ReviewAre there sex differences associated with the effects of ecstasy/3,4-methylenedioxymethamphetamine (MDMA)?
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.
References (209)
- et al.
Patterns of use and harm reduction practices of ecstasy users in Australia
Drug & Alcohol Dependence
(2006) - et al.
Opposite modulatory effects of ovarian hormones on rat brain dopamine and serotonin transporters
Brain Research
(1997) - et al.
Sex differences in the rapid and acute effects of estrogen on striatal D2 dopamine receptor binding
Brain Research
(1994) - et al.
Rapid effects of estrogen or progesterone on the amphetamine-induced increase in striatal dopamine are enhanced by estrogen priming: a microdialysis study
Pharmacology, Biochemistry and Behavior
(1999) - et al.
Sex difference in 5HT2 receptor in the living human brain
Neuroscience Letters
(1996) - et al.
Ovariectomy and estradiol treatment affect the dopamine transporter and its gene expression in the rat brain
Molecular Brain Research
(1997) - et al.
Gender differences in substance use disorders
Addictive Disorders
(1999) - et al.
CuZn-superoxide dismutase (CuZnSOD) transgenic mice show resistance to the lethal effects of methylenedioxyamphetamine (MDA) and of methylenedioxymethamphetamine (MDMA)
Brain Research
(1994) - et al.
Sex differences in the effects of gonadectomy on amphetamine-induced rotational behavior in rats
Behavioral and Neural Biology
(1986) - et al.
A regional study of sex differences in rat brain serotonin
Progress in Neuro-Psychopharmacology & Biological Psychiatry
(1988)
Sex and estrogen influence drug abuse
Trends in Pharmacological Science
Sex differences in striatal dopamine: in vivo microdialysis and behavioral studies
Brain Research
Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion
Biochemical Pharmacology
The pre-clinical behavioural pharmacology of 3,4-methylenedioxymethamphetamine (MDMA)
Neuroscience and Biobehavioral Reviews
Hyperthermia following MDMA administration in rats: effects of ambient temperature, water consumption, and chronic dosing
Physiology & Behavior
Neurotoxicity of MDMA (ecstasy): the limitations of scaling from animals to humans
Trends in Pharmacological Sciences
Gender differences in the brain: are they relevant to the pathogenesis of schizophrenia?
Comprehensive Psychiatry
Ketanserin and anxiety levels: influence of gender, estrous cycle, ovariectomy and ovarian hormones in female rats
Pharmacology, Biochemistry & Behavior
5-Hydroxytrytamine mediated behavior in male and female rats
Neuropharmacology
17beta-estradiol at a physiological dose acutely increases dopamine turnover in rat brain
European Journal of Pharmacology
Mood response to acute tryptophan depletion in healthy volunteers: sex differences and temporal stability
Neuropsychopharmacology
Effects of nicotine and stress on locomotion in Sprague-Dawley and Long-Evans male and female rats
Pharmacology, Biochemistry and Behavior
Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine
Hormones and Behavior
Sex differences in cocaine-induced behavioral responses, pharmacokinetics, and monoamine levels
Neuropharmacology
Sex steroid modulation of the serotonin behavioral syndrome
Life Sciences
Sex differences in the locomotor-activating effects of amphetamine: role of circulating testosterone in adulthood
Physiology & Behavior
Epidemiology, pathophysiology, and management of hyponatremic encephalopathy
American Journal of Medicine
Long-lasting effects of (±)3,4-methylenedioxymethamphetamine (ecstasy) on serotonin system function in humans
Biological Psychiatry
Differences in hypothalamic serotonin between estrous phases and gender: an in vivo microdialysis study
Brain Research
Characteristics of pregnant women who use ecstasy (3,4-methylenedioxymethamphetamine)
Neurotoxicology & Teratology
Gender differences in prevalence of drug use among high risk adolescents in Israel
Addictive Behaviors
Ecstasy (MDMA) dependence
Drug & Alcohol Dependence
Acute effects of d-amphetamine during the early and late follicular phases of the menstrual cycle in women
Pharmacology, Biochemistry & Behavior
Gender differences in brain and behavior: hormonal and neural basis
Pharmacology, Biochemistry & Behavior
Sex differences in dopamine receptor overproduction and elimination
Neuroreport
Pubertal changes in gonadal hormones do not underlie adolescent dopamine receptor overproduction
Psychoneuroendocrinology
Hyponatremia, convulsions, respiratory arrest, and permanent brain damage after elective surgery in healthy women
New England Journal of Medicine
Management of hyponatraemia
British Medical Journal
Chemical analysis of ecstasy pills
Journal of the American Medical Association
Somatic symptom reporting in women and men
Journal of General Internal Medicine
The influence of age and sex on the prevalence of depressive conditions: report from the National Survey of Psychiatric Morbidity
Psychological Medicine
Gender differences in the behavioral responses to cocaine and amphetamine. Implications for mechanisms mediating gender differences in drug abuse
Annals of New York Academy of Sciences
Strategies and methods for research on sex differences in brain and behavior
Endocrinology
Self-reported ecstasy use: the impact of assessment method on dosage estimates in recreational users
Journal of Psychopharmacology
Memory impairment in abstinent MDMA (“ecstasy”) users
Neurology
Age-related differences in the chronic and acute response to cocaine in the rat
Developmental Psychobiology
3,4-Methylenedioxymethamphetamine (ecstasy)-induced learning and memory impairments depend on the age of exposure during early development
Journal of Neuroscience
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