MDMA: Neurological and Behavioral Considerations
by Jason Graine
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MDMA (3,4-Methylenedioxymethamphetamine) or "Ecstasy" is an increasingly commonly used drug in today's population. Ecstasy, originally synthesized in the early 1900's as an appetite suppressant (but discontinued because of nausea), enjoyed a brief employment as a psychotherapeutic aid by upscale clinics in the late seventies and early eighties (Kirsch, 1986). In 1985, after determining MDMA had no medicinal value, therapeutic or otherwise, it was proclaimed a Schedule 1drug (in the US) by the Drug Enforcement Administration. Ecstasy has both amphetamine and hallucinogenic properties, and is often considered the grandchild of MDA , which is a more toxic chemical derivative of mescaline. It was described as having a high potential for abuse because of its "euphoria" producing properties, and overnight went from being available in nightclubs and bars (Kirsch,1986) to being an illicit drug with the same legal consequences as heroin. Ecstasy became increasingly popular in upscale gay communities in California and New York around this time, but stayed relatively underground. With the importing and gradual mainstreaming of the "rave" scene from England (all night drug fueled dances), ecstasy quickly became the drug of choice because of its amphetamine like properties which gave users stamina, and because of it's "empathetic" properties which provided users with a sense of well being and comfort, especially when relating to others (White, Obradovic, and Wheaton, 1996, Morland 2000). Today ecstasy is quite commonplace amongst many subcultures and is widely available on the black market (Hooft and van der Vorde, 1994).
While it is often reported by users that Ecstasy is not addictive and relatively harmless relative to other Schedule 1 drugs such as Cocaine and Heroin (Kirsch, 1986, White, Obradovic, and Wheaton, 1996), recent research has suggested otherwise. The neurological effects of MDMA will be covered in the first part of this paper. The second part will deal with behavior associated with Ecstasy use, and social consequences that may occur as a result of MDMA abuse. Specifically focussed on will be the effects of MDMA as a serotonin (5ht) neurotoxin in the raphe nucleus, as well as behavioral correlates that may be expected as a result of serotonin-tract degeneration. This may include psychopathological reactions such as depression or paranoia. Other things considered will include psychophysical danger associated with ecstasy use such as recent discoveries linking degenerated serotonin availability with decreased neural plasticity and, hence, decreased efficacy for environmental adaptation.
Most of the reward-inducing effects of MDMA, that is the euphoric "high" reported by users (Cregg and Tracey, 1993) is thought to be primarily mediated by increases in the monoaminergic neurotransmitters Dopamine (DA) and Serotonin (5ht), in regions such as the nucleus accumbens typically associated with reward. Experiments in awake rats have shown that injections into the nucleus accumbens of MDMA increases the levels of these transmitters as well as their metabolites (White, Obradovic, and Wheaton, 1996, McNamara et al., 1995). It has also been shown using autoradiographic techniques that repeated injections of low doses of MDMA produce what could be irreversible damage in the fine axonal tracts of the dorsal raphe nucleus that projects to the forebrain and hippocampus, areas involved in higher cognition and memory (Battaglia et al., 1991).
These findings suggest that humans as well may suffer similar damage. Higher doses seem to damage Dopamine axons as well in rats and only Dopamine axons in mice, suggesting again that humans may be at risk for dopaminergic degeneration with continued chronic use (Cadet et al. quoted in White et al. 1996). It has been demonstrated however that serotonin neurons are up to 10 times more sensitive to MDMA than Dopamine neurons in Vitro (Schmidt et al., 1987 quoted in White et al. 1996).
It appears as if MDMA exerts some of its effects on the brain by interfering with the serotonin transporter to cause excessive serotonin release to occur. This has been demonstrated by Berger et al. in 1992, by showing that MDMA induced serotonin release can be blocked by the administration of fluoxitine and imipramine, which are inhibitors of the serotonin transporter. It is thought that MDMA interacts with the transporter to reverse the direction of monoaminergic (serotonin and dopamine) flow, presumably causing some excessive feedback effect. Oddly, the release of carrier-mediated serotonin is not calcium dependent, as removal of Calcium in vitro does not inhibit release (Schmidt et al., 1987 quoted in White et al., 1996). MDMA has also been shown to produce greater monoaminergic effects by inhibiting re-uptake of monoamines at the synapse, and delaying metabolic degradation by inhibiting monoamine oxidase (Berger et al., 1992). Both of these mechanisms allow for greater availability and efficacy of synaptic monoamines, thus causing a rise in the intensity of attributable effects.
Repeated systemic injections of MDMA given to rats, guinea pigs, and monkeys produce long lasting decreases in neurochemical indices of serotonin function in the forebrain (White et al.,1996). MDMA reduces forebrain tissue levels of serotonin and its metabolite (5-hydroxyindolacetic acid or 5HIAA), and depresses the activity of tryptophan hydroxylase, which is the rate-limiting synthetic enzyme for Serotonin (Schmidt et al., quoted in White et al.,1996). This reduction may be associated with the degradation of dorsal raphe nucleus tract fibers (axons) which project to this area. Deficits in serotonin rich areas typically occur within 24 hours of the last dose and may persist from one week to over one year following multiple doses of MDMA (Battaglia et al., 1991, McNamara et al.,1995). However, single injections of MDMA directly into the median or dorsal raphe nuclei, which project to the forebrain, do not change monoamine levels in the hippocampus or striatum in rats measured 2 weeks after injection (Paris et al. 1992, quoted in White et al., 1996).
Interestingly, some researchers have found differences amongst some species of rat that suggests MDMA, while correlated with depleted serotonin levels, may not be a direct cause of serotonin depletion. Rather depletion may depend on a sex-specific metabolite found in some species. Chu, Kumagai, DiStefano, and Cho (1996) found that when comparing male Sprague-Dawley (SD), SD females, and Dark Agouti (DA) female rats these rats exhibited different capabilities for MDMA metabolism. Female DA rats, who lack an enzyme CYP2D which causes MDMA to be broken down into another metabolite (DHMA) were found to have higher levels of MDMA in the brain and plasma than female SD rats, while only minimum serotonin depletion (after 6 hours). Thus Chu et al. believe it is not the presence of MDMA per se that cause the degeneration in serotonin rich areas. Rather depletion may also involve some metabolite produced by CYP2D upon interaction with the drug. Hence it may be some metabolite of MDMA and not MDMA itself that may be involved in the neurotoxicity related to ecstasy use.
Dopamine as well has been demonstrated to have a mediating role in serotonin depletion and the degeneration of serotonergic tracts. Acute depletion of dopamine by pretreatment with a-methyl-p-tyrosine or reserpine attenuated MDMA dependent dopamine release in relevant areas (i.e. the striatum). This prevented subsequent decreases of serotonin uptake sites as well as tryptophan hydroxylase activity (Brodkin et al., 1993). These results suggest that dopamine activity is to some extent a necessary condition for serotonin tract degradation, in that without the presence of dopamine neurotoxic effects of MDMA are minimized. It has been suggested that serotonin depletion may increase vulnerability to excess dopamine released after MDMA administration, causing toxicity at serotonin sites (Sprague and Nichols, 1995, quoted in White et al., 1996). Depletion of serotonin alone does not lead to serotonin axonal and terminal degeneration. Rather, Sprague and Nichols (1995) suggest the following chain of events: "MDMA depletes serotonin from serotonin neurons which renders those neurons vulnerable to toxicity; MDMA dramatically increases dopamine synthesis and release; The dopamine from the increased extracellular pool is transported into depleted serotonin terminals by the serotonin uptake carrier where it is deaminated by MAO-B to generate hydrogen peroxide; This hydrogen peroxide then leads to lipid peroxidation and perhaps other oxidative insults and selective serotonin axonal degradation"(quoted in White et al., 1996). Such a scheme may explain why Paris et al.(quoted above) failed to show a depletion of serotonin in the striatum two weeks following single MDMA injections directly into the median and dorsal raphe nucleus, as dopaminergic activity in this area is comparatively quite small. Interestingly (as mentioned above) this effect is reversed in mice, in that MDMA administration causes degeneration of dopamine pathways while leaving serotonin tracts relatively unscathed.
As I begin to talk about the cognitive-behavioral correlates of MDMA use and, consequently serotonergic degeneration, one general observation makes a good starting point. Brezun and Daszuta (1999), have shown that a general depletion of serotonin can cause decreases in neurogenesis (the proliferation of neuronal plasticity and cellular development) in the denate gyrus and subventricular zone of adult rats. They have shown it to be the case that both the inhibition of serotonin synthesis (using serotonin antagonists) as well as selective lesioning of raphe nuclei axonal tracts projecting to the denate gyrus and subventricular zone, have caused significant reductions in the number of newly generated cells in both areas. Brezun and Daszuta show that, in addition to its role as a neurotransmitter, serotonin may also act as a "developmental regulatory signal" for neurogenesis. This suggests that the absence of serotonin may retard and limit the degree of neural plasticity available to the brain for learning and regeneration following neural insult. They also point out that decreases in serotonin in the hippocampus, a projection area of the raphe nucleus and an area often implicated in learning and memory, has often been associated with cognitive disorders such as depression, schizophrenia, and Alzheimer's disease (Abi-Dargham et al., 1997, Cross, 1990, quoted in Brezun and Daszuta, 1999). Thus, serotonin degeneration may affect the efficacy with which an individual can adjust to the stresses put on them by their environments.
MDMA produces many noticeable behavioral changes. It is generally rewarding to both lab animals and humans. Monkeys and rats will lever-press to self-administrate MDMA (Beardsley et al., 1986). White et al.(1996) point out however that "the ability of MDMA to alter neurotransmission in the brain is not restricted to brain regions that are implicated in the rewarding effects of abused drugs. MDMA produces the facilitation of somatic motoneuron excitability that would be expected of a drug that increased extracellular levels of 5HT, DA, and NE." Other behavioral aspects include hyperactivity, hyperthermia, head-weaving and excessive locomotion (White et al.,1996). The human equivalent of such behavior may include insomnia, teeth grinding, hyperthermia, excessive hand-wringing and sweating, and the increased desire to participate in sexual activity (Kirsch, 1986). Jorg Morland (2000) has given subjective reports of people on MDMA that include a sense of closeness to other people, difficulties in concentration, dizziness or vertigo, talkativeness, hallucination, and a sort of "drunken" drowsiness.
McNamara et al. (1995) found that treatment with MDMA in rats caused an increased locomotor activity, elevated basal serum corticosterone concentrations, decreased exploratory behavior, and changes in body temperature. McNamara et al.'s experiment sought to examine (among other things) the dose-related effects of subacute administration of MDMA (5, 10, and 20 mg/kg twice daily for 4 days) on locomotor activity, and "open field" and "step down passive avoidance" exploratory behaviors. Their results show that total locomotor activity counts were significantly increased by both 10 and 20 mg/kg MDMA (in a dose-related fashion) for the four days of drug administration, but decreased gradually from the first day of treatment on. This may be related to the "high" versus the "burnout" or fatigue based on development of tolerance and withdrawal typically associated with amphetamine abuse. Exploratory behavior was also found to decrease in a dose dependent fashion following the experiment (8-10 days after MDMA administration), thus being more pronounced following higher dosing (20mg/kg). Such findings suggest that serotonin depletion may cause a reduction in "approach" behavior following MDMA administration.
Jorg Morland (2000) reports that single dose MDMA use can produce a wide range of effects ranging from euphoria, central nervous system stimulation, and feelings of closeness, to hallucination, cognitive impairment, agitation, disturbed and bizarre behavior, and even psychosis. Morland also points out that such effects are often associated with higher incidences of fatalities and accidents, due to the extra-likelihood of engaging in reckless or impulsive behaviors while under the influence of MDMA. In one experiment (Parrot and Lasky, 1998. Quoted in Morland, 2000.) 3 groups of young people (aged 19-30) were studied. The groups were divided as follows: 1) 15 regular MDMA users who had taken the drug on ten or more occasions. 2) 15 novice MDMA users who had taken MDMA on fewer than 10 previous occasions. 3) 15 controls that have never done MDMA, but have done other drugs in the past. Each subject completed a cognitive and mood scale battery four times: 1) An initial drug free baseline 2) at a Saturday night dance club (on MDMA) 3) three days later 4) seven days later. The control group did not do MDMA. All groups used alcohol and other drugs as well, admittedly confounding the results to some degree. However, all participants in the experimental groups reported feelings of euphoria as a result of the MDMA. Two days after the dosing, MDMA users felt significantly more depressed, abnormal, withdrawn, ill tempered and quick to anger (impulsive). Cognitive performance on both tasks (vocal recall, visual scanning) was significantly reduced in the MDMA groups. Memory scores were also reduced in both MDMA groups with greater reductions in the habitual user group than in the novice group. Such an effect on memory may be due in part to the reduction in dorsal raphe nucleus serotonergic axonal projections to the hippocampus, the area most associated with memory function.
McGuire et al., (1994) studied the reports of people presenting to various British clinics between 1990 and 1992 with psychiatric symptoms that developed in the context of MDMA use. Interviews were conducted with this group and psychopathologies were assessed with the present State Examination and compared with instances of "drug-na?ve" psychopathology. Of the 40 people presenting, 8 patients described psychotic syndromes, two experienced visual hallucination, one had panic attacks, one suffered from depression, and one described chronic depersonalization and derealization. The psychopathology of MDMA users was found to be strikingly similar to that of controls.
This report suggests that use of MDMA may be associated with a broader spectrum of psychopathology than that assumed solely from serotonergic axonal tract degeneration. Interestingly only one patient presented with signs of depression. This is of interest because one may expect that depression would be the most pronounced symptom due to its known intimacy with serotonin depletion (Goodwin and Jameson,1990), as evidenced by its relief from administration of SSRI's which selectively target serotonin pathways. It is perhaps not surprising that depression may go unnoticed in this study. In comparison to psychosis such as panic or hallucination, depression may cause less people to seek out attention for depressive vs. more concerning states. Many other studies have implicated depression and related impulsiveness due to serotonin depletion as a major psychopathological consequence of chronic MDMA abuse (Morgan, 1998, Benazzi and Mazzoli, 1991).
Lastly, I would like to briefly mention some social consequences of MDMA that have been reported. Morland (2000) reports that many automobile related accidents have occurred that have been correlated with MDMA use. These include fatal car crashes and multiple episodes of reported dangerous driving (Henry et al., 1992, quoted in Morland, 2000). Hooft and van de Voorde (1994) report one case of a "car-surfing" accident turned fatal when a 26 year old man on MDMA died from severe brain contusion after falling from the roof of a moving car. While admittedly anecdotal, such behavior does exemplify the reckless impulsively associated with MDMA (Morgan, 1998). Such examples are correlational at best, but do tell us something about the behavior we can expect to find in populations of MDMA users.
This paper has attempted to describe the neurological and behavioral consequences of MDMA use/abuse. I have placed special importance on dorsal raphe nucleus serotonin tract (axonal) degeneration as a result of MDMA administration. I have also attempted to describe some behavioral consequences and psychopathologies that may be expected as a result of MDMA use.