetite Sleep Body temperature Circadian / seasonal rhythms Neurotoxicity Mechanism not elucidated Hypothesized to result from chemical cell damage 2o to sudden massive serotonin release and intracellular depletion Excessive dopamine may also contribute via free radical formation 2o to deamination Neurotoxicity 2 arms of research: 1. Biologic Animal studies Imaging studies Autopsy data 2. Psychological / Psychiatric Cognitive / memory testing Surveillance for mood and other disorders Neurotoxicity Animal data: Multitude of studies showing neurotoxic effect Concept of interspecies dosing: Smaller animals require proportionately larger doses to achieve toxic effects E.g. 5 mg/kg in squirrel = 1.4 mg/kg in humans Typical recreational human doses fall within toxic doses in animals corrected for interspecies dosing One report describes enduring serotonergic toxicity with a single dose in baboons Neurotoxicity: Animal Data Biphasic response to single dose: Acute 5-HT depletion 3-6 hrs post-ingestion Recovery by 24 hrs 2o 5-HT depletion 1 week post-ingestion Long-term neurotoxicity: See morphologic neuronal changes consistent w/ injury Either large single or moderate repetitive doses Lowest neurotoxic dose in primates 5 mg/kg bid x 4 days Only primates appear to have persistent damage Neurotoxicity Human data MDMA users have decreased levels of serotonin & its metabolites (HIAA) in CSF Blunted neuroendocrine responses to serotonin agonists PET & SPECT studies using selective ligands document decreased serotonin transporter levels & altered glucose metabolism EEG patterns similar to aging & dementia Human Neuroimaging Studies Most direct data supporting neurotoxicity Semple et al. 1999. Br J Psych. 175: 63-69 10 male MDMA users & 10 controls matched for age, education, and other drug use Neuropsych testing & SPECT imaging Showed dec’d SERT binding in MDMA users Showed correlation b/d life-time dose and trend towards dec’d verbal and spatial memory scores Neurotoxicity Psychological / Psychiatric Data: Memory impairment Cognitive impairment Increased impulsivity Anxiety symptoms & panic attacks Psychosis Depression / suicidality Flashbacks Parkinsonism Overall data suggests minimal sequelae in light users, but plausible morbidity w/ heavy use Street Sense Trivia What is “preloading”? A: ingesting prozac, or various other nutritional supplements prior to ecstasy use in a bid to prevent its neurotoxic effects Are SSRI’s Neuroprotective? Based on pre-clinical data, SSRI’s appear to block MDMA-induced serotonin release Contradictory reports regarding impact on subjective experience when pre-loaded DBRCT of 16 volunteers treated w/ MDMA & citalopram found reduced (but prolonged) subjective effects, as well as decreased CVS effects. Liechti et al. 2000. Neuropsychopharmacology. 22: 513-21 MDMA inhibits MAO-A & MAO-B in vitro, to a lesser extent than prozac ?breakdown > synthesis Efthimia et al. 1994. Neuropsychopharmacology. 10: 231-38 What About Dopamine? DBRCT of 14 volunteers found that pretreating w/ haldol decreased the pleasurable subjective effects of MDMA Liechti & Vollenweider. 2000. Eur Neuropsychopharmacology 10: 289-295 Dopaminergic toxicity not previoulsy noted More recent study of squirrel monkeys and baboons found significant dopaminergic toxicity when MDMA doses are stacked Ricaurte et al. 2002. Science. 297: 2260-2263 Dopaminergic Toxicity Numerous markers of serotenergic toxicity Dec’d tissue 5-HT, 5-HIAA, and SERT Direct demonstration of axonal degeneration Numerous markers of dopaminergic toxicity Dec’d tissue DA, DOPAC, & DAT Direct demonstration of axonal degeneration No change in noradrenergic neurons Inc’d sensitivity to AMPT motor dysfuxn Ricaurte et al. 2002. Science. 297: 2260-2263 Neurotoxicity Methodological problems w/ human studies: Differences may have been pre-existant, co-incidental, or predispose to MDMA use Retrospective & un-blinded Difficult to match controls / some studies don’t at all Confounding effects of other illicit drug use Small sample sizes Self-referral (unknown bias) Questionable drug histories / purity of drugs Numerous psychological tests in different studies Bottom line: Can’t prove causality Lab Testing MDMA & amphetamines detectable for 24-48 hrs post-ingestion (effects may outlast detectable serum levels) Immunoassay Drugwipe sweat testing kit Gas chromatography - Mass spectometry Approach: Screen with urine DOA test confirmatory testing if positive Street Sense Trivia Where does the expression “rolling on E” come from? A: a reference to the irregular eye movements associated with ecstasy intoxication Conclusion Use of designer amphetamines is growing rapidly These drugs are not benign, and their long-term toxicity is yet to be established Treatment is primarily supportive, with particular attention to cooling, hydration, & electrolyte balance Monitor for complications