The Role of MDMA Neurotoxicity in Anxiety
Casey R. Guillot, Mitchell E. Berman and Brenton R. Abadie
In : Neurotoxicity Syndromes, Chapter I
Editor: Linda R. Webster, pp. 1 – 36
© 2007 Nova Science Publishers, Inc.
The drug 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) long has been considered a neurotoxin selective for serotonin (5-hydroxytryptamine; 5-HT) axons in rats and nonhuman primates. MDMA is also thought to have the potential to cause persistent serotonergic alterations in humans. Since the serotonin system is involved in the regulation of anxiety, researchers have proposed that recreational Ecstasy users may be at risk for the development of anxiety disorders and symptoms. Although experimental studies in rats have presented evidence for a causative role of MDMA in the development of anxiety-like behaviors, the role of MDMA in the development of anxiety in humans is much less clear, due to several confounding factors common to retrospective studies of drug users (e.g., preexisting symptoms or vulnerabilities, polydrug use, drug purity). However, case studies have revealed that Ecstasy use can trigger panic attacks and other anxiety problems, and cross-sectional studies have reported higher levels of anxiety, obsessive-compulsive, and phobic anxiety symptoms in Ecstasy users. This chapter will provide an overview of the evidence from animal studies, as well as a critical review of
the human evidence, in an attempt to elucidate the role of MDMA in the development of anxiety disorders and symptoms. Limitations of past research and recommendations for future research will be discussed.
Recreational use of the drug 3,4-methylenedioxymethamphetamine (MDMA; Ecstasy) first appeared in California in the late 1960s (Seymour, 1986; Shulgin and Shulgin, 1992). Over the next 15 years, recreational MDMA use grew in popularity, spreading to Texas, Florida, and the northeastern United States (Liester, Grob, Bravo, and Walsh, 1992; Siegel, 1986). Then in 1985, a research report indicated that 3,4-methylenedioxyamphetamine (MDA), a compound closely related to MDMA, had destroyed serotonin (5- hydroxytryptamine; 5-HT) nerve terminals in the rat brain (Ricaurte, Bryan, Strauss, Seiden, and Schuster, 1985). Soon afterwards, the Drug Enforcement Administration placed MDMA
into Schedule I of the Controlled Substances Act (Eisner, 1994; Cohen, 1998). Subsequent research has revealed that MDMA causes long-term serotonergic deficits in several species of rodents and nonhuman primates, including Norway rats1 (Battaglia et al., 1987; Schmidt, 1987), guinea pigs (Battaglia, Yeh, and De Souza, 1988; Saadat, Elliott, Colado, and Green, 2004), rhesus monkeys (Insel, Battaglia, Johannessen, Marra, and De Souza, 1989; Slikker et al., 1988), squirrel monkeys (Fischer, Hatzidimitriou, Wlos, Katz, and Ricaurte, 1995; Ricaurte, Martello, Katz, and Martello, 1992), long-tailed macaques (Wilson, Ricaurte, and Molliver, 1989), and baboons (Scheffel et al., 1998). Following MDMA
administration, researchers have observed dose-dependent reductions in the density of 5-HT immunoreactive axons (O’Hearn, Battaglia, De Souza, Kuhar, and Molliver, 1988; Wilson et al., 1989) and radioligand-labeled 5-HT uptake sites (Commins et al., 1987; Ricaurte et al., 1992), as well as lower tissue concentrations of 5-HT (Scanzello, Hatzidimitriou, Martello, Katz, and Ricaurte, 1993; Winsauer et al., 2002), 5-hydroxyindoleacetic acid (5-HIAA; Byrne, Baker, and Poling, 2000; Slikker et al., 1989), and tryptophan hydroxylase (Stone, Hanson, and Gibb, 1987; Stone, Merchant, Hanson, and Gibb, 1987). Although the animals in most studies were injected with MDMA, experimental studies in rats and monkeys also have revealed alterations in 5-HT indices two to four weeks after oral administration (Ali et al., 1993; Mechan et al., 2006; Slikker et al., 1988, 1989). Notably, the serotonergic changes induced by MDMA have been shown to persist for up to 7 years in squirrel monkeys (Hatzidimitriou, McCann, and Ricaurte, 1999). Based on this body of evidence, MDMA has long been considered a neurotoxin selective for 5-HT axons.
It is highly likely that MDMA has the potential to cause persistent serotonergic alterations in the human brain as well. In fact, retrospective studies that have employed either positron emission tomography (PET) or single photon emission computed tomography (SPECT) have consistently revealed lower serotonin transporter (SERT) binding in the brains of recreational Ecstasy users in comparison to Ecstasy-naive controls (Buchert et al., 2003, 2004; McCann, Szabo, Scheffel, Dannals, and Ricaurte, 1998; McCann et al., 2005; Reneman, Booij, de Bruin, et al., 2001; Reneman, Lavalaye et al., 2001; Semple, Ebmeier, Glabus, O’Carroll, and Johnstone, 1999; Thomasius et al., 2003). The most common interpretation of these findings is that serotonergic neurotoxicity has occurred in some recreational Ecstasy users (Parrott, 2005; Reneman, Booij, Majoie, van den Brink, and den Heeten, 2001; Reneman, de Win, van den Brink, and den Heeten, 2006).
Abnormalities in the serotonin system have been implicated in a diversity of psychiatric disorders (Naughton, Mulrooney, and Leonard, 2000). In particular, the involvement of 5-HT neurotransmission in the regulation of anxiety has been documented extensively (Griebel, 1995; Naughton et al., 2000; Pyle, Argyropoulos, and Nutt, 2004). If MDMA neurotoxicity occurs in humans, then a greater prevalence of anxiety disorders and symptoms may be seen in recreational Ecstasy users. This chapter will provide an overview of the evidence from animal studies, as well as a critical review of the human evidence, in an attempt to elucidate the role of MDMA in the development of anxiety. Limitations of past research and
recommendations for future research will be discussed.
A Closer Look at MDMA Neurotoxicity
Grob, Bravo, Walsh, and Liester (1992) have stated that the meaning of MDMA neurotoxicity may need to be reevaluated, since serotonergic recovery has been shown to occur in rats after the presumed destruction of 5-HT axons by MDMA. In two such studies, Sprague-Dawley rats were injected with 10 mg/kg of MDMA every 2 hours for a cumulative dose of 40 mg/kg (Fischer et al., 1995; Scanzello et al., 1993). 5-HT uptake and tissue concentrations of 5-HT and 5-HIAA were reduced by about 40 to 80 percent in all brain regions examined. One year later, however, serotonergic markers had recovered completely, except for 5-HT uptake in the hippocampus. Sabol, Lew, Richards, Vosmer, and Seiden (1996) injected Sprague-Dawley rats with 20 mg/kg of MDMA twice daily for 4 days. One year later, the researchers found that tissue concentrations of 5-HT had increased in the hypothalamus and septum, recovered somewhat in the frontal-parietal cortex, occipitalparietal cortex, and hippocampus, and recovered completely in five other brain regions. In summary, rats have displayed a considerable degree of serotonergic recovery after being injected with high doses of MDMA.