Review
Are there sex differences associated with the effects of ecstasy/3,4-methylenedioxymethamphetamine (MDMA)?

https://doi.org/10.1016/j.neubiorev.2006.09.009Get rights and content

Abstract

Sex has been identified as an important factor in moderating the effects of several drugs of abuse. Given the increasing popularity of ecstasy (3,4-methylenedioxymethamphetamine [MDMA]) use, it is important for researchers and clinicians to understand the factors that may influence its pharmacological actions to improve education, harm reduction and treatment efforts. This review focuses on preclinical and clinical research that examines the role of sex as an independent variable in the effects of ecstasy/MDMA. A systematic search of PsycINFO and MEDLINE electronic databases from 1966 to April 2006 was conducted. Both preclinical and clinical studies show a sexually dimorphic pattern in the acute, subacute and possibly long-term effects of ecstasy/MDMA. Specifically, adult females are more sensitive than males to the acute and subacute physical and psychological effects of ecstasy/MDMA and long-term alterations in aspects of 5-HT functioning. Conversely, males are more sensitive to the acute physiological effects of ecstasy/MDMA. These findings are consistent with research outcomes reported for other substances such as amphetamines and cocaine. Potential reasons for these sex differences and directions for future research are discussed.

Introduction

Historically, women have been excluded from clinical psychopharmacology research due to concerns about pregnancy or because menstrual cycle hormonal fluctuations have been viewed as a confounding factor (Hamilton and Jensvold, 1995; Merkatz et al., 1993). Consequently, findings from predominantly male samples are often generalised to females. This is problematic given that there are known pharmacokinetic and pharmacodynamic differences between males and females (Gandhi et al., 2004; Harris et al., 1995; Yonkers et al., 1992).

Sex differences have been well characterised in animal and human studies of pharmacokinetic and pharmacodynamic responses to many substances of abuse, including alcohol, nicotine, and psychostimulants such as cocaine and amphetamine (Becker et al., 2001; Brady and Randall, 1999; Carroll et al., 2004; Lynch et al., 2002). Growing evidence suggests that females are more prone than males to a range of effects of substances of abuse. In humans, it is often difficult to distinguish whether drug (side) effects are the result of biological, psychological or a combination of both factors. The term ‘sex’ generally refers to the biological factors differentiating males and females, whereas ‘gender’ relates to the sociocultural differences between the sexes (Barsky et al., 2001; Hamilton and Jensvold, 1995). For simplicity, the term ‘sex’ rather than ‘gender’ will be used throughout this paper, though it is acknowledged that sociocultural and psychological factors may be important in the sex differences associated with drugs of abuse, including ecstasy/3,4-methylenedioxymethamphetamine (MDMA).

To date, only modest attention has been paid to the variable of sex in relation to the response to ecstasy/MDMA administration. This is explained by the fact that studies investigating the effects of ecstasy/MDMA recruit predominantly male subjects and of the several studies that have recruited female subjects, it is often unclear whether sex was included as an independent variable in the data analysis. Throughout this paper we refer to the term ‘ecstasy’ when studies have recruited participants who report ecstasy use. Even though the contents of ecstasy tablets are assumed to include MDMA this is usually not verified in research of ecstasy users (Cole and Sumnall, 2003), and research shows that ecstasy tablets may contain various other substances that may or may not be related to MDMA (Baggott et al., 2000; Wolff et al., 1995). We refer to the term ‘MDMA’ only when it is known with certainty that MDMA was the actual substance administered.

The paucity of research on sex differences in ecstasy/MDMA research is somewhat surprising given the rising popularity of ecstasy use over the past decade (Australian Institute of Health and Welfare [AIHW], 2005; Landry, 2002; Pedersen and Skrondal, 1999; Schuster et al., 1998; Strote et al., 2002). Using Australia as an example, population-level data indicate that lifetime use of ecstasy by Australians aged 14 years and over has risen from 2.4% in 1995 to 6.1% in 2001 and 7.5% in 2004 (Australian Institute of Health and Welfare, 2002, Australian Institute of Health and Welfare, 2005). Similarly, recent use (in the previous 12 months) increased more than twofold from 1.2% in 1993 to 3.4% in 2004 (AIHW, 2005). As is the case for other substances (see AIHW, 2005; Brady and Randall, 1999), the epidemiological literature shows that males outnumber females in their extent of ecstasy use (i.e., prevalence, dose, frequency, years of use) in various countries, including Germany (Schuster et al., 1998), Norway (Pedersen and Skrondal, 1999), New Zealand (Wilkins et al., 2003), England (Rodham et al., 2005), the United States of America (Maxwell, 2003) and Australia (Degenhardt et al., 2003; Lynskey et al., 1999). Notably however, recent reported use (past 12 months) of ecstasy increased significantly among females but not males in Australia from 1995 to 2001 (AIHW, 2002). These data have increased concerns about the specific issues for females and drug use (Isralowitz and Rawson, 2006; Litt, 2003; Maxwell, 2003; Wallace et al., 2003).

In contrast to other amphetamines that mainly act via dopaminergic and noradrenergic systems, MDMA acts primarily through the serotonergic (5-hydroxy tryptamine; 5-HT) system, which results in subsequent actions on the release of dopamine (DA) and noradrenaline (NA) (de la Torre et al., 2000; White et al., 1996). Therefore, the effects of ecstasy are distinguishable from amphetamines and hallucinogens, earning ecstasy its own classification as ‘entactogens’ (Martinez-Price et al., 2002; Nichols, 1986). Preclinical studies have provided evidence of 5-HT neurotoxicity following MDMA administration (Green et al., 2003), and neuroimaging studies have presented evidence of altered neurochemical functioning in human ecstasy users (Buchert et al., 2004; McCann et al., 1998; Reneman et al., 2001). These alterations in 5-HT functioning may be associated with psychiatric and cognitive deficits (Green et al., 2003; Montoya et al., 2002).

Determining whether there are sex differences associated with the effects of ecstasy/MDMA is important because it will improve our understanding of the pharmacological actions of MDMA and tailor approaches to intervention in both males and females. To date, only a small body of research has evaluated sex differences in animals and humans in the behavioural, subjective and biological responses to ecstasy/MDMA, although researchers are recognising the need for further research in this area (e.g., Easton and Marsden, 2006; Reneman et al., 2006). The purpose of this review is to provide a thorough overview of the literature pertaining to the variable of sex and its relationship to the effects of ecstasy/MDMA in animals and humans. Potential explanations for the apparent sex differences and directions for future research will also be discussed.

Section snippets

Method

The PsycINFO and MEDLINE electronic databases were searched for articles published from 1966 to April 2006 using the following terms: ‘MDMA’ or ‘ecstasy’ combined with ‘sex’, ‘sex differences’, ‘gender’ or ‘gender differences’. Only English-language articles were included. There were 135 articles identified by the initial search. These articles were screened for relevance based on title, key words and abstract. For the purpose of this review, articles were required to include sex/gender as an

Animal studies

The majority of animal studies that have examined the effects of MDMA have used only males. However, there is a small body of research that has used males and females (primarily rat studies), which shows a dissociation between the sexes in the acute behavioural effects of MDMA (see Table 1). The earliest study to examine sex differences in the effects of MDMA was conducted by Slikker et al. (1989). They measured a range of behaviours in adult Sprague-Dawley rats (SD) following oral

Human studies

Table 2 summarises the human studies that have examined the role of sex as a variable in the effects of ecstasy/MDMA. The findings are discussed according to acute/subacute administration, long-term neurological effects (neurotoxicity) and long-term cognitive/psychological sequelae. It is important to note that differentiating acute and subacute effects from long-term (potentially neurotoxic) effects is often difficult. This is because MDMA can only be biochemically detected 24–48 h after use,

Discussion and conclusions

Based on a review of a small body of literature, the combined findings of preclinical and clinical studies that have included sex as an independent variable suggest that adult females are more susceptible than males to the acute and subacute psychological and physical adverse effects of ecstasy/MDMA. However, males appear more sensitive to the acute physiological effects of ecstasy/MDMA. In addition, alterations in various measures of 5-HT functioning are more pronounced in female current

Acknowledgements

We would like to sincerely thank Ben Canny and Jillian Broadbear for their helpful comments in preparing this manuscript. Thanks also to the anonymous reviewers for their constructive feedback on an earlier version of this manuscript. Kelly Allott is the recipient of an Australian Postgraduate Award.

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