User:SpencerMorrissey
Introduction
Ecstasy is the commonly used name to designate an amphetamine derivative, the 3.4-methylendioximetanphetamine (MDMA), a prototype of the so-called "design or synthesis drugs". These substances (Table 1), of characteristics similar to amphetamine and mescaline, are not products of new synthesis, contrary to what might seem, but are derived from drugs that never came to market or were abandoned due to lack of clinical effectiveness and subsequently passed to the clandestine market1.
The use of synthesis drugs has acquired, in recent years, great relevance in certain groups of young people, basically in urban media and under a pattern of weekend use, associated with play activities, although, at present, there is a phenomenon of wide expansion towards rural media. Among the reasons for this rapid expansion, we must mention the false idea of consumers of a null toxicity and the lack of risk for health, together with the conviction that their use ostensibly improves the capacity of interpersonal and fun relation2.
Historical background
The MDMA was synthesized in Germany in 1914, by Merck Pharmaceutical Company and patented as anorexigenous, with the patent number 274.350. However, despite the fact that it never came to market, the Edgewood Chemical Warfare Service of the American Navy was interested in this substance (called "experiment agent number 1478") and, in 1953, performed various experimental tests at the University of Michigan, which determined their toxicity in animals, results that were not published until 20 years later, when the information was unclassified. The first report on the psychoactive effects of MOTAPM on the human being was published by Shulgin and Nichols in 1976, and it states: "Within the effective dosing range, between 75 and 150 mg taken orally, the effects are noticed very quickly, almost always half an hour after its administration... There are few physical indicators of intoxication and psychological sequelae are practically nonexistent. Qualitatively, the drug seems to evoke an altered, easily controlable state of consciousness with emotional and sensual suggestions."4
In the 1970s, ecstasy was used by a group of U.S. psychiatrists, as a supporter of psychotherapy, given its ability to facilitate communication between the patient and his psychiatrist.5 Although toxicity in humans was not studied, this drug began to become popular in the late 1970s, in the framework of psychodelic and underground culture, when a Californian laboratory came to manufacture the MOTAPM, accompanied by an advertising that invited to live an extalent experience. The drug was sold on the market with different names: "emphaty", "love-drug", "essence", "adam", "clarity", "XTC", "zen", "banana split", "M strangerM", and the name "éxtasis" was most popular. Since 1983, it began to document its use as recreational drug. Among the most commented characteristics of this substance and other related features were the intensification of communication and the exploration of interpersonal relations, so they were called "empatogens" (generators of empathy). But, on the other hand, the capacity described by some subjects that ecstasy allowed them to maintain an internal contact or to come into contact with oneself, and facilitated the communication of their internal emotional states, has conditioned that, both to the ecstasy itself, and to some similar substances, as the 3.4-methylenendioxianphetamine (MDA) or the 3.4-methylenedylaxygenoustamine,
However, in 1985, by the emergency procedure, the DEA (Drug Enforcement Administration) of the United States and the WHO Commission on Narcotic Drugs, in 1986, included ecstasy in List I of the United Nations Convention on Psychotropic Substances (Vienna Convention, 21 February 1971). In Spain, it was included in its corresponding list by Ministerial Order of 6 June 1986. These prohibitions triggered a huge controversy, as their inclusion in the aforementioned list took place without specific studies on humans, based primarily on the neurotoxicity caused by the analogous MDA. The confusion created came to our environment and, while the National High Court (Section 1.a of the Criminal Chamber of 12 January 1994), based on expert reports, described the MOTAPM as a low-hazard substance, the Supreme Court considered it "very harmful to health" and, therefore, its illegal traffic was classified as a crime against public health.5-6. The controversy has been moving to different social strata, with groups favorable to consumption, which use the Internet7 network as a communication element, compared to authors who consider consumption to be high risk8, or those who point out that there is no tangible evidence of neurotoxicity.9
With the birth of the Acid House movement in the late 1980s, the consumption of ecstasy experienced its greatest boom, coinciding with the appearance in the market of the first pills manufactured in large Dutch laboratories. These were ritual meetings in which, according to the press of the time, the mystique of trance, drug use and sexual practices was combined.10 This movement found its maximum expression, with the corresponding peculiarities, on the island of Ibiza, and from there it was exported to the London environment. Precisely, the first cases of acute intoxication and MDMA consumption deaths were reported in the United Kingdom during the second half of . In our midst, the "Kanao Route" is the heritage of these movements, which under the banner of the "machine music", enjoyed great preaching among certain groups of young people during the years, and was associated with a great accidentality in the weekends and at the end of large drugs. In 1996, the first case of death by acute reaction during the consumption of ecstasy was reported in Spain.
Epidemiological data and consumption patterns
Although the epidemiological studies on ecstasy consumption have a significant bias, due to the lack of representative samples, the lack of veracity in the response to the surveys, given the illegality of the substance, etc., some data have been published that may give an idea of the magnitude of this type of consumption1: in the United States, 2 per cent of the students in secondary schools reported having consumed MDis As a summary, the percentage of consumers among European schoolchildren ranged from 8-9% of the Netherlands, Ireland and the United Kingdom to 1-2% of Denmark, Finland and Sweden. In global terms, Landry14 estimates that MOTAPM has been consumed by 6.4 million individuals.
In Spain, according to the Domiciliary Drug Consumption Surveys, the use of these design amphetamines in the last 12 months was 3 per cent of the student population aged 14 to 18 in 1994 and 3.9 per cent in 1996, while in the 1994 survey, 3.5 per cent of the respondents acknowledged having consumed it at some time and in 1996, 5.1 per cent. In the Community of Madrid, these figures reach 3.9% of the employed working population and 6.4% of the unemployed, and highlights the age range between 16 and 24 years16, percentages similar to those obtained in the Basque Country, where 4.1% of the youth between 13 and 19 years reported having consumed these substances17. In a study on a sample of 3,634 young people who served military service in Asturias between 1995 and 1999, Bobes et al18 found a prevalence of MDMA consumption throughout the life of 10.9% (7.8% in the previous year and 4.5% in the previous month). Despite the fact that the data provided by the Spanish Observatory on Drugs (OED)19 in its 1998 Survey on Drugs to School Population confirmed a certain slowdown in the usual and sporadic use of design drugs, which fell to the figures published in 1994, in the Report No. 5 of this observatory20, where data from the Survey on Drugs to School Consumers are collected during the period, an increase in cocaine is confirmed. 5.7 per cent of the students surveyed reported having used design drugs sometime in their lives, 4.8 per cent in the past 12 months and 2.5 per cent in the last month.
It should also be borne in mind that an important characteristic of the use of ecstasy is the rare thing of its unique use, since it is common to polyconsumption with other substances: cannabis (90.9%), alcohol (87.2%), amphetamines (41.3%), cocaine (40%), opiates (8.9%), etc.16. Similar figures are reported in the OED's 5th report regarding the secondary student population: cocaine (50.9%), cannabis (88.7%), hallucinogens (48.8%), alcohol (98.1%), tobacco (80.5%). On the other hand, most consumers of this substance (up to 80%) stop using it before 30 years.21
In relation to consumption patterns, different types appear to exist. On the one hand, the use of this drug has been proposed, under a certain health control, as a psychotherapeutic agent, in order to facilitate communication between the patient and his interviewer. However, this method lacks the authorization of the FDA and other health administrations, and is purely anecdotal. Moreover, as Schuckit22 says, the scant controlled studies in this type of use conclude that there is no therapeutic benefit with the use of this substance.
The main and most problematic pattern of consumption must be circumscribed in its use as a recreational substance. In this way, ecstasy is consumed preferably in parties with repetitive music at high volume (scores with music "machine", "acid", "raves", "bakalao" or "Baleares sound") and in areas where there is usually a high temperature, which can produce different psychic and physical effects23-24. The usual dose, in this type of recreational consumption, is usually 1-2 tablets, whose MDMA content ranges from mg per tablet25. In our country, a study of the psychosocial and psychopathological profile of ecstasy consumers has been carried out by the Psychiatry Group of the University of Oviedo, which highlights that none of the subjects studied had previously requested public or private clinical assistance. These subjects maintain regular contacts with other drug users and consume ecstasy exclusively during weekends, consumption that relate to playful activities and always in the company of other people. The group's profile corresponds to the sensation seeker, with ever-changing animal states and high levels of anxiety and impulsivity. The search for new ways of having fun or escaping boredom would be the apparent reason that could lead these people to using this type of design drugs26. The average age of ecstasy consumption in Spain, in 2000, was 17.9 years.20.
Finally, there is a third type of consumption, which does not appear to be implanted in our environment, called "new age". It is a spiritualist movement that considers the MOTAPM as a substance that facilitates communication and is capable of inducing positive moods, feeling of intimacy and tranquillity, that improve empathy and communication among practitioners of this ideology.27
The attractiveness of the MOTAPM can therefore be justified in two main reasons. Attribution of their therapeutic and/or spiritual benefits and their renowned euforizing and sensual properties. Most users appreciate both qualities, although they show considerable disagreement regarding their relative importance. In general, individuals who use the MOTAPM as a therapeutic and spiritual helper do not actually use other drugs, except for psychedelics. On the contrary, those who seek euphoria or sensuality associated with ecstasy generally use a broad spectrum of drugs and describe finding in ecstasy some of the qualities previously sought with other substances, such as cocaine26.
In recent years, as Boot et al25 relates, MOTAPM usage patterns seem to change, as parenteral consumption has increased, the intervals between consumptions have been reduced, as well as the intake of multiple tablets in one time. In these cases, the risk of neurotoxicity is obviously quite higher.
Physical-chemical properties
The MDMA is, as discussed, a derivative of feniletyilamine, as well as mescalin and amphetamine. Figure 1 represents the chemical structure of the MOTAPM; it is, in its pure form, a white powder of bitter taste. Initially, these products were presented in the form of capsules, but at present they are usually found in the form of tablets (mg of weight), with different colors, among which stand out the white, gray, beige and pale yellow, and apparently decorated. It is important to note that the illicit manufacture of ecstasy is relatively simple and that, in most cases, these galvanic preparations contain other substances in its composition, sometimes even in greater proportion than the CDM itself. Common components of ecstasy are often found to include amphetamines and other derivatives such as MDEA, MDA, MDB (3.4-methylenedioxyphenylbutanamine), caffeine, LSD, cocaine, codeine, phenciclidine, estricnine, ketamine or efedrine. Sometimes, ecstasy is adulterated by galvanic supports such as starch, sacrose or lactose, cellulose, etc. In Spain N-etil-MDMA is very common, which, at some time, has been able to overcome the MDMA proportionally. On the other hand, it should also be borne in mind that the active principle content can differ tremendously between the different tablets existing in the clandestine market (differences up to 5 times in the amount of MDMA or any of its derivatives).
Figure 1. Chemical structure of the MOTAPM.
Finally, it should also be considered that MOTAPM is presented as a racemic mixture, and contains a similar amount of the 2 enantiomers. Some authors point out that the S-(+)-MDMA form is more toxic29 and responsible for the precocious dopaminergic effects of ecstasy30.
Pharmacological aspects
Pharmacokinetic Characteristics of MDMA
The specific study of the pharmacokinetic properties of MOTAPM in humans is very low31, given the illicit characteristics of its consumption and use. Therefore, most of the existing data up to the mid-1990s came from the general pharmacokinetics of feniletyilamines and certain metabolic studies in rodents32. Subsequently, some specific pharmacokinetic studies were conducted in humans33-35.
The most common path of administration of MOTAPM is oral, and consumers of this substance usually do so with an empty stomach, in order to achieve faster absorption. Although there are no specific rigorous studies, the absorption process should be very fast36, as after min the first effects of the substance are observed. If we extrapolate this parameter to other amphetamines, the absorption could be complete at 3-6 h of intake. Helmlin et al34, in a study with 2 subjects, obtained, after the oral administration of ecstasy, a 2-h CT for the MDMA and 6.3 h for the MDA metabolite. In this regard, it is necessary to bear in mind that although the oral administration is the most used, there are 3 other possible pathways: intravascular, intranasal and inhalatory (smoky ecstasy).
The organic distribution of phenyl-isopropil-amines is very wide, since they are substances that are well undergoing the hematoencephalic barrier, with the consequent risk of accumulating in the central nervous system (CNS). They are also widely distributed, albeit to a lesser extent, in the kidney and lungs. Also known are the plasma protein binding indices of new design drugs, although amphetamines, as a group, have very low union rates (15% methylphenidate, 16% amphetamine and 34% phenfluramine).
For its part, the metabolism of amphetamines is liver, and a high proportion is eliminated without metabolizing by urine. In fact, in a case studied, for the administration of a single subject of 50 mg MDMA, 7% metabolized to MDA and 65% excreted without metabolizing2. In the rat, the liver metabolism of the MDMA is similar to that of amphetamines, and 2 main metabolites are obtained, one via N-demethylation, which gives rise to MDA, and another pathway O-dealulation, which originates DHMA (3.4-dihydroxymetanphetamine)32. The enzymatic complex of cytochrome P-450 would be involved in the DHMA genesis, specifically the enzymatic subfamilies CYP2D and CYP2B37. For its part, in humans, the participation of CYP2D6 isoenzyme in the metabolism of MDMA to DHMA33 has been proven in vitro. Certain authors estimate that the metabolism of MOTAPM can be saturable, with the subsequent risk of accumulation and induction of toxic phenomena36. In addition, it should be mentioned that approximately 10 per cent of the Caucasian population, the activity of the CYP2D6 is notoriously reduced, which prolongs the average life of elimination, and makes these subjects especially susceptible to adverse reactions of the substance.33
On the other hand, Camí et al35 have confirmed that the MDMA has a nonlinear pharmacokinetics, for ma that small increases in the administered dose are translated into disproportionate increases in plasma concentrations (Table 2), which may pose a significant risk of acute poisoning and explain certain cases of death from ecstasy consumption.38 Thus, this fact can also explain why of the highest proportion of physical and psychological adverse effects observed in women39, given their lower average body weight.
The percentage of urinary removal of the MDMA depends on the pH of the urine, so that its acidification increases significantly the elimination, so this strategy is usually used in cases of intoxication. For its part, the average life of elimination, in one of the studies commented, was 7.6 h2.
MOTAPM Action Mechanism
With regard to the MOTAPM action mechanism, it should be borne in mind that almost all studies that have been carried out have been carried out in laboratory animals, basically in rodents and primates, and that the results obtained are not always extrapolated to the human being.
In laboratory animals, the acute behavioral effects of MOTAPM appear to be more similar to those of psychostimulants than those of hallucinogens. Drug discrimination studies show that MDMA is replaced by amphetamine, but is not replaced by hallucinogen DOM (2.5-dimetoxi-4-methylamphetamine). In addition, various high-power serotonergic agents are also able to replace, in the evidence of discrimination, MOTAPM, such as phenfluramine, norphefluramine and MDMA counterpart N-methyl-1-(1,3-benzodioxol-5)-2-butanamine (MBDB). Generally speaking, the effects of the MOTAPM on locomotive activity are different from those of amphetamine and appear to be mid-by-sided by a serotonergic mechanism, while the effects of the MOTAPM on operational conduct responses appear to be more of the stimulant type than of hallucinogenic type40.
In any case, experiments in laboratory animals describe two different phases in relation to the action of the MOTAPM; an acute phase, which lasts approximately 24 hours, and a chronic phase, whose effects last up to 12 months or even more. The mechanism of action of both stages does not have to be associated.41
Neurochemical effects induced by MDMA in acute administration
Studies conducted in rat brain synaptomomas show that the application of MDMA produces a release of serotonin (fig. 2), as well as dopamine, a phenomenon that does not depend on calcium. In fact, an acute dose of MDMA can cause the release of up to 80% of centrally stored serotonin.43 In this regard, it should be noted that MOTAPM is a serotonin-releasing agent to a greater extent than dopamine in vitro. Thus, at the sterile level, the release of serotonin occurs at concentrations 10 times lower than those necessary to stimulate the release of dopamine44. On the other hand, recent studies, which use in vitro techniques, have also confirmed the ability of the MOTAPM to release noradrenaline, with a power even similar to that of serotonin45.
Figure 2. Temporary course of the cortical concentrations of serotonin in the rat. TRI-OH (tryptophan-hydroxylase).
The mechanism by which the MDMA releases serotonin appears to be mediated by a modification of the membrane conveyor of this, since the effect is blocked by fluoxetin, citalopram or imipramine. Preclinical studies have confirmed that fluoxetin decreases, depending on the dose, the release of serotonin induced by MDMA in the prefrontal cortex and the striated nucleus.46 Similarly, the release of noradrenaline produced by MDMA in hippocampus cuts is blocked by demethylimipramine, which indicates that this effect is also produced in the noradrenaline conveyor. Since the MOTAPM does not accumulate in the synaptosomas, it is thought that the ability to release monoamines is produced by changing the direction of the conveyor flow of these or, what is the same, the MOTAPM would reverit the flow direction of the neurotransmitter47.
In addition to stimulating the release of serotonin, dopamine and noradrenaline, MDMA also increases the concentrations of the three monoamins in the synaptic hendid, inhibiting their recaptation48 and delaying their metabolization, thanks to their ability to inhibit monoaminooxidase (MAO). The possibility of the MOTAPM sharply stimulating dopamine synthesis in the striated core has also been postulated.49 This effect appears to be mediated via 5HT2 receptor stimulus.
All of these observations suggest that the main mechanism by which MDMA can acutely affect neuronal excitability in the brain is to increase extracellular concentrations of serotonin and catecholamines and, consequently, activate serotonergic, dopaminergic, and noradrenergic receptors. But, in addition to these facts, changes in the neuropeptideal neurotransmission induced by MDMA have been verified. Thus, the acute MDMA administration increased the concentration of neurotensin in homogenized neoestriated, accumbens and black substance.50 However, these changes seem to be secondary to dopaminergic stimulation51, as they can be blocked by D1 receptor antagonists.
As a result of the mechanisms described, it has been possible to demonstrate, through studies of in vivo microdialysis, that the MDMA administration causes a marked increase in extracellular dopamine in the brain regions that are richly inervaged by axons of dopaminergic neurons. The acute systemic injection of MDMA increases extracellular concentrations of dopamine in the striated nucleus. In addition, serotonin concentrations are also increased in this brain nucleus, but to a much lesser extent than dopamine concentrations.52
Irrespective of the indirect effects caused by the release of monoamines induced by the MDMA, this substance exhibits direct actions, as a result of its ability to stimulate different types of receptors53: 5HT2, *2-adrenergic (increase of blood pressure), H1 histaminergic and M1 muscarinic (effects on motor activity and memory). The global effects of the MOTAPM are therefore a consequence of both actions, and their breakdown is even more difficult given the existence of these pre- and post-synaptic receptors. However, most studies indicate that the predominant effects are the result of the release of monoamines.41
Neurochemical effects induced by the repetitive administration of MOTAPM
The repetitive administration of MDMA to the experimental animal (rata, guinea pigs and primates) causes a long-lasting decrease in neurochemical parameters and histological tests of serotonergic functionalism in the brain trunk. In this sense, the MDMA administration induces a reduction in the thysular concentrations of serotonin, as well as its metabolite, 5-hydroxy-indole-aacetic acid (5-HIAA), and the activity of the tryptophan-hydroxylasa, a limiting step of serotonin synthesis44. Described deficits may persist for months or even years, depending on the area studied and the type of animal of experimentation (Fig. 2).
In addition to the changes described, there is also a decrease in the locus of serotonin recaptation in different brain areas (corteza, caudated core, hippocampo, accumbens core, olfactory tube and other thalamic cores). These changes appear to be specific to the airlift, while atelaminergics are not affected.54 Higher doses of MDMA (up to 40 mg/kg) also produce a decrease in the concentrations of noradrenaline and dopamine in cerebral cores of the cobaya55. Asymism, in the rat, an upward regulation of the 5-HT2A post-sympathy receptors has been described in the occipital cortex due, possibly, to a compensatory effect of the low concentrations of synaptic serotonin.56
The neurobiological effects discussed are more pronounced and more intense in primates than in the rat. Serotonergic depletion and decrease in serotonin recaptation locus in the cerebral cortex of monkeys occur more in a more pronounced way and at lower doses than those used in the rat. For example, a repeated dose of 2.5 mg/kg MDMA causes a reduction in the density of serotonergic axons in the primate similar to that caused in the rat by a repeated dose of 4 mg/kg57. Similarly, while in this rodent the biochemical changes detected persist up to 32 weeks, in the primates these modifications are more durable, have been studied up to 18 months, and can become permanent58. Also, neurohistological changes are more pronounced in the monkey; while in the rat, an axonal regeneration and a re-inervation of the affected region have been described, from the neuronal somas of the nuclei of the raf, which are not affected (the so-called " neuronal pruning"), the histological changes detected in the primate appear to be permanent.
The lesion of serotonergic axons, observed in rats and primates, occurs by a mechanism not perfectly diluted, but in which dopamine appears to play a fundamental role. Thus, it is known that substances that reduce the release of dopamine induced by MDMA, such as alpha-methyl-parathyrosine, reserpina, D2 antagonists, such as haloperidol, or 5HT2 antagonists, decrease the serotonergic toxicity produced by MDMA60-62. On the contrary, those substances that enhance the release of dopamine induced by MDMA, such as L-dopa or 5HT2 agonists, accelerate and increase the serotonergic aggression produced by the drug63 (fig. 3).
Figure 3. MDMA hypothetical toxicity mechanism on serotoninergic neurons. DA: dopamine; 5HT: serotonin; DOPAC: acid 3.4-dihydroxyphenylacetic; H2O2: hydrogen peroxide; MAO-B: monoaminooxidase type B.
In short, some authors64 suggest that the intimate mechanism by which serotonergic axonal degeneration occurs could follow the following sequence (Fig. 3): the MDMA would abruptly deplete the neuronal concentrations of serotonin, which would make these neurons more vulnerable to the toxic process. In turn, the MOTAPM would significantly increase the synthesis and release of dopamine, which would be captured into the serotonergic terminals, where it would be removed by MAO-B, generating hydrogen peroxide, which would result in the peroxidation of the lipids of the cell membrane. The latter process would cause the phenomenon of degeneration and destruction of serotoninergic axons. In this sense, MAO-B inhibitors, such as prenile, would be able to protect the serotonergic axonal destruction, because it would decrease the peroxidation of the lipids of the neuronal membrane64.
The MTAM neurotoxicity mechanism also appears to involve extradopaminergic-type mechanisms. Thus, excitatory amino acids could be involved. In this regard, while a glytamic acid increase after MDMA administration is not observed, Colado et al65 showed that glytamatosergic receptor antagonists, such as dizolcipin, protect from MDMA-induced toxicity. However, this effect seems to be because dizolcipin protects from MDMA-induced hyperthermia, as this drug is ineffective if it keeps the animal at temperature of 38.4 °C. A fact that speaks in favor of what is said is that MOTAPM does not exert toxic action on serotonergic axon when low temperatures are maintained in the experimental animal. On the other hand, selective serotonin reuptake inhibitors (ISRS), such as fluoxetin and citalopram66, antagonize the neurotoxicity induced by MDMA, without the need to modify the temperature. Therefore, the hyperthermia produced by MDMA and the release of serotonin produced by this substance seem to contribute, independently, to the neurotoxicity exercised by this substance.
On the other hand, as we have already commented, although most of the effects induced by the MDMA are secondary to the release of monoamines, the MDMA per can also stimulate 5HT2, 5HT1, receptors *2 and muscarinic receptors, while on the contrary, it has a low affinity over dopaminergic receptors53 D1 and D2. The indirect stimulus of 5HT1B receptors could play a relevant role in hyperactivity mediated by MDMA. In fact, experimentally, 5HT1B antagonists are able to reverse the induced hyperactivity by low doses of MDMA, an effect not observed with 5HT1A antagonists, while 5HT2A antagonist would block the high-dose hypermotility of MDMA67-68. For its part, the stimulus of 5HT2 receptors is more manifest after chronic treatment, when the depletion of serotonin has already occurred. This 5HT2 affinity could explain certain ethological characteristics described by Navarro and Maldonado69 in male mice, such as a marked reduction in offensive behaviors and social research or an increase in distance exploration and defensive behavior. For their part, in humans, the stimulation of these receptors could explain certain psychological symptoms of visual type, such as flashbacks and hallucinations70, which are slightly attenuated with the co-administration of the 5HT2 ketanserina antagonist71.
Other authors postulate the generation of a toxic metabolite of this drug as a mechanism of MDMA neurotoxicity.72 As discussed, the MDMA is metaboly in vitro giving rise to the metabolite DHMA, thanks to the catalytic action of the debrisoquina-hydroxylasa enzyme. In turn, this metabolite is oxidized, so it generates the corresponding compounds with catecol and quinona structure33, whose subsequent metabolism causes the formation of free radicals, which would induce a phenomenon of oxidative stress and corresponding neuronal damage72. In this sense, the administration of free radical trapped compounds, such as alpha-phenyl-N-terbutyl-nitrone (PBN), prevents the genesis of free radicals induced by MDMA and protects against the neurotoxic action of this substance.73
In conclusion, the MDMA administration causes a series of long-term effects on serotonergic axons and, probably, dopaminergic in the striated core and the accumbens core. These late changes can explain the psychopathological manifestations described by patients, after long periods of the last exposure to MDMA74.
Role of the Mesolimbocortical Way in the phenomenon of dependence on MOTAPM
The mesolimbocortical dopaminergic pathway, and specifically the accumbens core, seems to be capital in the phenomena of reward caused by various abuse drugs.75 This route is mainly originated in the ventral tegmental area (ATV), where dopaminergic axons are mainly projected to the accumbens core, although they also reach the olfactory tubercle, the frontal cortex, the tonsil and the septal area. Different pharmacological agents, such as opiates, alcohol, amphetamines and cocaine, have the common property to increase extracellular concentrations of dopamine in that nucleus76 (Fig. 4). Similarly, the systemic administration of MDMA also increases extracellular concentrations of dopamine in this region, which could explain the strengthening properties of this substance, experimentally observed (Table 3). In addition, White et al78 demonstrated that the MDMA directly administered in the rat accumbens core increases extracellular concentrations of both dopamine and serotonin, an increase that is essential in the strengthening properties of these substances. From a quantitative point of view, this increase in dopamine, following the acute administration of MDMA, was higher in this nucleus than in serotonin (Fig. 5). Infusion of serotonin or serotonergic agonists at this level increases the release of dopamine, so it is thought that the release effect of dopamine induced by MDMA involves serotonergic mechanisms.
Figure 4. Effect of MOTAPM and other abuse drugs on mesocorticolymbic dopaminergic pathway. The administration of these agents causes an increase in extracellular concentrations of dopamine in the nucleus accumbens. N. Acc: kernel accumbens; ATV: ventral tegmental area; DA: dopamine.
Figure 5. Monoamine concentrations in rat accumben core, following the MDMA administration. DA: dopamine; 5HT: serotonin.
The role of serotonin in the nucleus accumbens is less known than dopamine, although it is known that many abuse drugs increase extracellular concentrations of serotonin in that nucleus78. In addition, serotonin would increase the release of dopamine at this level. Similarly, the role of the excitatory amino acids (glutamate and/or aspartate) that are present in this mesolicimbic way is not known.79 (Fig. 4).
It has also been found that the administration of MOTAPM reduces the exciting activity of other pathways involved in these phenomena, as a result of the increase in extracellular serotonin that it produces. Such is the case of the excitatory pathways that, coming from the medial prefrontal cortex, reach the accumbens core. The rheal core of the rafe is the most important source of serotonergic fibers that end in the accumbens core, and are the most vulnerable to the repetitive action of the MOTAPM. The MDMA can act directly in the spinal core, releasing serotonin, which ultimately inhibits the discharge of these neurons over the accumbens core. However, these effects can be counterbalanced by the direct release of serotonin and dopamine on the ATV and the accumbens51 core.
The acute administration of MDMA partially inhibits spontaneous discharges of dopaminergic neurons of ATV and of the black substance, a effect mediated by an increase in the release of dopamine and partially counteracted by the release of serotonin80. In this sense, the exact mechanism by which the MDMA inhibits dopaminergic discharges on the ATV is not known. However, this inhibitory effect, caused by other drugs, such as cocaine, is due to hyperpolarization due to blocking of dopamine recaptation and inhibiting the release of gammaaminobutyric acid (GABA), as a result of the blocking of serotonin recaptation81. In both cases, the complexity of actions is manifest, due to the additional capacity to release dopamine and serotonin from pre-synamitic endings.
On the other hand, data involving the accumben core in the mediation of the drug-induced reward of abuse, both stimulating (cocaine, amphetamine, MDMA), and depressors (opiates, alcohol and certain foods), are multiple76. In this sense, the MDMA microiontophoretic application causes an inhibition of the electrical discharge induced by glutamic acid, similar to that produced by dopamine or serotonin, so it is thought that the effect caused by the MDMA will be mediated, at least in part, by the release of these amines, which, by acting on the pre-synaptic terminal, will reduce the excitatory tone.
In fact, in rats treated with MDMA for 4 days it was observed that the inhibitory effect of dopamine and serotonin on the electrical discharge produced by glutamate in neurons of the accumbens kernel was virtually abolished after more than a week of the last administration of the drug. Therefore, treatment with neurotoxic doses of MDMA selectively reduces the inhibitory effects of dopamine and serotonin on the neurons of the accumbens core, beyond a week of the last administration. This phenomenon is opposed to the expected dose of cocaine, as repeated cocaine administrations are accompanied by increased concentrations, both dopamine and serotonin. On the contrary, repetitive doses of MDMA can cause only an initial episode of dopamine and serotonin increase, followed by repeated episodes of extracellular increase of, only, dopamine. Since cocaine is not neurotoxic in serotoninergic axons, this may explain the opposite effects that are observed with both drugs of abuse, as well as the absence of craving observed with MDMA during the abstinence period, a phenomenon that occurs in cocaine users.
From a clinical perspective, and bearing in mind all these neurobiological events, Cottler et al82 have recently studied and for the first time the ability of the MOTAPM to cause abuse and dependency disorders in humans. These authors have used DSM-IV diagnostic criteria, and have confirmed that 34% of a sample of 52 adolescents and young ecstasy consumers met abuse requirements and 43% dependency criteria, which confirms the alleged addictive nature of this substance, proven experimentally. In addition, as with amphetamines and cocaine, there is an accused phenomenon of pharmacodynamic tolerance for the purposes of the chronic administration of ecstasy83.
Drug and toxicological effects of ecstasy in humans
Factors that limit the knowledge of the neurobiological bases of the action of ecstasy
The knowledge of the neurobiological bases by which any psychoactive substance acts is not simple, but in the case of MOTAPM there are different additional problems that make this objective difficult.41 On the one hand, as a drug included in List I of WHO, the study of its pharmacological and therapeutic actions can only be carried out with strict official permits, which makes it extremely difficult for the commission of controlled clinical studies with this drug. From an ethical perspective, some authors84 have defended their refusal to the experimental administration of MOTAPM in humans, even though the data that could be obtained were tremendously interesting, as they claim that the long-term neurotoxic effects, experimentally demonstrated and in small populations of MDMA consumers, would morally invalidate the initiation of such studies. In this sense, the design of double-blind, placebo-controlled trials with repeated doses meets all the requirements to consider them unviable ethically.83 On the other hand, the large number of pollutants that form part of the so-called "ectasis", makes many of the toxicological effects that are observed after the consumption of this substance are due to other active principles that are sometimes even more dangerous than the MOTAPM itself or which can enhance its toxic and behavioral effects. In addition, the neurobiological actions of ecstasy seem to be different, according to their different patterns of use.
All of these factors, which condition a scientific documentary body on the toxic effects of MOTAPM relatively low compared to other substances of abuse, such as cocaine and heroin, make some authors85, unlike those previously commented, raise certain ethical dilemmas about human research restrictions, especially given the high prevalence of the use of this substance.
Subjective effects of ecstasy consumption in humans
The description of the subjective effects caused by the consumption of ecstasy is very variable; therefore, we have focused mainly on the works of Cohen86 and Parrott et al87. In the first one, a total of 500 ecstasy consumers were interviewed about the psychological and physical symptomatology perceived by these individuals, in the short and long term, while in the second one was found on this type of symptomatology to a sample of 282 subjects, classified on occasional consumers (1-9 occasions), moderate consumers (10-99 occasions) and large consumers (resource 100 times). The results of these interviews are reflected in figures 6-8.
Figure 6. Physical symptoms of ecstasy consumers (n = 500). Difference between short- and long-term symptoms.
Figure 7. Psychological symptoms of ecstasy consumers (n = 500). Difference between short- and long-term symptoms.
Figure 8. Main symptoms observed in ecstasy consumers, depending on the frequency and intensity of consumption (n = 282).
Generally speaking, the immediate subjective states most frequently induced by MOTAPM include a certain degree of euphoria, which is different according to the subjective descriptions of each individual, increase of energy, and sexual excitement. Most consumers note that the drug creates a sense of "love", happiness, peace and capacity to "connect". However, a series of less comforting effects, such as bruxism, are recounted, which sometimes requires clinical assistance, and nausea. The residual effects include insomnia, feeling of depersonalization, depression and flashbacks, along with physical effects of the type of headaches, vomiting and lumbalgias (Table 4). Many of these symptoms continue time after MDMA is consumed. Some individuals present depression, which may appear months and even years later, after the completion of the pleasant effects of the drug. Bobes et al18 confirm that the young consumers of MDMA score, during the year prior to consumption, significantly more in the subscales of neuroticism and psychoticism of the Eysenck Personality Questionnaire, as well as in the Zuckerman Sensation Search Scale. Contrary to what happens with other psychodelic agents, MOTAPM often produces changes in visual perception86. Fox et al88 have recently confirmed the negative effect of MOTAPM on learning and memory consolidation processes. These effects would be related to serotoninergic dysfunction in the temporal lobe.
As noted above, the MOTAPM causes an increase in serotonin release by interacting on the conveyor of this indolamine. This state of "hyperserotoninergia" would be responsible for much of the subjective symptoms of a psychological nature that ecstasy consumers report, as well as other adverse effects, such as those of the cardiovascular sphere (Table 4). Precisely, some studies have confirmed that these psychophysiological changes are reduced with the co-administration of ISRS, such as fluoxetin and citalopram71. However, these adverse effects, even reduced in intensity, can be longer in time in simultaneous MDMA and ISRS consumers, as these antidepressants are inhibiting agents of CYP2D hepatic isoenzymes6, precisely those responsible for much of the MDMA metabolism. On the other hand, it has been observed that pre-treatment with haloperi dol, a dopaminergic antagonist D2, causes a reduction in the euphoric state induced by MDMA, leading to a dysphoric state and a slight increase in levels of anxiety71.
From the above-mentioned clinical research, it can be concluded that there is no standard criterion in relation to the problems caused by MOTAPM with the number of times the substance has been consumed. Thus, Cohen86 states that there is no relation between the number of times the subject has been exposed to the drug and the appearance of symptomatology, which might suggest that the adverse effects on the CDM might even occur after a minimal exposure to this substance. For their part, Parrott et al87 conclude that the incidence of problems attributed to the MOTAPM is directly related to the number of times it has been consumed, highlighting, in this regard, the memory problems, reported in 19% by occasional consumers, in 52% of moderate consumers and up to 73% of large consumers.
Generally speaking, from a behavioral point of view, it can be noted that MOTAPM has similarities with both amphetamines and LSDs. Its sympathetic and alerting effects are similar to those observed with amphetamine, while the propensity to intensify sensory experiences seems closer to those of LSD89. These authors carried out a study with 21 polydrogodependents, MDMA users, LSDs and amphetamines, who completed a modified questionnaire of the mood profile, in order to indicate their typical sensations with each drug. The results of this work show that MOTAPM was considered as an agent with intermediate activity, superior to the LSD and lower than amphetamines, in terms of the feeling of energy, security and mental lucidity. However, in other humor profiles, the MOTAPM was more specific, and caused a greater sense of well-being, serenity and euphoria than the LSD or amphetamines. These results are similar to those reported by other authors in different countries90-93. In short, while some authors categorize MOTAPM as a hallucinogenic amphetamine, others have suggested that the CDM profile allows it to be included in a new class, which have called "entactogenic" substances.
Physical symptoms of ecstasy in humans
In addition to the subjective symptoms mentioned above, another series of physical symptoms have been described (Table 4), characteristic of sympathetic hyperstimulation, of a cardiovascular and neurological nature. Among them, there is dry mouth, hypersudoration and hyperreflexia, midriasis, increased blood pressure and horizontal nistagmus, as well as certain residual effects such as insomnia and anorexia94. Some of these patients, especially after the use of high doses of MDMA, may present hyperthermia and seizures, and may evolve to rhabdomiolysis, dissemination intravascular coagulation, acute kidney failure, and death. Davison and Parrott95 confirmed, through subjective reports, that between 80 and 90% of ecstasy consumers in clubs and nightclubs experienced an increase in body temperature, sweating and dehydration.
Certain cardiovascular complications observed in ecstasy consumers may be related to abnormalities in catecolaminergic functionalism, as confirmed by Stuerenburg et al96. These authors have determined the plasma concentrations of noradrenaline, adrenaline and dopamine in 159 ecstasy consumers, and have confirmed an increase in these, as well as a persistence of this noradrenergy hyperactivity in the interconsumption intervals, which could explain the phenomena of tachycardia, arrhythmias and hypertensive crises described in these subjects.
For its part, Sthephenson et al97 have experimentally demonstrated, as the MDMA administration is associated with an increase in the expression of the c-fos immediate response gene in different brain areas related to the symptoms discussed. Thus, as an example, they observed elevated concentrations of the expression c-phos in the supraoptic, medium preoptic, chewing, as well as in the cerebelous floculus, centers related to the control of the liquid balance, of the body temperature, of the motor activity of mastication and of the overall motor coordination, and possibly involved in the phenomena commented of hyponatremia, hyperactivity and
On the other hand, some authors have described how the regular and frequent use of MOTAPM causes a phenomenon of tolerance for the desired effects of ecstasy, as well as an increase in the adverse effects of this substance.90 These include a loss of memory98, sleep disorders and a higher incidence of psychiatric disorders99,100. In fact, MOTAPM and its derivatives are the substances of abuse that cause more acute psychopathological reactions that require urgent assistance (24.3% of the 110 episodes of emergency reported in Spain in 2000 directly related to the consumption of these substances), according to OED20 data.
The most serious toxic effects described in MDMA consumers can be grouped into 4 large groups: strokes, such as bleeding, thrombosis and brain infarction; acute liver failures, some of them with a fatal result; hyponatremias, either of a dilutional type, by excessive water consumption, or by inadequate secretion of anti-diarrheal hormone; malignant hyperthermias, which can lead to acute renal disease. We also have to bear in mind the possibility of a serotonergic syndrome, with all its symptomatological cortex; hyperactivity, mental confusion, agitation, hyperreflexia, fever, tachycardia, myoclonus, nistagmus, tremors, etc. In Spain, the latest OED data, for the year 2000, reflect 110 cases of emergency assistance for ecstasy, of which 58.3 per cent were due to overdose or acute poisoning, and 7 cases of acute reaction death (1.6 per cent of total acute reaction deaths during drug use).20
MDMA neurotoxic effects on humans
Ecstasy neurotoxicity has been demonstrated in different animal species, including primates. In humans, no histopathological studies have been conducted in this regard. However, it is known that MOTAPM in humans decreases the replacement of serotonin, as evidenced by the decrease in the concentrations of the main metabolite of serotonin, 5-hydroxy-indole-acetic acid (5HIAA) in cerebrospinal fluid of consumers of this drug, after 2 weeks of withdrawal, with respect to individuals control101. These consumers have also described a decrease in the response of prolactin to serotonergic agonists, such as l-triptófano102, m-chlorofenilpiperazina103 or l-triptofano102, m-chlorophenylpiperazina103 or
d-fenfluramine104. These data, together with certain symptoms observed in these patients, such as the alteration of sleep architecture and impulsivity disorders, make the thought of a possible lesion of serotoninergic neurons.
The great development that has taken place in recent years in the field of neuroimagen techniques has made it possible to gain significant progress in the study of the neurotoxic effects of MOTAPM, and the observations described previously with invasive techniques in experimental animals have been confirmed in humans. Thus, McCann et al105 have described, for the first time, the use of postitron emission tomography (PET), the toxic effects of MDMA on brain serotonergic neurons. To do this, they used 11C-McM-5652 as a linking of the serotonin conveyor, and observed, in chronic ecstasy consumers, a marked reduction of this conveyor, as well as a loss of serotonergic terminals, in all the cerebral regions, except in the thalamus. For their part, Semple et al106 have also confirmed this data, by means of computed tomography by emission of single photon (SPECT) and the use of 123I-ß-CIT as a ligand of serotonin conveyor, and have observed a significant decrease in the density of this conveyor, especially in neocortex. By using this same ligand (123I-ß-CIT), some authors have replicated the previous results, and have confirmed the neurotoxic effect of MDMA high doses consumption on serotonergic neurons, in several brain regions rich in this type of neurons. In addition, it has been observed that this effect is more significant in women, suggesting greater gender susceptibility in the neurotoxic effects of this substance.107.
Reneman et al108 have also studied in humans the effect of MDMA consumption on 5HT2A receptor density (through SPECT techniques with the 123I-R-91150 ligand) and on brain blood flow (through magnetic resonance techniques of perfusion), as well as the relationship between both parameters. After a 7-week period of consumption, these authors found, in certain cortical regions, an increase in the density of 5HT2A receptors (indicative of a low serotonin synaptic rate), which was correlated with a high value in the determinations of the cerebral blood flow (local vasodilation indicator), while in the areas where the density of 5HT2A receptors was low, the blood flow). These facts indicate that MDMA can also affect the cerebral vascular system.
The neurotoxic effect of the MOTAPM on the human serotonergic system has also been revealed through recent electrophysiological studies.109 These authors have evaluated serotonergic functionalism in 22 regular MDMA consumers, by measuring the attenuation of the neurological response to auditory stimuli, obtained in an electroencephalographic record (audive evoked potentials), and have confirmed a serotonergic dysfunction associated with the total amount of the consumed drug (bombed dose) and not the frequency of consumption.
Neurotoxic effects of chronic use of MDMA in humans may not be confined to serotoninergic neurotransmission systems, as appears to be derived from the Obrocki et al110 study. These authors have measured the metabolic consumption indices of glucose with PET, using 2-(18F)-fluoro-2-deoxi-D-glucosa (FDG) and have confirmed a decrease in their consumption in different brain areas, such as amigdala, hippocampus and cingulated cortex, and an increase in the nuclei and whorem and areas of Brodmann 11. The authors claim that these facts can secondaryly reflect mid-transneuronal effects by neurotoxic lesions of aferent serotonergic fibers.
These findings obtained with neuroimage techniques could be correlated with the high incidence of behavioral, cognitive and affective neuropsychiatric sequelae25, observed in the long term in chronic MDMA consumers (Table 5): psychotic symptoms, hallucinations, panic attacks, anxiety disorders, aggressiveness, depressive pictures, suicidal ideation, etc.112. In fact, recently, Lieb et al113, in a longitudinal retrospective study, with a sample of 2,462 subjects, have confirmed that MDMA consumers pose a significantly greater risk of psychiatric disorder, according to DSM-IV criteria, than non-consumer. On the other hand, since serotonin is closely related to other physiological phenomena, such as appetite or thermoregulation, as well as certain cognitive processes, it is possible that the alterations of these phenomena, observed in ecstasy consumers, are expression of lesions in serotoninergic regions.25 In fact, the Reneman group has confirmed a close correlation between the lesions observed with the previously commented neuroimagen (SPECT) techniques and a deficit in cognitive function, in which the memory capacity was evaluated by a repeat word test (Rey Auditory Verbal Learning Test)107. Similarly, Dafters et al114 have found, in chronic MDMA consumers, electroencephalographic records similar to those of elderly individuals and dementia affections.
However, the observation of some of these alterations in consumer subjects of unimportant amounts of ecstasy, is not the manifestation of brain damage, but rather the evidence of a predisposition or vulnerability to these diseases, mediated by a drug capable of modifying central aminergic functionalism115. On the other hand, the lesion of serotonergic neurons can initially be asymptomatic and manifest many years later, when the serotonergic function is very low. In this sense, C. Schuster's opinion is remarkable, when, being director of the NIDA (National Institute of Drug Abuse) in the United States, he stated that "we do not know if young MDMA consumers within 20 or 30 years, when they are 45, will begin to manifest the symptoms and signs of degeneration of the central nervous system that do not usually begin to be observed until the age of 70 or 80 years."
Therapeutic coordination of disorders induced by the consumption of ecstasy
First of all, it is necessary to differentiate between the treatment of the proper addictive behavior and the complications arising from its chronic consumption, and the approach of the patient under acute MDMA poisoning. In relation to this last aspect, in addition to gastric washing and punctual symptomatological treatment (convulsions, arrhythmias, acute psychiatric manifestations, etc.), there are specific aspects that need to be considered116, as a rapid cooling of the hyperthermal patient, in order to avoid rabdomiolysis and the risks of disseminated intravascular coagulation117, and proper hydration. Some authors recommend intravenous (i.v.) administration of dantrolene for the treatment of hyperthermia118, as well as muscle cramps and spasms. It has been confirmed that the acidification of urine facilitates the elimination of MOTAPM, but it must be prudent, as it can facilitate kidney failure by reducing myoglobin clarification.5. In patients with anxiety, agitation, panic attacks or seizures, use of short-lived benzodiazepines, such as lorazepam i.v. or intramuscular (i.m.), may be useful, and in case of arrhythmias, the administration of beta blockers or antagonists of calcium channels can be used27.
In relation to the psychic problems caused by the consumption of ecstasy (anxiety disorders, psychotic and affective, hallucinations and/or flashbacks, etc.), the use of the same pharmacological agents that would be used in the management of these pictures, regardless of whether they are induced by MDMA (benzodiazepines, antipsychotics or antidepressants).
On the other hand, in the pharmacological treatment of chronic consumption there are very few published data, although a number of drugs, such as ISRS, antioxidant agents and serotonergic precursors (triptophane or thyrosine), are being tested experimentally. Certain authors have published some cases that confirm the possible clinical usefulness of the ISRS in those patients with difficulty in quitting ecstasy119. Finally, we highlight the important role that is being given throughout Europe to a series of environmental and educational measures aimed at harm reduction (consumption in environments with high temperatures, intense exercise, dehydration, polyconsumption of substances, etc.)120. Recently, the Spanish Society of Psychiatry has published some Consensus Documents on the "Diagnostic and Treatment of Alcoholism and Other Units"121, which reflect the guidelines to be followed in the therapeutic approach based on the disorders induced by design drugs.
criminological and medical-legal aspects
The consumption of psychotropic substances and their consequences (abuse and/or dependence) not only cause health problems to society at present, but this problem transcends other areas, such as politics, economics and, of course, legal. Focusing on the consumption of ecstasy, its interest, from the criminological and medical-legal point of view, is, as we mentioned earlier, in that this substance, prototype of the so-called "design or synthesis drugs", is a drug classified by the authorities as illegal or uninstitutionalized and therefore proceeds from an important clandestine market.
With this in mind, it is evident that the relationship between the traffic and consumption of this substance and the phenomena of criminalization is evident, which is shown on a regular basis in the memories of the Office of the Attorney General of the State, as well as in the reports of the OED of the Ministry of the Interior. Crime originated around ecstasy is part of the category of "delinquity as conduct", that is, it is a behavior opposed to social laws, which can be done by anyone, which is not related to neurobiological anomalies and is determined by external factors. This anti-social behavior is contemplated, from the Spanish legal perspective, in Law 10/95 of 23 November (Criminal Code, article 10, "crimes and faults").
In the area of the relationship between the consumption of ecstasy and delictogenesis, it is advisable to establish a practical differentiation. Thus, the phenomena of relational crime, i.e. those criminal activities related to their possession and trafficking, are the most common crimes of those contained in articles 368 to 378 of the Criminal Code (delitions related to trafficking, development, facilitation and induction to consumption, i.e., crimes against public health), of the phenomena of induced crime, i.e., that originates because of the effects produced by drugs. Among the most common crimes observed in this category are offences against the security of traffic (article 379 of the Criminal Code) and, although they are not as such, acts of suicide. As a common factor to induced crimes, the use of violence is found, with a special significance being the polyconsumption of drugs, especially the co-administration of alcohol, which substantially enhances the effects of both drugs on CNS. Finally, it should be noted that the so-called functional crime (which is based on the behaviours that aim to continue with the administration of the substance in order to avoid the undesirable consequences of the lack of consumption, and which are mainly translated into crimes against property, as well as in prostitution) is not common in ecstasy consumers.
In relation to relational crime, the first arrests of ecstasy traffickers in Spain (2 Belgian citizens and 4 Italians) take place in August 1987 in Ibiza, for possession of 120 tablets or capsules, and their trial, also the first for ecstasy traffic, was held in February 1988 in the Audiencia de Palma de Mallorca. The data for police confiscations in Spain (Fig. 9) confirm a huge increase in seizures in the years ahead, which have passed from 187 pills in 1987 to 891,652 in 2000. The data on apprehensions in Spain confirm the communities of Valencia, Madrid and the Balearic Islands as those of the largest drug trafficking in design. If you enjoyed this information and you would such as to get even more info concerning [https://jbhnews.com/prescription-medications-to-treat-overweight-obesity/100789/ JBHNews] kindly check out our own site. In addition, cases of detection of these synthesis drugs in biological fluids of subjects detained for criminal acts are increasingly common.
Figure 9. Evolution of MDMA confiscations in Spain during the period.
For its part, in the field of induced crime, it should be borne in mind that the United Nations recognized, in 1994, that these substances were directly responsible for numerous traffic accidents in young people from 18 to 25 years during the weekends. In Spain, the Directorate General of Traffic also spoke on this line, in relation to the high sinisterness observed on the Madrid-Valencia road during the apogee of the so-called "bakalao route". The OED19 Survey on Drugs to School Population provides very disturbing data in this regard. Twenty-two per cent of the students surveyed in 1998 ecstasy consumers claimed that they had driven mopeds under the effects of that substance and 51 per cent had travelled in a vehicle driven by a person who was also under that effect. In this sense, it is known that the MOTAPM decreases concentration capacity, reflexes and visibility, increases reaction time and can cause visual and hearing hallucinations, facts that condition a large decrease in the ability to safely drive a car.
These data have been shown in a specific study conducted by the General Directorate of Traffic, in collaboration with the University of Valladolid. This is a study carried out on a sample of 144 people who died in traffic accidents. Of this sample, alcohol and other drugs (opiates, cocaine, amphetamines, cannabis and design drugs) were detected in 18% of cases. Ecstasy, as such, was detected in 4 cases, which occurred precisely during weekends. The study concludes with the existence of an increase in risk and accidental behaviour among consumers of different substances of abuse, including ecstasy122. A similar study is that carried out by the Ministry of the Interior and published in the OED20 report number 5. This report shows the results of the toxicological analysis performed by the National Institute of Toxicology to 1,363 drivers who died in traffic accident during 2000. MDMA or derivatives were detected in 12 subjects (0.9 per cent of the total), which doubled to that obtained in the previous year (0.4 per cent).
On the other hand, MOTAPM shares some behavioral properties with psychostimulants (cocaine, amphetamine) and psychodisleptics (alucinogens), which would facilitate an increase in aggressive behaviour and, therefore, injury crimes. The execution of the offence would occur, in particular, at times of intoxication, during which the subject could present a disorganized conduct. In this regard, 12 per cent of the young people who had consumed ecstasy interviewed in the last Survey on Drugs to School Population (year 2000) referred to having had problems of the type of irritability, discussions and strife during the time of consumption. With regard to this possible type of crime, the Spanish Criminal Code (Organic Law 10/1995 of 23 November), in its article 20, specifies as eximent of responsibility, of a biological nature, in addition to abstinence syndrome, the full intoxication of psychotropic substances, being these same mitigating causes (article 21) when all the necessary requirements for the release of responsibility are not met. If criminal action takes place when the subject is immersed in one of the two cases, and its intensity prevents the subject from understanding the wrongfulness of his conduct or alters his ability to act according to this understanding, imputability would be mercied, and even completely nullified, and with it responsibility. In this context, the figure of the transitional mental disorder secondary to the intoxication of substance abuse, should be placed, provided that a complete annulment of knowledge and volitive freedom is generated, but the duration of which is limited and refers without sequelae and without the likelihood of repetition.
Conclusions
Regardless of the disputes that, both in the scientific and popular spheres, took place over the past decade in relation to the toxic effects of ecstasy, an editorial by The Lancet, already in 1996, noted that MOTAPM lacked identified therapeutic potential, was not a soft drug and was directly responsible for a disproportionate number of toxic effects and deaths.123. At present, reports on acute and chronic intoxication associated with the MOTAPM are becoming more and more numerous and, despite the fact that data on the actual prevalence of the consumption of this substance and the serious problems caused by it are not known, its consumption has become, at least in a certain sector of the population, a genuine socio-anitarian problem.124.
The psychic effects caused by MOTAPM appear to be due to the increase in monoamine rates in CNS, so ecstasy would mimic the neurophysiological actions of these. In addition, the MOTAPM facilitates motor nervous excitability (mediated by noradrenergy, dopaminergic or serotonergic pathways), which explains the musculoskeletal hypertony observed in ecstasy consumers. The main mechanism of MDMA-induced euphoria is the serotonergic and dopaminergic increase that causes this substance in the nucleus accumbens, a property that can be used with other abuse drugs, such as cocaine, alcohol and opiates, among others. Precisely, the connections of the post-synaptic neurons of the accumbens kernel are vital in the MDMA-induced reward phenomenon.
The administration of MOTAPM repetitively leads to a process of destruction, sometimes definitively, of serotoninergic axons. In this sense, the neurotoxicity described in experimental animals and in humans, together with the psychopathological tables observed in ecstasy consumers, suggest that MOTAPM is not a suitable substance for recreational use.
Morbimortality due to ecstasy is due to hyperthermia, heart arrhythmia, dissected intravascular coagulation, rhabdomiolysis, acute renal insufficiency and liver toxicity27. From a clinical point of view, ecstasy poisoning can be framed between a serotonergic syndrome and a malignant neuroleptic syndrome box125.
