Posted by Larry Hoover on April 14, 2003, at 9:30:43
In reply to Re: Xyrem = GHB. Please don't. » Larry Hoover, posted by pelorojo on April 14, 2003, at 9:12:31
MDMA
History
The drug MDMA (Ecstasy, "E") is a ring-substituted amphetamine analog commonly taken as a recreational drug of abuse. It was synthesized in 1912 by Merck Pharmaceuticals and patented in 1914.[4] However, MDMA did not become popular until the 1970s when it was promoted as a useful adjunct to psychotherapy. It allegedly improved self-esteem and enhanced communication within significant emotional relationships.[5] Therapeutic applications for MDMA were not well established, however, and the Drug Enforcement Administration (DEA) classified MDMA as a schedule I drug in 1985 after its recreational use became more widespread and publicized.[6] It also was shown that 3,4-methylenedioxyamphetamine (MDA), an analog and metabolite of MDMA, had a neurotoxic effect in animals.[7]Availability
The drug MDMA is commonly distributed as small tablets, capsules, or white powder. Ecstasy tablets may contain various chemicals other than pure MDMA, including MDA, 3,4-methylene-dioxyethylamphetamine (MDEA), caffeine, dextromethorphan, ephedrine, phenyl-propanolamine, methamphetamine, ampheta-mine, diphenhydramine, ketamine, cocaine, and diazepam. Some have contained no active drugs at all.[8] Results of analyses of tablets from all over the United Kingdom, given to the Leeds Addiction Unit, confirm that there are many ingredients in Ecstasy tablets other than MDMA.[9] In another report, MDMA concentrations in 25 tablets varied 70-fold, and 9 of the tablets did not contain either MDMA or any related MDMA analog.[10] Furthermore, MDMA tablets collected by the Haight Ashbury Free Medical Clinic contained from 16-150 mg of MDMA/tablet. Owing to the great variability in the dose of MDMA in any given tablet, it is very difficult for users of MDMA to control their dose. Larger-than-expected doses of MDMA may be taken accidentally, leading to adverse effects.[11] Furthermore, because of the variety of substances that may be found in any given MDMA tablet, the clinical presentation of acute intoxication may vary significantly.Chemistry
The chemical designation of MDMA is N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (Figure 3). Structurally it resembles both the stimulant amphetamine and the hallucinogen mescaline.[12] The drug MDMA is optically active, with the dextrorotatory isomer (S+) having higher central activity than the levorotatory isomer.[4, 13](click image to zoom) Figure 3. Mechanism of MDMA elimination. The parent compound MDMA and its metabolites are excreted in the urine to varying degrees (see text). Also, MDMA may be metabolized by ring hydroxylation and demethylenation to potential serotonergic neurotoxins.
Pharmacokinetics
Pharmacokinetic Parameters
The pharmacokinetics of MDMA after oral ingestion have been studied by various researchers.[14-17] The time to maximum concentration (Tmax) is 2 hours after oral ingestion of MDMA 50, 75, or 125 mg.[14-17] The half-life shows little variation after a wide range of doses. After a 50-, 75-, or 125-mg dose, the half-life is 8 hours.[16, 17] Other studies found the half-life to be 9.53 hours after a 75-mg dose and 9.12 hours after a 125-mg dose.[14] The maximum concentration (Cmax) after oral ingestion appears to be dose dependent. A Cmax of 105.6 ng/ml was reported in a single subject who took a 50-mg dose,[16] whereas a Cmax of 330 ng/ml was found in another subject who took MDMA 135 mg.[18] In a group of eight subjects, the Cmax values after ingestion of MDMA 75 mg and 125 mg were 126.5 and 226.3 ng/ml, respectively,[14] whereas in another group of eight subjects, Cmax values of 130.9 ng/ml and 236.4 ng/ml were obtained after ingestion of MDMA 75 mg and 125 mg, respectively.[17] In these studies, the Cmax exhibits a slightly greater-than-expected increase compared with the increase in dose. According to these observations, after the usual recreational dose of 100-150 mg, the Cmax should be 200-300 ng/ml. The area under the concentration-time curve (AUC) data from these studies also suggest nonlinearity. The AUC measured over 24 hours after ingestion of a 125-mg dose (2235.9 µg/Lhr) is more than twice the AUC after ingestion of a 75-mg dose (995.4 µg/Lhr).[14] Nonlinearity is further supported by other evidence, in which the dose ratio of MDMA was 1:3 (50 mg and 150 mg), whereas the AUC ratio over 24 hours after ingestion was greater than 1:10. The authors suggested that the nonrenal clearance of MDMA is dose dependent (i.e., HMMA, one of the many metabolites of MDMA metabolism [Figure 3], was the major product in plasma at lower doses, whereas MDMA was the predominant product at higher doses). This resulted in a disproportionate increase in plasma AUC and an increase in the proportion of MDMA excreted in the urine as the dose increased. It is possible that demethylenation may be inhibited as MDMA accumulates or one of the MDMA metabolites may inhibit cytochrome P450 (CYP) 2D6, which is responsible for a substantial proportion of MDMA nonrenal clearance. Alternatively, there might be an increase in the fraction of drug bioavailable as the dose increases.[15] Unfortunately, to our knowledge, the oral bioavailability of MDMA has not been determined in humans.
Primary Metabolism
The primary metabolic pathways for MDMA have been elucidated, with a number of metabolites having been identified in both animals and humans (Figure 3). The main meta-bolic pathway appears to be demethylenation to the catechol metabolite 3,4-dihydroxy-methamphetamine (DHMA; also called N-methyl-a-methyldopamine).[19] The metabolite DHMA is the major metabolite of MDMA in rat liver[19, 20] and in rat brain microsomes.[21] Microsomes from yeast expressing human CYP2D6 demethylenate MDMA to the metabolite DHMA.[22, 23]Furthermore, using human liver microsomes, CYP2D6 is the primary isoenzyme responsible for the demethylenation of MDMA.[24] If CYP2D6 is the isoenzyme responsible for the majority of MDMA metabolism in humans, then poor metabolizers could be sensitive to the acute physiologic effects of MDMA, but less prone to any long-term toxic effects of MDMA arising from metabolites. However, case reports have indicated that fatal MDMA intoxications have occurred in patients who were shown to be CYP2D6 extensive metabolizers,[25] and it also has been shown in vivo that in the absence of functional CYP2D6 a considerable amount of metabolism of MDMAanalogs occurs by demethylenation.[24] It may be that more than one metabolic pathway can lead to an MDMA-induced toxic reaction.
Secondary Metabolism
A second pathway of MDMA metabolism is N-demethylation to MDA, which appears to be a minor metabolite of MDMA[14] and is an abused drug in its own right. Concentrations of MDA in plasma range from 3-5% of those corresponding to MDMA.[14] When formed from MDMA, the MDA formation rate constant is approximately 0.75/hour and the half-life is 16-28 hours, depending on the dose of MDMA given. The Cmax for MDA occurs at 5-7 hours, and, on the basis of plasma AUC comparisons of MDMA and MDA, 8-9% of MDMA is converted to MDA, which may be further metabolized before elimination. The urinary recovery of unchanged MDA accounts for approximately 1% of the dose of MDMA.[17] It is unlikely that significant accumulation of MDA would occur after a single dose of MDMA. Given the prolonged half-life of MDA, however, it could accumulate in an individual taking MDMA 3 or more times/week.Toxic Metabolites
It has been hypothesized that some of the neurotoxic actions of MDMA may result from quinones formed from the metabolism of DHMA, which can combine with glutathione and other thiol compounds.[19, 22] A 6-hydroxy-dopamine analog is formed by the aromatic hydroxylation and demethylenation of MDMA that also could be neurotoxic.[22, 26] Catecholamines formed from MDMA, such as DHMA, are highly polar compounds that cannot cross the blood-brain barrier. However, these highly polar compounds have been detected in the brain after peripheral administration of MDMA,[27] indicating that some MDMA metabolism may occur in the brain.Drug Interactions
There is a single report, to our knowledge, of a possible drug interaction involving MDMA and ritonavir.[28] A patient receiving ritonavir for the treatment of human immunodeficiency virus ingested MDMA in an estimated dose of 180 mg. The resultant blood MDMA level was 4.56 µg/ml, which is much higher than would be expected from this dose of MDMA. The authors suggest that the coadministration of MDMA and ritonavir (an inhibitor of CYP2D6) is the explanation for the unusually high levels of MDMA after a commonly used recreational dose.[28] Preincubation of MDMA with human liver microsomes and nicotinamide adenine dinucleotide phosphate (NADPH) resulted in significant inhibition of CYP2D6 activity. Therefore, MDMA may be a potent inhibitor of CYP2D6 in vivo, and the interaction of MDMA with this metabolic pathway may cause long-lasting drug interactions with other CYP2D6 substrates.[29] No clinical data are available in support of this theory.Elimination
In humans, approximately 50-70%[15, 16] of the total MDMA dose is recovered in the urine as MDMA and other metabolites. Although MDMA is metabolized in the body, a large proportion is excreted unchanged in the urine. A report based on one patient indicated that after a single oral ingestion of MDMA 50 mg, 32.52 mg (65%) of unchanged drug was excreted in the urine over 72 hours.[16] In another study,[15] urine collection showed an increase in the amount of unchanged MDMA excreted by a factor of 20, from the 50-mg to the 150-mg dose, whereas the urinary recovery of 4-hydroxy-3-methoxymetham-phetamine (HMMA), a metabolite of MDMA metabolism, remained unchanged. No significant changes in the urinary pH or creatinine clearance occurred during this study. Although the renal clearance remained fairly constant, the nonrenal clearance appeared to be dose dependent.[15]
Pharmacology
Receptor Biochemistry
The drug MDMA is a potent indirect monoaminergic agonist, which is thought to act by both increasing the release and inhibiting the reuptake of serotonin and, to a lesser extent, dopamine.[30] Serotonin is involved in the regulation of a variety of behavioral functions, including mood, anxiety, aggression, appetite, and sleep. Dopamine is the primary neuro-transmitter of the "reward pathway" and is involved in motivational processes such as reward and reinforcement. Norepinephrine has important roles in the processes of attention and arousal. In vitro, MDMA causes release of serotonin, dopamine, and norepinephrine from synaptosomes[31, 32] and rat brain slices.[33, 34] In vivo, in freely moving rats, MDMA increases both serotonin and dopamine release in the caudate.[35] In a similar study, MDMA increased dopamine release in vivo in awake rats, resulting in region-, time-, and dose-dependent behavior.[36] In rat brain synaptosomes, MDMA inhibited the uptake of serotonin and norepinephrine and, to a lesser extent, dopamine.[37] The local administration of MDMA to the rat nucleus accumbens resulted in increases in the extracellular levels of both serotonin and dopamine in this region,[38] which is part of the reward pathway activated by other abused substances such as amphetamine and cocaine. These actions in the nucleus accumbens may account for the euphoric effects produced by MDMA.
In addition to causing the release of serotonin and inhibiting its reuptake, MDMA may have direct agonist effects on serotonin and dopamine receptors.[39] It has affinities for a broad range of neurotransmitter recognition sites[39, 40] and may act at both serotonin receptors, 5-HT2A and 5-HT2C.[41] Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and citalopram block the release of serotonin induced by MDMA, both in vitro[42, 43] and in vivo.[44, 45] They also reportedly block the subjective effects produced by MDMA in humans.[46] Consequently, the release of serotonin by MDMA may be dependent on the serotonin transporter. Different potencies for the neurotransmitter systems are shown by MDMA than by either amphetamines or the hallucinogens. Owing to its individual biochemical profile and the subjective effects it produces in humans, MDMA has been called an entactogen, which means, "producing a touching within."[13]Abuse Liability and Psychomotor Performance
In controlled studies, MDMA produced marked feelings of euphoria and well-being[47, 48] and possessed amphetamine-like properties.[47] Indexes of positive psychologic states have been shown to increase with increasing MDMA dosage.[49] Subjective effects peak between 90 minutes and 2 hours after ingestion of MDMA and return to baseline approximately 4 hours after ingestion.[47] The drug MDMA produces mild changes in perceptions but does not commonly cause hallucinations or psychotic episodes.[47] It also produces moderate derealization and depersonalization, as well as anxiety without marked increases in psychomotor drive.[48]Cardiovascular Effects
Ingestion of MDMA 75 and 125 mg causes an increase in blood pressure and heart rate, which occurs maximally at 90 minutes and 60 minutes, respectively.[17] Marked increases in blood pressure and heart rate have been seen after doses of MDMA 0.25-1.0 mg/kg[49] and 1.7 mg/kg, respectively.[48] In the latter investigation, peak increases in blood pressure occurred 2 hours after drug administration, and 12 of the 13 subjects had a peak blood pressure of 160/100 mm Hg, whereas blood pressure in the last patient peaked at 240/145 mm Hg.[48]Neuroendocrine Effects
Plasma cortisol levels are significantly increased after ingesting MDMA at both 75 and 125 mg, and the 125-mg dose causes significant elevations in prolactin levels as well. The increases in cortisol and prolactin levels reach a peak at 2 hours after MDMA administration.[17] Other findings state that adrenocorticotropic hormone (ACTH) and prolactin concentrations are increased after the oral administration of MDMA 0.75-1.0 mg/kg[49] and that increases in serotonergic function increase both cortisol and prolactin levels. For example, fenfluramine, a drug that causes serotonin release, produces dose-related increases in the concentrations of both cortisol and prolactin.[50] In addition to cortisol and prolactin, plasma vasopressin (arginine vasopressin [AVP]) is significantly elevated 1-2 hours after MDMA administration, which may be accompanied by a small decrease in serum sodium levels and unchanged cortisol levels. Therefore, the slight hyponatremic effect could be related to the ability of MDMA to release AVP rather than a stress response, as elevated AVP levels may be accompanied by unchanged cortisol levels.[51] However, similar doses caused significant elevations in ACTH in a study by a different group of researchers.[49]Ocular Effects
Ingestion of MDMA 75 and 125 mg produces significant mydriasis, with a maximal change in pupillary diameter occurring 1-2 hours after drug administration. Furthermore, MDMA 125 mg produces significant esophoria (tendency for the eyes to turn inward).[47]
Compound Lethality
The lethality of a compound (LD50) is the dose of a drug that will kill 50% of the animals receiving that dose. Work done by the U.S. Army in 1953-1954 compared the 24-hour LD50 among five different animals (mice, rats, guinea pigs, dogs, and monkeys). Of the five known human hallucinogens that were tested, MDMA was the second most toxic agent.[52] The LD50 was 49 mg/kg in rats, 14 mg/kg in dogs, and 22 mg/kg in rhesus monkeys. It is difficult to extrapolate these data to humans because the animal data were obtained after intravenous or intraperitoneal administration, and MDMA is taken orally (its oral bioavailability in humans is unknown). However, these findings indicate that MDMA causes a significant dose-dependent toxic reaction and death in many animals.Preclinical Neurotoxic Reactions
In animals, extensive data describe MDMA-induced neurotoxic effects to the serotonergic system.[53] Dose-related reductions in brain levels of both serotonin and its major metabolite, 5-hydroxyindoleacetic acid (5-HIAA), are caused by MDMA in the rat,[54-56] guinea pig,[56] and monkey.[57-59] The activity of tryptophan hydroxylase, which is the rate-limiting enzyme in the synthesis of serotonin, is decreased after MDMA administration.[55, 60, 61] Reductions in the density of serotonin uptake sites have been noted.[56, 62, 63]
Furthermore, immunocytochemical studies, which provide visualization of the serotonergic axons, have shown neurodegenerative changes including swollen, fragmented serotonin axons, with the fine serotonin axon terminals being especially vulnerable to the toxic effects of MDMA.[64-66] One study found a marked reduc-tion in the number and density of serotonin-immunoreactive axons throughout the cerebral cortex in monkeys who also displayed reductions in brain concentrations of serotonin and 5-HIAA. This is important as it provides some evidence that reductions in serotonin and 5-HIAA may be directly associated with morphologic findings of damage to serotonergic axons.[59]In one study that used positron emission tomography (PET) in the nonhuman primate,[67] a substantial loss of serotonin transporters was found in the central nervous system (CNS) after MDMA treatment. Reasonably good agreement was noted between the PET data and reductions in serotonin, 5-HIAA, and serotonin transporter density, measured neurochemically in postmortem brain tissue 3 weeks after the last PET study was performed.[67] The neurotoxic effects of MDMA on the serotonergic system of the monkey may be long-lasting and still evident from 18 months[68] to 7 years[69] after the administration of MDMA. There is evidence of some regrowth of the axons, but it may be abnormal and incomplete,[69] with some reorganization of ascending serotonergic projections.[70]
Clinical Neurotoxic Reactions
In addition to the extensive animal data providing evidence for serotonergic neurotoxic effects, there is evidence of possible neurotoxic reactions in human users of MDMA. The serotonergic neurotoxic evidence can be classified into three domains: neurobiologic (i.e., neuroendocrine and brain imaging), psychologic and somatic, and psychiatric.
Neurobiologic Domain
Studies have shown dose-dependent decreases in the concentrations of the serotonin metabolite 5-HIAA in the cerebrospinal fluid of individuals taking MDMA.[71, 72] Another technique to assess serotonergic damage in humans is to administer serotonergic agonists and examine neuro-endocrine responses. Various serotonergic agonists such as L-tryptophan, m-chlorophenyl-piperazine (m-CPP), and D-fenfluramine (D-fen) have been used to assess the prolactin response.[71, 73-75] Two studies evaluated the prolactin response after the administration of L-tryptophan, a serotonin precursor known to increase serum prolactin concentration. One investigation found a nonsignificant trend toward a blunted prolactin response in those who took MDMA, as compared with control subjects,[74] whereas the other study did not find significant differences in the prolactin response to L-tryptophan in those who last took MDMA 18 weeks-2 years before the beginning of the study, in comparison with the control group.[71] With use of m-CPP, 25 individuals who took MDMA were less sensitive to the anxiogenic effects of m-CPP compared with 25 controls, and the men who took MDMA had a diminished prolactin and cortisol response to m-CPP.[73] A blunted neuroendocrine response also was found with the serotonin releaser, D-fen, in 15 individuals abstaining from taking MDMA in comparison with control subjects. Prolactin response to D-fen was significantly reduced in individuals taking MDMA at both 3 weeks and 12 months after last MDMA use. In contrast, cortisol response to D-fen was reduced at 3 weeks but had recovered by 12 months in those taking MDMA. The authors suggest that the cortisol response at 12 months may indicate either partial recovery to the neurotoxic actions of MDMA or selective neurotoxic actions of MDMA on different serotonin receptors and pathways.[75]A study using PET with [11C] McN5652 (a radioligand selective for the 5-HT transporter) found that individuals who abstained from taking MDMA (at least 3 weeks since last use) showed significant reductions in 5-HT transporter binding compared with that of control subjects who had never taken MDMA. This was attributed to a reduced density of serotonin uptake sites. Furthermore, reduced binding was positively correlated with the amount of previous MDMA use.[76] Another study using PET imaging found a reduction in the brain glucose metabolism in individuals taking MDMA. The PET scans were obtained in seven individuals who had taken MDMA from 1-39 months and seven age-matched control subjects with no history of illicit drug use. Glucose uptake was lowered in the hippocampus, amygdala, and cingulate bilaterally in the MDMA group.[77] A decrease in the density of serotonin uptake sites has been found with use of other brain imaging techniques as well. Ten men who had taken MDMA long term were compared with 10 individuals who had not taken MDMA, matched for the consumption of other drugs. Each subject was examined with single photon emission computed tomography (SPECT) with a 5-HT transporter ligand. The MDMA group showed a reduction in cortical serotonin transporter binding.[78] In another SPECT study,[79] cortical 5-HT2A receptor densities in the occipital cortex were increased in five individuals who abstained from taking MDMA (at least 2 months since last use) compared with nine healthy control subjects. The authors suggested an upregulation of postsynaptic 5-HT2A receptors due to serotonin depletion.[80] Only the subjects with apparent high densities of postsynaptic 5-HT2 receptors in the occipital area showed detectable decreases in memory function.
Psychologic and Somatic Domain
Memory decrements are more pronounced in those taking MDMA regularly (10 or more occasions) than in those just beginning (9 or fewer occasions).[81] In addition, both those just beginning to take MDMA and those regularly taking MDMA exhibit significantly lower immediate word recall and delayed word recall compared with control subjects.[81] Significant memory impairment has been reported in those who take only MDMA compared with those who take many drugs but who had never taken MDMA, suggesting that the memory impairments are caused primarily by the MDMA rather than the various other drugs consumed by these individuals.[82]Psychiatric Domain
Two studies suggest a depression of mood in the days after taking MDMA.[83, 84] In one study, those who took MDMA scored in the mild-to-moderate clinical range for depression on the Beck Depression Inventory.[83] In the other study, visual analog mood scales were used to assess 16 mood states. Those taking MDMA reported feeling significantly more depressed, abnormal, unsociable, unpleasant, and less good tempered 2 days after the ingestion of MDMA than did the control subjects.[84 ]
Subjective Effects
There are very few controlled studies evaluating MDMA in humans, mostly because MDMA is a schedule I drug in the U.S. and therefore is difficult to obtain for study purposes. Also, the safety of human research subjects who take MDMA cannot be guaranteed. The information that is available, with the exception of a few small controlled trials, comes from information collected retrospectively from people who have taken MDMA outside of a controlled research environment. The high rate of concurrent multisubstance abuse, the uncontrolled content of active MDMA in any given pill, as well as the historical accuracy of information reported by the person who takes recreational drugs lend some uncertainty to the conclusions drawn from these reports. According to these reports, MDMA is ingested orally in a dose of approximately 100-150 mg, with an onset of effects usually around 30 minutes, which is described as an amphetamine-like rush.
The earliest reports of MDMA effects were primarily anecdotal. Although users stressed the positive feelings associated with MDMA, negative effects were also reported. Some of the positive effects include a sense of "closeness" toward others, heightened alertness, increased ability to interact with others, decreased defensiveness, decreased fear, decreased sense of alienation from others, increased awareness of emotions, decreased aggression, euphoria, increased energy, and sexual arousal.[85-87] The negative effects include tachycardia, trismus (jaw clenching), bruxism (teeth grinding), decreased appetite, lower back pain, and decreased desire to perform mental or physical activities.[85-87] Aftereffects ("hangover") most often described by those who have taken MDMA include lethargy, anorexia, decreased motivation, sleepiness, depressed mood, and fatigue.[85, 86] Of interest, many of the subjects reported that with regular MDMA usage ( six separate doses), the positive effects lessened while the negative effects increased.[85] Consequently, many individuals space their usage.[5]Two early reports on the effects of MDMA were prospective studies, involving 50 patients, that were completed before the government restriction of MDMA to schedule 1.[5, 88] In both studies, patients provided positive and negative descriptions of the experience. The positive experiences included a perception of enhanced communication, increased feelings of intimacy, cognitive enhancement, euphoria, increased self-confidence, a heightened sense of sensual awareness (with some subjects reporting increased sexual arousal and an increase in physical and emotional energy). Adverse effects that were described by all of the subjects include those similar to amphetamines such as tachycardia, dry mouth, palpitations, bruxism, trismus, nausea, anorexia, headaches, eyelid twitches, and insomnia. Unlike with amphetamines, there appeared to be no "crash" or depression up to 24 hours after ingestion.[5, 88]
Pharmacologic Pretreatment
Three studies have investigated the feasibility of giving pharmacologic agents to block or attenuate MDMA effects. Citalopram is a serotonin reuptake inhibitor that should block the uptake of MDMA into the neuronal terminal. Pretreatment with intravenous administration of citalopram 40 mg attenuated the acute psychologic effects of MDMA 1.5 mg/kg in healthy volunteers. Some of the effects attenuated by citalopram included MDMA-induced increases in positive mood, derealization and depersonalization phenomena, and the loss of thought and body control. The attenuation of the psychologic effects induced by MDMA as a result of citalopram pretreatment suggests that MDMA actions are at least partly dependent on a carrier-mediated release of serotonin.[46] The same investigators performed another study designed to test the effect of haloperidol 1.4 mg intravenously (dopamine D2 antagonist) on the psychologic and physiologic responses to MDMA. Haloperidol treatment before MDMA administration reduced the positive mood and euphoria induced by MDMA, but not the cardiovascular effects. The authors suggested that there may be a role for dopamine in the euphoria-producing effects of MDMA and that serotonin or norepinephrine may mediate the physiologic effects.[89] The final study, also by this group, used ketanserin (5-HT2 antagonist) to examine the role of 5-HT2 receptors on MDMA's actions. Ketanserin 50 mg was given orally to healthy volunteers before the oral administration of MDMA 1.5 mg/kg. Ketanserin attenuated perceptual changes and emotional excitation induced by MDMA but had little effect on MDMA-induced positive mood, well-being, and extroversion. Furthermore, body temperature was lower after the MDMA-ketanserin combination than with MDMA alone.[90]Adverse Effects and Acute Toxic Reactions
Acute Syndrome
One of the dangers of MDMA is the apparent lack of relationship between alleged dose and severity of acute toxic reaction.[91, 92] Although one person attempted suicide after reportedly taking 42 pills of Ecstasy with a resultant plasma MDMA level of 7.72 µg/ml and displayed only hypertension and tachycardia,[93] others have died with much lower plasma MDMA levels ranging from 0.05-1.26 µg/ml.[91] Furthermore, serum MDMA levels do not correlate well with clinical symptoms.[94] Acute toxic reactions usually develop within 15 minutes-6 hours after the ingestion of MDMA.[91] Symptoms of an acute MDMA toxic reaction include agitation, tachycardia, hypertension, dilated pupils, trismus, and sweating, whereas the more severe cases may be characterized by hyperthermia, disseminated intravascular coagulation (DIC), rhabdomyolysis, and acute renal failure.[93] In more severe cases, elevated creatine kinase levels are often present,[95-98] with levels as high as 122,341-555,000 IU/L being reported.[97, 98] Other frequently reported acute adverse effects occurring after the ingestion of MDMA include lack of appetite, difficulty concentrating, impaired balance, and restless legs.[48]
The toxic effects of MDMA were divided into three categories in one investigation to help distinguish acute toxic reactions from long-term residual effects. These categories were acute reactions at therapeutic doses, overdose reactions, and residual effects.[11] At moderate doses (85-100 mg), acute effects included transient nausea occurring about 30 minutes after ingestion and lasting about 30 minutes, increases in both blood pressure and heart rate, and symptoms related to increased muscle tonicity, such as jaw clenching and teeth grinding. In those subjects who were particularly sensitive to MDMA, higher doses ( 100 mg) caused numbness and tingling in the extremities, luminescence of objects, increased sensitivity to cold, increased color acuity, and vomiting. Residual effects occurring from 2 hours-2 weeks after ingestion included exhaustion, fatigue, and nausea. Doses higher than 200 mg result in a classic toxic psychosis with symptoms of paranoia and auditory and visual hallucinations.Hyperthermia
Hyperthermia (temperature > 40°C) is the most common adverse effect associated with a severe acute toxic reaction to MDMA. The increase in body temperature is probably due to serotonergic actions of MDMA in the thermo-regulatory center in the hypothalamus[99] because animal studies have shown that the hyperthermia caused by compounds such as MDMA is mediated by actions at serotonin receptors in the CNS.[100] Hyperthermia also may be caused by excessive heat production due to sustained muscle hyperactivity, increased metabolic rate, rigidity, and seizures.[101] Hyperthermia is believed to be the beginning of the cascade leading to DIC, rhabdomyolysis, myoglobinuria, and acute renal failure. However, the exact pathophysiology of this cascade after MDMA intoxication has not been fully elucidated.Cardiovascular Effects
Similar to cocaine and amphetamine, MDMA may cause sympathetic stimulation and increase myocardial oxygen demand, leading to varying degrees of tachycardia, vasoconstriction, changes in blood pressure, and arrhythmias. In severe cases, vasospasm leading to acute myocardial infarction and irreversible dilated cardio-myopathy may occur.[102] Abnormal electro-cardiographic changes that show widespread ST segment elevation indicating acute myocardial infarction have been seen with laboratory evidence in the urine of MDMA users.[103] During postmortem evaluations, necrosis of the heart (contraction band necrosis or widespread foci of necrosis) has been seen[104] and may be due to excessive catecholamines.[102] These findings do not necessarily establish a cause and effect relationship, since other substances or circumstances may have contributed.Cerebrovascular Effects
"Designer drugs" such as MDMA are associated with intracerebral hemorrhage, often in conjunction with an underlying vascular malformation.[105] Other investigators have postulated that those who take MDMA are at an increased risk for cerebrovascular accidents due to the altered 5-HT system because postsynaptic 5-HT receptors are involved in the regulation of the brain microvasculature.[106] Other cerebro-vascular adverse effects that have been associated with MDMA include subarachnoid hemorrhage, cerebral infarction, and cerebral venous sinus thrombosis.[107] Magnetic resonance imaging revealed a left basal ganglia hematoma after the ingestion of MDMA in a patient with no apparent cardiovascular risk factors.[108]Neuroendocrine Effects
Numerous cases of hyponatremia have been associated with MDMA use, often in combination with seizures, catatonic stupor, and incontinence of urine.[109-114] It is possible that hyponatremia is a direct result of MDMA neuroendocrine effects or from massive water intake leading to dilutional hyponatremia. Since many users take MDMA during all-night dancing parties, large amounts of fluid are ingested, both as a natural consequence of physical activity and because of MDMA-induced hyperthermia. Hyponatremia may be due to the syndrome of inappropriate antidiuretic hormone,[111, 112] because MDMA causes the release of AVP.[51] In addition, the extreme dehydration caused by sweating and/or vomiting associated with MDMA use combined with massive water intake could lead to hyponatremia.[115] In one report of a fatality due to MDMA, hyponatremia leading to cerebral edema appeared to be the main cause of death.[116] Contamination of the MDMA tablets with other substances has been postulated as the cause of hyponatremia associated with MDMA use.[110] Postcards have been distributed in some clubs and bars advising patrons who take MDMA that they should drink about a pint of water an hour and eat or drink something salty, such as a sports drink, to replace lost sodium.[117]Hepatotoxicity
Hepatotoxic effects have been associated with MDMA.[91, 93, 104, 118, 119] In one case series of seven fatalities associated with the use of ring-substituted amphetamines, including MDMA, necrosis of the liver was seen in all cases.[104] Two of the most likely mechanisms for causing a hepatotoxic reaction are immune-mediated reaction or injury secondary to hyperthermia.[119] Hepatotoxic reaction arising from drug impurities or MDMA metabolites is also possible. Liver transplantation has been required because of hepatic damage associated with MDMA use.[118]Psychopathology
A psychotic syndrome characterized by delusions, usually of the persecutory type, may be caused by MDMA. Other nonpsychotic conditions include visual phenomena, depersonalization and derealization, panic attacks, and depression. Persons who display such symptoms may have at least one first-degree relative with a history of psychiatric illness and be predisposed to have psychiatric symptoms.[120] Anxiety attacks, persistent insomnia, rage reactions, and psychosis (especially at higher doses) have occurred after MDMA use, although in most cases the premorbid psychiatric status of these patients was not known.[11] Compared with control subjects who do not take MDMA, those who frequently take MDMA have significantly higher scores on scales used to assess somatization, obsessionality, anxiety, hostility, phobic-anxiety, paranoid ideation, psychoticism, poor appetite, and restless or disturbed sleep. They also showed greater impulsiveness.[121]Death
Conditions commonly contributing to death due to MDMA include dehydration, hyper-thermia, disseminated intravascular coagulation, rhabdomyolysis, acute renal failure, tachycardia and other cardiac arrhythmias, and convulsions.[93, 122] In other fatal cases involving MDMA, necrosis of the liver and heart were found at autopsy as were various injuries to the brain such as focal hemorrhages and severe cerebral edema consistent with water intoxication.[104]
Treatment
The diagnosis of acute toxic reaction to MDMA is made based on the history and clinical features of intoxication. Initial examination should include blood chemistry analysis, complete blood count, liver function tests, cardiac enzyme and creatine kinase measurements, and a urine toxicology screen. Quantitative serum levels do not correlate well with severity of symptoms and are not generally available.[94] A complete history and physical examination should be performed, and the patient should be assessed for hyper-tensive crisis or life-threatening arrhythmias. An electrocardiogram for chest pain or a computed tomographic (CT) scan of the brain for persistent mental status changes should be obtained.[123, 124] Amphetamines and related drugs (i.e., metham-phetamine, MDMA) can be detected in the urine, but there is a high degree of cross-reactivity between amphetamine derivatives and adrenergic amines. Therefore, confirmatory testing usually is required.[94]Resuscitation
There is no antidote for MDMA intoxication, and in general, recommended treatment of MDMA overdose is similar to the treatment of amphetamine or methamphetamine overdose. The first priority should be maintaining the airway, breathing, and circulation.[123, 124] Treatment will then be aimed at reducing various symptoms, including hyperthermia, agitation, cardiovascular and cerebrovascular incidents, neuroendocrine abnormalities, and neurologic problems.
Decontamination and Elimination
Decontamination of the gastrointestinal tract with lavage, activated charcoal, and cathartic techniques has been used. Induction of emesis is not appropriate because of the potential for CNS depression and seizures.[94] Because approxi-mately 50-70%[15, 16] of MDMA is recovered in the urine, renal failure would significantly decrease the elimination of MDMA from the body, so maintaining adequate hydration is essential. Because MDMA is a weak base and a significant proportion is eliminated in the urine, acidifying the urine is likely to be an effective means of increasing renal elimination, but it may precipitate acute renal failure in patients with myoglobinuria and is not recommended.[94]Hyperthermia
Although fatalities may be due to many different causes, hyperthermia is probably the single most important condition to treat because it may lead to further severe complications, such as rhabdomyolysis and DIC.[125] Mortality has been correlated to both the extent of hyper-thermia and the duration, and active cooling measures are indicated in cases of MDMA-induced hyperthermia (see Supportive Care section).[99] It is important to control agitation to limit further heat production.[126] Neuromuscular blockers, such as pancuronium, have been given, but their use requires ventilation and endotracheal intubation.[94]Dantrolene sodium, a drug that is indicated for the treatment of malignant hyperthermia and that inhibits the release of calcium from the sarcoplasmic reticulum, is recommended by many clinicians to treat hyperthermia secondary to MDMA use.[93, 95, 96, 99, 127-132] Speculative hypotheses notwithstanding, the use of dantrolene for the treatment of MDMA intoxication remains controversial. The efficacy of dantrolene in treating this condition has been questioned, as some patients have improved with supportive care only[133] and some clinicians assert that there is insufficient evidence to recommend dantrolene in cases of MDMA acute toxic reaction.[134-136]
To determine if MDMA caused an increase of calcium within the muscle, which would suggest that an inhibitor of calcium release in skeletal muscle, such as dantrolene, might be efficacious in treating MDMA intoxication, in vitro experiments using human muscle subjected to halothane and caffeine contracture tests were performed (used to test for susceptibility to malignant hyperthermia). It was hypothesized that if MDMA raised the calcium levels within the muscle, then dantrolene should be effective in treating MDMA acute toxic reaction, since it is effective in treating malignant hyperthermia. The results indicated that the hyperthermia from MDMA intoxication is associated with an elevation in the myoplasmic calcium concen-trations, similar to that seen in malignant hyperthermia, which suggests that dantrolene might be a helpful agent in treating MDMA-induced hyperthermia.[137] It has been argued that MDMA-induced hyperthermia results from augmentation of central serotonin, and since dantrolene has no central activity (inhibits calcium peripherally in the skeletal muscle), it should not be effective. Therefore, a non-depolarizing neuromuscular blocker may be just as effective in treating MDMA acute toxic reaction.[92] As stated previously, however, ventilation and intubation may be required.[94] Although, there are not sufficient data in humans to confirm that the hyperpyrexia associated with MDMA is a centrally mediated effect, the use of dantrolene should not be precluded because it does appear to reduce pyrexia secondary to exertional heatstroke.[138] It is hypothesized that the unpredictable hyperthermia associated with MDMA may result from an underlying metabolic myopathy, similar to that seen with exertional heatstroke, and associated with a skeletal muscle abnormality similar to malignant hyperthermia.[139 ]
Cardiovascular Treatment
Tachycardia without hemodynamic compromise does not need to be treated. Sedative dosages of benzodiazepines may be helpful by reducing blood pressure and heart rate, which may reduce myocardial oxygen demand.[140] b-Blockers should be avoided when treating stimulant-induced hypertension because this may result in unopposed a-adrenergic vasoconstriction. Hypertension can be treated with an a-blocker such as phentolamine or with a direct-acting vasodilator such as nitroprusside.[94, 123] Another option is the use of a b-blocker concurrently with phentolamine.[126] Myocardial ischemia caused by stimulants should be treated with oxygen, aspirin, and benzodiazepines. If these options do not reverse the ischemia, then vasodilators or phentolamine should be given.[102] Arterial spasm may be treated with sublingual or intravenous nitroglycerin.[94] Arrhythmias should be treated according to advanced cardiac life support guidelines.[123, 126] Thrombolytic agents have been given safely to patients with stimulant-induced myocardial infarction.[140]Cerebrovascular Treatment
Patients with altered mental status, lethargy, or obtundation should undergo CT of the brain because of the risk for intracranial hemorrhage and infarct.[123] In patients with nontraumatic intracranial hemorrhage, arteriography should be performed and a thorough history of the use of illicit substances should be evaluated.[105]Neurologic Treatment
Patients who are agitated may require treatment with a benzodiazepine, such as diazepam, lorazepam, or midazolam.[94, 123] It is very important to control agitation as this may decrease further heat production.[126] Some of the conditions associated with MDMA acute toxic reaction (mental status changes, hyperthermia, autonomic instability, increased motor restlessness, myoclonus, elevated creatine kinase level, diaphoresis, and death due to renal failure) are similar to the findings in both neuroleptic malignant syndrome and serotonin syndrome.[91, 127] Pharmacologic treatments effective in these syndromes are recommended by some clinicians,[127] including methysergide maleate (nonspecific serotonin antagonist),[141] b-blockers (5-HT1A antagonists),[142] or bromocriptine (a dopamine agonist).[143] However, none of these drugs has been prospectively evaluated for the treatment of MDMA acute toxic reaction.Caution may be warranted in using antipsychotic agents when treating MDMA intoxication. Antipsychotics decrease the seizure threshold, and blocking dopamine receptors may affect the thermoregulatory system leading to hyperthermia or exacerbation of existing hyperthermia. In addition, SSRIs may further increase serotonergic transmission by blocking the reuptake of synaptic serotonin, possibly raising the risk for development of the serotonin syndrome or aggravating already existing hyperthermia.[144]
Hepatotoxicity
Owing to the risk for hepatotoxicity, it would be prudent to monitor liver function in persons suspected of taking MDMA,[119] and any person with unexplained jaundice or hepatomegaly should be screened for a history of MDMA use.[93] Treatment will be primarily supportive (see Supportive Care section). If severe hepatic necrosis has occurred, transplantation may be the only option[101] and has been performed successfully in patients with acute liver failure due to MDMA use.[118]Supportive Care
Supportive therapy includes rehydration with intravenous fluids and lowering the temperature of the patient with use of cooling blankets or ice baths.[143] In some cases, lowering the body temperature may require infusion of cold intravenous fluids or peritoneal lavage with cool dialysate.[92] Crystalloids may be given to help treat both the profuse sweating that often accompanies MDMA acute toxic reaction as well as prophylaxis against acute renal failure secondary to rhabdomyolysis and myoglobinuria.[95] Furthermore, judicious fluid support may help with symptoms of hepatotoxicity as it may increase liver blood flow and prevent further hepatic damage.[119]
Summary
The use of MDMA is on the rise, especially over the last couple of years. Although it causes pleasant sensations, MDMA can be a very dangerous drug when used recreationally. Particularly severe adverse reactions include hyperthermia, rhabdomyolysis, DIC, renal failure, cardiac complications, intracranial hemorrhage, and hepatotoxicity. The long-term neurotoxic effects, particularly in the serotonergic system, of MDMA have not been fully elucidated. It is imperative that clinicians be familiar with the symptoms and treatment options for acute toxic reaction to MDMA.--------------------------------------------------------------------------------
poster:Larry Hoover
thread:218347
URL: http://www.dr-bob.org/babble/20030411/msgs/219191.html