1.1 THERAPEUTIC/TOXIC CLASS
A) The methoxylated and/or methylenedioxy derivatives of amphetamine have properties in common with both amphetamine and mescaline.
B) BODY PACKERS/BODY STUFFERS - Please refer to the appropriate management if body packing or body stuffing is known/suspected.
1.2 SPECIFIC SUBSTANCES
A) MDMA Ectasy
A) 4-METHYL AMINOREX
A) METHYL AMINOREX
2. CAS 29493-77-4
1. 4-bromo-2,5-methoxy phenylethylamine
1. 4-bromo-2,5-dimethoxy amphetamine
1.4 GEOGRAPHICAL LOCATION
A) COLLEGE CAMPUSES: 143 of 369 (39%) of students randomly interviewed at a college campus admitted use of MDMA. The median number of usages per person was 4, and the mean was 5.4 (Peroutka, 1987).
1.6 AVAILABLE FORMS/SOURCES
1) More than 50 hallucinogenic amphetamines have been synthesized. Some agents (e.g., MDA, MDMA) have been classified by the FDA as schedule I substances (no accepted medical use and high abuse potential).
2) Since most hallucinogenic amphetamines have not yet been classified, they can be synthesized and sold without restriction or legal penalties. The purity and identity of street samples should always be questioned until confirmed by laboratory analysis.
3) Hallucinogenic amphetamines are usually ingested but occasionally may be taken intranasally or intravenously.
4) Street names of the most popular agents are given below.
Agent Street Names
DOB Bromo DMA, Golden Eagle,
PBR, LSD-25, Psychodrine,
Tile, 100X, Bromo-STP
DOM Pink Wedge, STP (Serenity,
Tranquility, and Peace)
MDA Harmony, Love, Love Drug,
Speed for Lovers
MDMA Adam, Bean, Buffalo,
California Sunrise, Dove,
Double Diamond, Ecstasy,
Love Heart, MDM, X, XTC,
Essence, Roll, Rhubarb &
Custard (red and yellow
capsule), Snowball, White
Burger, Whizz, Whizz Bomb
2CB Eve, Spectrum
a) Is found in tablet, capsule and powder form in doses of 50 to 110 mg. Of samples alleged to contain MDMA, 58% actually contained this compound. Samples were contaminated with MDA in 24 of 101 samples. Other adulterants were not found (Renfroe, 1986).
b) Street samples alleged to contain 120 mg of MDMA actually contained an average of 101 mg; samples alleged to contain 130 to 135 mg actually contained 108 mg (Siegel, 1986).
c) Although MDMA is classified as a schedule 1 drug, it is estimated by the US media that annually hundreds of thousands of doses are used illegally. Most commonly used by young people as they "roll" at underground rave parties that can last for many hours (Rella et al, 2000).
d) NOTE: The term "Ecstasy" which is most often associated with MDMA has also been linked to gammahydroxybutyrate (GHB), 'liquid ecstasy'; and 'herbal ecstasy', an ephedrine-containing preparation. Because these agents are pharmacologically different, it is necessary to correctly identify the suspected agent(s) (Doyon, 2001).
6) 2CB: Is found in gelatin capsules containing 25 mg.
7) DOB: It is sold as drug-impregnated pieces of paper (Buchanan & Brown, 1988).
a) Paramethoxyamphetamine (PMA, "death") a ring substituted amphetamine (a methoxylated phenethylamine derivative) has been deceptively marketed as MDMA (White et al, 1997)(Felgate et al, 1998) and has resulted in several deaths (Byard et al, 1999). It has purportedly been used infrequently in Australia with minimal cases reported in the United States or United Kingdom (Byard et al, 1999).
b) Two cases of lead poisoning associated with methamphetamine use have been reported; lead acetate is a component of one methamphetamine synthesis procedure (Alcott et al, 1987).
c) In some studies, adulteration of MDMA tablets has included oriental herbal ephedrine (Ma Huang) and ketamine (Schwartz & Miller, 1997).
d) In a study conducted in the United Kingdom, the composition of illicitly manufactured ecstasy tablets sold on the streets was analyzed by gas chromatography. The results indicated frequently that other stimulants (e.g., caffeine, amphetamine, methamphetamine, paracetamol, and ketamine ) may be found in tablets that are sold as ecstasy. In this particular study, ecstasy tablets were not found to contain cocaine, heroin, or other opiates as might be reported by users. The authors also noted that "brand" names did not provide any guarantee of either the ingredient or concentration (Sherlock et al, 1999).
1) MDMA is considered an entheogen (a neologism derived from Greek roots) which means to become divine from within. Entheogen is used to describe shamanic or ecstatic possession induced by ingestion of mind-altering drugs. The drug is popular because of the desire for euphoria, intense closeness, and a need to feel serenity or peace (Rella et al, 2000). Also known as the "hug drug" because it gives the user feelings that "all is right with the world" (Shannon, 2000).
9.2 TOXICOLOGIC MECHANISM
A) The hallucinogenic methoxylated and/or methylenedioxy derivatives of amphetamines have properties in common with amphetamine and mescaline (3,4,5-trimethoxyphenylethylamine).
1) Their ability to stimulate both the sympathetic and central nervous systems ultimately results from their structural similarity to the endogenous catecholamines, epinephrine, norepinephrine, and dopamine.
2) Methoxylation and methylenedioxylation of the catechol ring is responsible for their hallucinogenic activity.
B) MOA - Although their exact mechanism of action remains uncertain, proposed mechanisms include:
1) Sympathetic receptor stimulation (false transmitter)
2) Indirect receptor stimulation by causing the release of endogenous neurotransmitters
3) Inhibition of monoamine oxidase (responsible for catecholamine degradation) (Fellows & Bernheim, 1950)(Schmidt et al, 1986)
4) Inhibition of catecholamine reuptake by presynaptic neurons (primary mechanism for terminating the effects of neurotransmitters)
5) Biotransformation of these agents to indolamines related to serotonin (5-hydroxytryptamine)
C) RATS -
1) MDA, MDMA, and MDEA produce toxicity to serotonergic neurons in the rat brain.
a) 5-hydroxytryptamine levels are markedly reduced following acute administration of 10 mg/kg (Stone et al, 1986)(Commins et al, 1987)(Schmidt, 1987a).
b) MDMA was neurotoxic in rats given parenteral doses approximately 4 times the human oral dose (Schmidt et al, 1986).
c) A biphasic effect on serotonergic neurons has been observed with MDMA. An initial reversible depletion of serotonin was followed later by a partially reversible neurotoxic effect on the nerve terminal.
d) The doses in this study were 4 to 8 times the human oral dose (Schmidt, 1987).
2) The ability of hallucinogenic amphetamines to release dopamine from rat striatal slices decreased as the size of the N-alkyl substituent increased. Thus the dopamine-releasing potency was greatest with MDA, less with MDMA, and least with MDEA (Schmidt, 1987a). Thus amphetamine-like side effects may be less with the latter two agents.
D) PRIMATES -
1) Single doses of MDMA have also been shown to produce long-lasting serotonin depletion (30% of neurons for up to 2 weeks) when administered orally to monkeys at near usual human doses (5 mg/kg) (usual doses in humans are 1 to 4 mg/kg) (Ricaurte et al, 1988).
2) Repeated administration of subcutaneous doses of MDMA twice daily to monkeys for 4 days resulted in a dose-dependent depletion of serotonin in the somatosensory cortex.
a) A dose of 2.5 and 5 mg/kg produced 44 and 90% depletion, respectively. Serotonin was also depleted in the cerebral cortex, with a 44% depletion at 2.5 mg/kg. Neither dopamine nor norepinephrine were depleted.
b) Axonal damage to serotonin nerve fibers in the cerebral cortex was demonstrated. Cell body damage was also shown (Ricaurte et al, 1988a).
1) Paramethoxyamphetamine (PMA) is a methoxylated phenethylamine derivative. It is structurally related to MDA, MDMA, and MDEA and mescaline and has been sold under the name "ecstasy" in Australia. It does have hallucinogenic properties. Toxicity (i.e., agitation, delirium, hyperthermia) appears similar to MDMA and deaths have been reported (Felgate et al, 1998).
10.1 PHYSICAL CHARACTERISTICS
A) MDMA: Powder
B) "Ecstasy": Crystals
10.3 MOLECULAR WEIGHT
A) MDMA: 193.25
Chemical Name: N,ð-Dimethyl-1,3-benzodioxole-5-ethanamine
Chemical Formula: C11H15NO2
Molecular Weight: 193.2
CAS Number: 42542-10-9
Synonyms: MDMA; Methylenedioxymethamphetamine; 3,4-Methylenedioxymethamphetamine; Metilendioximetanfetamina
Indications: Central stimulant
Revision Date: 19960705; 19980330; 20000417; 20011120; 20040415
Methylenedioxymethamfetamine is a phenylethylamine compound structurally related to amfetamine and mescaline and is an analogue of tenamfetamine (Tenamfetamine). It is subject to abuse. Its toxicity is similar to that of dexamfetamine (see Stimulants and Anorectics - Abuse. and Stimulants and Anorectics - Adverse Effects) and may be treated similarly.
Methylenedioxymethamfetamine may be ingested as tablets, capsules, or inhaled as a powder. It is often mixed with a combination of adulterants such as amfetamines, caffeine, ephedrine, and pseudoephedrine.1
The toxicity associated with abuse of methylenedioxymethamfetamine has been the subject of a number of discussions.2-7 Acute effects can be severe and symptoms have included cardiac arrhythmias, fulminant hyperthermia, convulsions, disseminated intravascular coagulation, rhabdomyolysis, and acute renal failure; fatalities may occur. Repeated use may cause hepatic damage. Psychiatric effects reported include psychosis8-10 and depression.9-11 Damage to central serotonergic nerves has been implicated8-12 and hence there is some concern regarding the long-term effects of methylenedioxymethamfetamine abuse.13,14 Hyponatraemia, inappropriate antidiuretic hormone secretion, and cerebral oedema have also been reported;15-20 the severity may be increased by excessive fluid intake that is frequently advocated to prevent dehydration and hyperthermia.18-22 Urinary retention has also been reported.23
Concern has been expressed regarding abuse during pregnancy. Twelve congenital malformations, including 2 cases of congenital heart disease, have been noted among 78 liveborn infants whose mothers had taken methylenedioxymethamfetamine, often with other drugs of abuse, during their pregnancies.24
For reviews of the properties of other phenylethylamine compounds, see under Tenamfetamine, Stimulants and Anorectics.
1. Smith KM, et al. Club drugs: methylenedioxymethamphetamine, flunitrazepam, ketamine hydrochloride, and γ-hydroxybutyrate. Am J Health-Syst Pharm 2002; 59: 1067-76.
2. Henry JA. Ecstasy and the dance of death. BMJ 1992; 305: 5-6.
3. Henry JA, et al. Toxicity and deaths from 3,4-methylenedioxymethamphetamine ("ecstasy"). Lancet 1992; 340: 384-7.
4. O'Connor B. Hazards associated with the recreational drug `ecstasy'. Br J Hosp Med 1994; 52: 507-14.
5. McCann UD, et al. Adverse reactions with 3,4-methylenedioxymethamphetamine (MDMA; `Ecstasy'). Drug Safety 1996; 15: 107-115.
6. Hall AP. Ecstasy and the anaesthetist. Br J Anaesth 1997; 79: 697-8.
7. Schwartz RH, Miller NS. MDMA (ecstasy) and the rave: a review. Pediatrics 1997; 100: 705-8.
8. McGuire P, Fahy T. Chronic paranoid psychosis after misuse of MDMA ("ecstasy"). BMJ 1991; 302: 697.
9. Winstock AR. Chronic paranoid psychosis after misuse of MDMA. BMJ 1991; 302: 1150-1.
10. Schifano F. Chronic atypical psychosis associated with MDMA ("ecstasy") abuse. Lancet 1991; 338: 1335.
11. Benazzi F, Mazzoli M. Psychiatric illness associated with "ecstasy". Lancet 1991; 338: 1520.
12. McCann UD, et al. Positron emission tomographic evidence of toxic effect of MDMA ("Ecstasy") on brain serotonin neurons in human beings. Lancet 1998; 352: 1433-7.
13. Green AR, Goodwin GM. Ecstasy and neurodegeneration. BMJ 1996; 312: 1493-4.
14. Bolla KI, et al. Memory impairment in abstinent MDMA ("Ecstasy") users. Neurology 1998; 51: 1532-7.
15. Maxwell DL, et al. Hyponatraemia and catatonic stupor after taking "ecstasy". BMJ 1993; 307: 1399.
16. Kessel B. Hyponatraemia after ingestion of "ecstasy". BMJ 1994; 308: 414.
17. Satchell SC, Connaughton M. Inappropriate antidiuretic hormone secretion and extreme rises in serum creatinine kinase following MDMA ingestion. Br J Hosp Med 1994; 51: 495.
18. Holden R, Jackson MA. Near-fatal hyponatraemic coma due to vasopressin over-secretion after ecstasy (3,4-MDMA). Lancet 1996; 347: 1052.
19. Matthai SM, et al. Cerebral oedema after ingestion of MDMA (ecstasy) and unrestricted intake of water. BMJ 1996; 312: 1359.
20. Parr MJA, et al. Hyponatraemia and death after ecstasy ingestion. Med J Aust 1997; 166: 136-7.
21. Cook TM. Cerebral oedema after MDMA (`ecstasy') and unrestricted water intake. BMJ 1996; 313: 689.
22. Henry JA, et al. Low-dose MDMA ("ecstasy") induces vasopressin secretion. Lancet 1998; 351: 1784.
23. Bryden AA, et al. Urinary retention with misuse of `ecstasy'. BMJ 1995; 310: 504.
24. McElhatton PR, et al. Congenital anomalies after prenatal ecstasy exposure. Lancet 1999; 354: 1441-2.
A psychotic reaction has been reported in a patient who took methylenedioxymethamfetamine while receiving therapy with citalopram.1
A patient receiving phenelzine and lithium therapy experienced a serotonin syndrome (Antidepressants - Serotonin syndrome.) after ingesting methylenedioxymethamfetamine.2 Symptoms included markedly increased muscle tension, tremulousness, abnormal posturing, limited pain response, tachycardia, hypertension, hyperthermia, increased white blood cell count, increased creatine phosphokinase concentration, respiratory acidosis, metabolic acidosis, delirium, and agitation. Within 15 minutes of methylenedioxymethamfetamine ingestion the patient was comatose; within 5 hours the patient was alert with a normal muscle tone. An interaction between phenelzine and methylenedioxymethamfetamine was suggested as the cause of the serotonin syndrome.
A fatal serotonergic reaction to methylenedioxymethamfetamine possibly due to an interaction with ritonavir has been described.3 A prolonged and exaggerated effect from a small dose of methylenedioxymethamfetamine has been reported4 in another patient also receiving ritonavir. Although this patient was also receiving saquinavir, the authors postulated that the mechanism may be ritonavir-induced inhibition of the cytochrome P450 isoenzyme CYP2D6.
1. Lauerma H, et al. Interaction of serotonin reuptake inhibitor and 3,4-methylenedioxymethamphetamine? Biol Psychiatry 1998; 43: 923-8.
2. Kaskey GB. Possible interaction between an MAOI and "ecstasy". Am J Psychiatry 1992; 149: 411-12.
3. Henry JA, Hill IR. Fatal interaction between ritonavir and MDMA. Lancet 1998; 352: 1751-2.
4. Harrington RD, et al. Life-threatening interactions between HIV-1 protease inhibitors and the illicit drugs MDMA and γ-hydroxybutyrate. Arch Intern Med 1999; 159: 2221-4.
0.1 LIFE SUPPORT
A) This overview assumes that basic life support measures have been instituted.
0.2 CLINICAL EFFECTS
0.2.1 SUMMARY OF EXPOSURE
A) OVERDOSE - In general, most cases of MDMA and MDEA toxicity result in mild symptoms that can include: agitation, hypertension, tachycardia, mydriasis, trismus, and diaphoresis. Fatigue and difficulty concentrating are also commonly reported. Occasionally, intense dysphoria (depression, anxiety), confusion, or delirium can occur. However, severe overdoses appear to follow a clear pattern of toxicity characterized by hyperthermia, disseminated intravascular coagulation (DIC), rhabdomyolysis, dysrhythmias, seizures, and acute renal failure. Severe toxicity can develop after typical recreational doses.
B) Ecstasy-associated (MDMA) morbidity and mortality have been related to hyponatremia, dehydration, hyperthermia, hypertensive crisis, and cardiac dysrhythmias.
C) Long-term effects of MDMA use may result in serotonin terminal degeneration and depletion, which may result in psychiatric disturbances, cognitive impairment, and memory deficits.
D) Teratogenic effects have been reported.
E) ONSET - Approximately 30 to 45 seconds after ingestion (on an empty stomach) of ecstasy a "rush" can occur, which lasts 15 to 30 minutes. This is followed by a sense of clarity and and feelings of happiness. A booster dose may be taken at this point, to prolong these feelings. Thirty minutes to 3 hours after the initial ingestion a "plateau" phase occurs in which repetitive or trance-like movements become extremely pleasurable. Rhabdomyolysis can develop during this phase due to extended activity. The "coming down" phase occurs 3 to 6 hours after the initial ingestion, and can lead to negative feelings or emotions (e.g., depression, anxiety). Symptoms may persist for several days.
F) NOTE: The term "Ecstasy" which is most often associated with MDMA has also been linked to gammahydroxybutyrate (GHB), 'liquid ecstasy'; and 'herbal ecstasy', an ephedrine-containing preparation. Because these agents are pharmacologically different, it is necessary to correctly identify the suspected agent(s).
G) USUAL DOSING - A usual dose of Ecstasy taken by young adults/teens is 1 to 2 mg/kg body weight (125 to 180 milligrams). "Candyflipping" is the intentional combination of ectasy with LSD. Another method of use is called "stacking" in which 3 or more tablets of MDMA are taken at once; or mixing MDMA with alcohol, marijuana or other drugs of abuse (e.g., ketamine, GHB, cocaine) in order to modulate the high. "Stacking" can increase the risk of overdose, since MDMA, acting as a stimulant, can mask the sedative effects of alcohol or opiates.
H) ADULTERANTS - Adulteration of so called "Ecstasy" (MDMA) tablets has included oriental herbal ephedrine (Ma Huang), ketamine, paracetamol and caffeine. So called brand names do not guarantee purity or concentration.
I) BODY PACKERS/BODY STUFFERS - Please refer to the appropriate management if body packing or body stuffing is known/suspected.
0.2.3 VITAL SIGNS
A) Hypertension, tachycardia, and tachypnea are common. In severe cases, hyperthermia, hypotension, and cardiovascular collapse may occur.
A) MYDRIASIS - Dilated pupils are virtually always present. Blurred vision and dry mucous membranes may be present.
A) Hypertension and tachycardia are common. Dysrhythmias, hypotension, and cardiovascular collapse may occur in severe cases.
A) Increased respiratory rate is common. Noncardiogenic pulmonary edema and ARDS may occur following MDMA use.
A) Excitement, agitation, anorexia, and nystagmus are common. Delirium, seizures, and coma may occur. Cerebral edema, with hyponatremia and SIADH, has been reported.
A) Nausea, vomiting and diarrhea may occur.
A) Hepatotoxicity may develop in patients with acute toxicity. Hepatitis has been reported with chronic abuse.
A) Myoglobinuria and rhabdomyolysis may occur.
B) Acute renal failure has been reported.
A) Metabolic (lactic) acidosis may be develop.
A) Hyperkalemia and dehydration have been reported.
B) Hyponatremia, associated with SIADH, has been reported after MDMA abuse.
A) Coagulopathy, DIC, and thrombocytopenia have been reported.
A) Pallor, diaphoresis, and piloerection may occur.
A) Muscle spasms, jaw clenching, tremors, and hyperreflexia are common.
B) Clonus, myoclonus, opisthotonus, rigidity, akinesia, and rhabdomyolysis may occur.
A) Symptomatic hyponatremia, secondary to SIADH, has been reported after MDMA abuse.
A) Anxiety, antisocial behavior, emotional instability, euphoria, paranoia, and hallucinations are often present.
A) Ecstasy has been associated with cardiovascular and musculoskeletal malformations in babies exposed in utero.
A) Blood levels have not correlated with toxicity, but may confirm the intoxicant.
B) Follow serum electrolytes, renal and hepatic function tests, CPK, complete blood count, platelet counts and coagulation studies (INR or PT and PTT) in patients with severe toxicity.
0.4 TREATMENT OVERVIEW
0.4.2 ORAL/PARENTERAL EXPOSURE
A) EMESIS: Ipecac-induced emesis is not recommended because of the potential for CNS depression, seizures and cardiovascular instability.
B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
C) AGITATION/HALLUCINATIONS - Administer diazepam. Dose: ADULT 10 mg PO or 5 mg IV, repeating if not responsive. CHILD 0.1 mg/kg IV or 0.3 mg/kg PO. Phenothiazines are not recommended.
D) SEIZURES: Administer a benzodiazepine IV; DIAZEPAM (ADULT: 5 to 10 mg, repeat every 10 to 15 min as needed. CHILD: 0.2 to 0.5 mg/kg, repeat every 5 min as needed) or LORAZEPAM (ADULT: 2 to 4 mg; CHILD: 0.05 to 0.1 mg/kg).
1) Consider phenobarbital if seizures recur after diazepam 30 mg (adults) or 10 mg (children > 5 years).
2) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, hypoxia.
E) HYPERTENSION - Often responds to sedation with benzodiazepines. If severe hypertension is unresponsive to sedation, nitroprusside is the drug of choice. DOSE: begin at 10 mcg/kg/min IV.
F) HYPERTHERMIA - Place patient in a cool room. Minimize physical activity, sponge patient with tepid to cool water, and use fans to maximize evaporative heat loss. Place patient on a hypothermia blanket. Other methods include convection evaporation, intubation and cool air ventilation, and gastric lavage with iced saline. Dantrolene 1 mg/kg IV has been used in severe cases.
G) SUPRAVENTRICULAR DYSRHYTHMIAS - Treatment is not necessary unless hemodynamic instability develops. Sedation with benzodiazepines may help control tachycardia in agitated patients. If severe tachycardia with hemodynamic instability develops, consider a short acting, cardioselective agent such as esmolol. Monitor for hypertension from unopposed alpha adrenergic effects.
H) VENTRICULAR DYSRHYTHMIAS - Lidocaine, amiodarone, or esmolol may be used.
I) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
J) RHABDOMYOLYSIS: Administer sufficient 0.9% saline to maintain urine output of 2 to 3 mL/kg/hr. Monitor input and output, serum electrolytes, CK, and renal function. Diuretics may be necessary to maintain urine output. Urinary alkalinization is NOT routinely recommended.
K) HYPONATREMIA - Usually corrects with free water restriction and judicious use of 0.9% saline. In patients with severe, life threatening hyponatremia, slow correction with 3% NaCl should be considered. Consider central venous pressure or pulmonary capillary wedge pressure monitoring to accurately evaluate extracellular fluid volume.
0.5 RANGE OF TOXICITY
A) Hallucinogenic doses range from 1 to 5 mg for DOB, 40 to 150 mg for MDA, and 50 to 150 mg for MDMA. An acute single dose of 200 mg or greater is considered an overdose of MDMA.
B) Fatalities have been reported after ingestion of a single capsule of MDMA. Deaths have been associated with the development of hyperthermia following MDMA intoxication.
C) An adult found at home survived a massive ingestion of Ecstasy (50 tablets - each tablet thought to contain 50 to 150 milligrams of MDMA), oxazepam (10 mg), and alcohol (5 units).