George A. Ricaurte

Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration.

This study compared the toxic effects of oral versus subcutaneous and single versus multiple doses of 3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in non-human primates. Orally administered MDMA was approximately one-half as effective as subcutaneously administered drug. Multiple doses were more effective than single doses, but a single 5 mg/kg dose of MDMA given orally still produced a long-lasting depletion of serotonin in the monkey brain. These results indicate that when MDMA is given to monkeys in a manner similar to that employed by humans, it exerts toxic effects on central serotonergic neurons. This suggests that humans using MDMA may be at risk for incurring central serotonergic neuronal damage.

Long-term effects of chronic methamphetamine administration in rhesus monkeys

Biochemical and neuropathological effects of exposure to a high dose regimen of methamphetamine were evaluated in rhesus monkeys approximately 4 years after the last drug injection. Concentrations of dopamine and serotonin in caudate were below control levels as were concentrations of serotonin in several other brain regions. These changes were more severe in a monkey that was exposed twice to the drug regimen. A decrease in caudate synaptosomal uptake of both neurotransmitters as well as neuropathological changes were evident in that monkey. Although it is possible that partial recovery occurred, these results strongly suggest that methamphetamine-induced neurotoxicity may be permanent.

Neurotoxic amphetamine analogues: effects in monkeys and implications for humans.

A wealth of evidence has accrued over the last 20 years indicating that certain amphetamine analogues have the potential to damage central monoaminergic neurons. For example, amphetamine has been shown to be toxic to dopamine neurons, MDMA to serotonin neurons, and methamphetamine to both (Table 1). In rodents, the toxic effects of amphetamines appear to be limited to axon terminals, and regenerative sprouting tends to be the rule. By contrast, in primates, nerve cell bodies appear to be affected, and the deleterious effects of amphetamine derivatives tend to be longer lasting, and possibly permanent (Fig. 2). Although findings in animals are compelling, observations in humans are less clear. In particular, it remains to be determined whether amphetamine analogues damage central monoaminergic neurons in humans and, if they do, whether functional consequences ensue. Also, the mechanism by which amphetamines damage monoaminergic neurons remains to be defined. Further insight into these basic and clinical aspects of amphetamine neurotoxicity should enhance our understanding of central monoaminergic systems in normal brain function, and their role in the pathophysiology of neuropsychiatric disorders.

Recognition and management of complications of new recreational drug use

Use of illicit drugs in clubs and large dance parties (so-called raves) is a burgeoning cultural trend. Such recreational drug use is associated with several medical complications, both acute and longlasting. Although few, if any, of the drugs currently used in recreational venues are truly new, their patterns and context of use have changed (a great deal in some instances). For some of these substances, this cultural repackaging of the drug experience has resulted in various medical disorders that have previously gone undocumented. This review aims to help treating physicians recognise and manage complications associated with the use of new drugs in clubs, including methylenedioxymethamfetamine, ephedrine, gamma-hydroxybutyrate; gamma-butyrolactone, 1,4-butanediol, flunitrazepam, ketamine, and nitrites. We also alert researchers to specific toxic effects of club-drugs on which more basic information is needed.

Aminergic metabolites in cerebrospinal fluid of humans previously exposed to MDMA: preliminary observations.

Recreational use of the neurotoxic drug ( +)3,4-methylenedioxymethamphetamine (MDMA, Ecstasy) poses a public health problem of uncertain proportions. The reason for this is twofold. First, there is little information regarding the number of individuals that have been exposed to the drug, and even less about how many people are continuing to use it. According to one informal survey, 39% of students on an undergraduate campus reported having experimented with MDMA on at least one occasion. Other informal surveys on different college campuses have yielded lower figures (6-25%). In 1985, Siegel reported that approximately 30,000 dosage units of MDMA were being sold in the United States each month. More recently (1989), Doblin provided an estimate of 100,000 dosage units per month. Whether this represents a true increase in MDMA use, or whether these estimates vary as a function of how they were ascertained is not clear. However, given MDMAs neurotoxic potential (see below), formal epidemiologic efforts to determine the incidence of recreational MDMA use are in order. The second reason why it is difficult to gauge the seriousness of the threat that MDMA poses to public health is that, although the long-term serotonin-depleting effects of MDMA have been convincingly demonstrated in animals,4- such docurnentation is lacking in humans. Moreover, the doses, routes, and schedules of MDMA administration used in most (but not all, see reference 11) animal studies have differed significantly from those typically employed by humans. Hence, it is difficult to know to what extent the findings in animals can be generalized to humans.

5-Hydroxyindoleacetic acid in cerebrospinal fluid reflects serotonergic damage induced by 3,4-methylenedioxymethamphetamine in CNS of non-human primates.

This study examined whether 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) could be used to detect serotonergic damage induced by (+/-)-3,4-methylenedioxymethamphetamine (MDMA) in the central nervous system (CNS) of non-human primates. Monkeys were administered toxic doses of MDMA; two weeks later, the animals were lightly anesthetized with ether and CSF was obtained by means of cervical puncture. Later that same day, the animals were killed for direct determination of CNS serotonin and 5-HIAA concentrations. Monkeys with 73-94% depletions of serotonin and 5-HIAA in brain and 42-45% depletions of serotonin and 5-HIAA in the spinal cord had a 60 +/- 7% reduction of 5-HIAA in CSF, without any change in homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenethyleneglycol (MHPG). These findings indicate that CSF 5-HIAA can be employed to detect central serotonergic damage produced by MDMA in non-human primates, and suggest that CSF 5-HIAA may be useful for detecting MDMA-induced neuronal damage in humans.

MDMA (“Ecstasy”) and panic disorder: Induction by a single dose

( +_ )3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic amphetamine analogue used recreationally by humans in the United States (Pcroutka 1987) and Western Europe (Anon 1992), and is thought by some to have potential utility as a psychotherapoutic adjunct (Grinspoon and Bakalar 1986). It is generally believed that MDMA acts via central monoamines, primariJy by inducing transmitter release and interfering with monoamine reuptake inactivation (Johnson et al 1991; McKenna and Peroutka 1990). In animals, MDMA has been shown to damage brain serotonin neurons, and in the monkey the neurotoxic dose closely approximates the dose typically ingested by humans (Ricaurte et al 1988). Concern that MDMA may damage serotonin neurons in the human brain is largely responsible for MDMAs Schedule I status in the United States, and consequently, the dearth of controlled studies comparing the risks of MDMA to its possible benefit as a therapeutic adjunct. There have been several recent reports of lasting adverse neuropsychiatric sequelae in humans who have taken repeated (usually high) doses of MDMA (Crcighton et al 1991; Benazzi and Mazzoli 1991; McGuir¢ and Fahy 1991; Schifano 1991; McCann and Ricaurte 1991). These reports suggest that individuals with prior psychiatric histories may have an increased susceptibility to MDMAs adverse effects. Lingering psychiatric syndromes associated with MDMA ingestion have included chronic paranoid psychosis (Schifano 1991; McGuir¢ and Fahy 1991), recurrent acute paranoid psychosis (Crcighton et al 1991), depression with suicidality (Benazzi and Mazzoli 1991), and panic disorder with secondary depression (McCann and Ricaurte 1991). Although untoward effects of high neurotoxic doses of MDMA might be anticipated, particularly in vulnerable individuals, enduring psychiatric illness following a single moderate dose of MDMA in a healthy individual has not been reported. We describe an individual with no prior psychiatric history who developed panic disorder after ingesting a single typical dose of MDMA.

Orally administered MDMA causes a long-term depletion of serotonin in rat brain

Recent studies suggest that 3,4-methylenedioxymethylamphetamine (MDMA), when administered subcutaneously, is toxic to central serotonergic neurons in rats. Because humans typically self-administer this drug orally, we compared this route to the s.c. route of administration. Orally administered MDMA produced a dose-related depletion of serotonin comparable to that produced by the s.c. route. These findings suggest that MDMA, when given orally, retains it neurotoxic activity and that humans using MDMA may be at risk for developing a persistent depletion of brain serotonin.

Effect of depleting vesicular and cytoplasmic dopamine on methylenedioxymethamphetamine neurotoxicity

The mechanism by which 3,4‐methylenedioxymethamphetamine (MDMA) produces serotonin (5‐HT) neurotoxicity is unknown but considerable evidence suggests that endogenous brain dopamine (DA) is involved. However, it has recently become apparent that some of the data implicating brain DA in MDMA neurotoxicity may be confounded by drug effects on thermoregulation. The purpose of the present studies was to examine the role of DA in MDMA neurotoxicity, while controlling for possible confounding effects of drug‐ induced changes in core temperature. Rats were treated with reserpine, alone and in combination with α‐methyl‐p‐tyrosine (AMPT), to deplete vesicular and cytoplasmic stores of DA. When drug‐induced hypothermia was averted (by raising ambient temperature), the 5‐HT neuroprotective effects of reserpine and AMPT were no longer apparent. The lack of neuroprotection by AMPT and reserpine, alone and in combination, in studies that control for the effects of these drugs on core temperature, suggests that DA per se is not essential for the expression of MDMA‐induced 5‐HT neurotoxicity.

The effects of repeated administration of MDMA on the expression of sexual behavior in the male rat

3,4-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a potent neurotoxin which preferentially produces 5-HT nerve terminal degeneration in the CNS in both rodents and primates. Timely research on the behavioral effects of acute and long term treatment of MDMA is critical due to the neuropathological effects of MDMA and its abuse liability. Presently, there are no published reports that have systematically examined the effects of acute or chronic treatment of MDMA on animal sexual behavior. Accordingly, the effects of repeated systemic administration of MDMA on a variety of parameters of male sexual behavior in sexually vigorous male rats were studied. Treatment consisted of subcutaneous injections of MDMA (40 mg/kg) or saline (1 ml/kg) every 12 hours for 4 consecutive days. In addition, neurochemical assessments of brain 5-HT and 5-HIAA depletion following repeated MDMA treatment were also conducted using reverse phase liquid chromatography. The results of this study revealed that repeated systemic administration of MDMA to sexually vigorous male rats produced a transient disruption of the expression of male copulatory behavior. In addition, in MDMA-treated males that did display copulatory behavior, both the ejaculation latency and postejaculatory interval were dramatically lengthened when compared to saline injected controls. Surprisingly, one week after the first behavioral test, copulatory behavior in MDMA treated rats appeared unaffected despite a marked depletion of 5-HT and 5-HIAA content in the striatum, and hippocampus.