ReviewIs ecstasy a drug of dependence?
Introduction
Increases in production, availability and consumption of 3,4-methylenedioxymethamphetamine (MDMA), or “ecstasy” (United Nations Office on Drugs and Crime, 2008a, United Nations Office on Drugs and Crime, 2008b) render appropriate a contemporary review of the dependence potential of the drug. The documentation of infrequent, context-specific and time-limited patterns of use meant it was long considered impossible to become dependent upon ecstasy (Peroutka, 1990). More recently, users’ reports of frequent use, bingeing and injecting (Dunn et al., 2007, White et al., 2006a), together with perceptions of associated risks and harms (Dunn et al., 2007, Topp et al., 1999, White et al., 2006b), have reflected the development of problems among some ecstasy users.
First, we describe the proposed features of a valid psychiatric diagnosis, the concept of drug dependence, and its theoretical basis. In accordance with the two major psychiatric classification systems, we use the term “dependence” rather than the term “addiction”. It is nevertheless acknowledged that some would disagree with this decision, and controversy surrounding terminology exists (O’Brien et al., 2006). The animal and human literatures pertaining to ecstasy dependence, and their limitations, are subsequently reviewed. To inform this review, searches were conducted using PubMed, PsycInfo and EMBASE to identify literature relevant to the existence and nature of any ecstasy dependence syndrome.1
In most areas of medicine the underlying pathogens of disease are understood and “gold standard” diagnostic tests exist. In contrast, the mechanisms underlying psychiatric illness are complex and relatively incompletely described. Features proposed to characterise a valid psychiatric diagnosis include that the diagnostic entity: (1) predicts a patient's prognosis (relative to someone who does not meet criteria); (2) is independent of other diagnoses; (3) predicts treatment response; (4) predicts the course over time; and (5) is related to neurobiology (Kendell, 1989a, Kendell, 1989b, Robins and Guze, 1970, Robins, 2004).
Alcohol dependence was, from an early stage, conceptualised as a cluster of symptoms in heavy drinkers that were distinguishable from alcohol-related problems (Edwards and Gross, 1976, Edwards et al., 1977). Seven core symptoms were described: (1) narrowing of the behavioural repertoire surrounding alcohol use; (2) salience of drinking (alcohol use given priority over other activities); (3) subjective awareness of a compulsion to use (loss of control over use, or an inability to stop); (4) increased tolerance; (5) repeated withdrawal symptoms; (6) relief or avoidance of withdrawal by further drinking; and (7) rapid reinstatement of dependent drinking after abstinence. These can be conceived as more psychological indicators (e.g. salience of drinking and awareness of compulsion) versus more overtly neurobiological (e.g. tolerance and withdrawal).
Dependence syndromes subsequently described for cannabis, tobacco, amphetamines, opioids and sedatives have demonstrated validity in terms of predicting prognosis (Kidorf et al., 1998), treatment response, and course over time. Neurobiological evidence supports a shared pathology underlying these syndromes (Koob, 2006, Koob and LeMoal, 1997, Nutt, 1997).
The most recent operationalisations of dependence are the DSM-IV (American Psychiatric Association, 2000) and ICD-10 (World Health Organization, 1993) classification systems (Hasin et al., 2006). Although no specific ecstasy/MDMA dependence diagnosis exists, it is possible to classify an ecstasy user as dependent upon hallucinogens and/or amphetamines (American Psychiatric Association, 2000). These differ both nosologically and empirically.
Amphetamine dependence criteria include a withdrawal syndrome (American Psychiatric Association, 2000), with symptoms including craving, fatigue, psychological distress and physical problems (Topp and Mattick, 1997b). Similar to drugs such as alcohol, opiates and cocaine (Nelson et al., 1999), DSM-IV diagnostic criteria for amphetamine dependence are unifactorial (Topp and Mattick, 1997b), results taken to signify a single underlying biological mechanism for the syndrome (Hasin et al., 2006) reflecting functional changes in an integrated neurobiological circuit affected by chronic drug use (Koob and LeMoal, 2005).
Hallucinogen dependence does not include a withdrawal syndrome (American Psychiatric Association, 2000). The limited research investigating this syndrome suggests that it is less severe than for amphetamines, and may conform to a two-factor structure (Morgenstern et al., 1994), suggestive of distinguishable processes underlying its pathology.
Two major neural systems have been implicated as substrates for the actions of most drugs of dependence (Koob, 2006, Koob and LeMoal, 1997, Nutt, 1997): the mesolimbic–frontocortical dopaminergic pathway and the endogenous opioid receptor system. Acute and chronic use of many drugs of dependence directly or indirectly affect the dopaminergic pathway (Nestler, 2005). Activation of 5-HT1A receptors is also important for behaviours related to psychostimulant dependence (Muller et al., 2007).
Neuroadaptation refers to complex functional changes in brain chemistry that occur, following repeated substance administration, to oppose the substance's effects in order that brain systems can maintain homeostasis. Adaptations include down-regulation of reward neural circuitry and up-regulation of neural systems mediating stress; and are thus thought to increase the likelihood of persistent dysphoria. Following discontinuation of use, the adaptations are no longer opposed; hence the brain's homeostasis is disrupted (Koob et al., 1997, Koob and LeMoal, 2001). According to this hypothesis, neuroadaptation explains the development of tolerance and withdrawal (Koob et al., 1997), which maintain drug use and may contribute to vulnerability to relapse (Koob and LeMoal, 1997). In contrast, the incentive sensitisation model (Robinson and Berridge, 2001, Robinson and Berridge, 1993) attempts to explain drug craving, even after extended abstinence, by distinguishing between ‘liking’ and ‘wanting’ a drug. It proposes that neuroadaptations render brain reward systems hypersensitive to drugs and associated cues, changes which are independent of drugs’ euphoric effects, such that a dependent user can ‘want’ a drug while not ‘liking’ its effects.
Behavioural models of dependence focus on directly observable behaviour. One class of behavioural model recognises that behaviour is maintained (or made more likely) by the consequences (reinforcers) of such behaviour (West, 1989). Drug self-administration is thus an example of instrumental behaviour because the activities of persons (or animals in an experiment) are instrumental in obtaining the desired consequences (the substance's subjective effects). When psychoactive drugs are available, many species of drug-naïve animals will self-administer them, often to excess, using a variety of routes of administration (Altman et al., 1996, Institute of Medicine, 1996). This observation underlies the operant reinforcement model of substance use. Substances might be reinforcing through their direct effects of upon brain reward systems; their effects upon other reinforcers such as social or sexual reinforcers, or through removing aversive stimuli such as distress or dysphoria; or cognitive effects such as increased attention (Altman et al., 1996).
A second class of behavioural theory of dependence is based on classical conditioning (Greeley and Westbrook, 1991, Heather and Greeley, 1990). Cue exposure (Drummond et al., 1995, Heather and Greeley, 1990) postulates that a cue previously present during substance administration will elicit a conditioned response (cue reactivity), which may underlie craving. Cue reactivity may explain the persistence of drug craving following extended abstinence (Heather and Greeley, 1990, Stewart et al., 1984). The environments in which withdrawal is typically experienced can become associated with the aversive effects of withdrawal itself, which may lead to drug craving, drug seeking and relapse to use after abstinence (Kenny, 2007, Schulteis et al., 2000).
There are numerous other theories of the development of dependence (Koob and LeMoal, 2005, West, 2006), with increasing evidence for interactions between behavioural and neurobiological processes, such that the two classes of models can be seen as complementary. The operationalisation of the dependence syndrome in DSM-IV and ICD-10 includes both physical and behavioural components. This takes into account that for some drug classes (and for some individuals) either aspect may be more prominent in the manifestation of dependence.
Research is increasingly elucidating the ways in which features that are typically considered as psychological components are expressed neurobiologically (Everitt and Robbins, 2005, Leshner, 1997, Volkow and Li, 2004). Drug dependence is likely to ultimately be well understood through its neurobiological underpinnings. Although that is imperative, the expression of such changes through psychological symptoms has clinical importance since it is those symptoms that will indicate changes that have occurred, and/or present opportunities for intervention.
Section snippets
Complicating issues in generalising laboratory research to recreational human use
The content of pills sold as “ecstasy” may not contain MDMA at all. As such, persons developing regular or “dependent” use of the drug “ecstasy” may not be consuming MDMA. Although the importance of expectancies in the subjective experience of acute drug effects has been established (e.g. Zinberg, 1984), the way in which this might facilitate dependent use is as yet unexplored.
Related to this is the possibility that some (or many) pills sold as ecstasy may contain methamphetamine, rather than
Case studies of ecstasy dependence
In 1999, Jansen described three cases of ecstasy dependence. Two were persons who had access to large amounts of high purity MDMA; the third involved escalating use by a person suffering from post-traumatic stress disorder. Each had developed clear tolerance to the effects of the drug; spent increasing amounts of time using and recovering from ecstasy; neglected other activities; perceived harms related to their use and had unsuccessfully attempted to cease use; and reported mild withdrawal
Summary and implications
The evidence for an ecstasy dependence syndrome is limited in both scope and design. Animal evidence suggests that MDMA may be a less potent reinforcer than other drugs, but that it nonetheless has dependence potential. This suggests that (a) the physiological basis of an ecstasy dependence syndrome might be relatively weaker in comparison to drugs with clear and marked dependence potential (e.g. opioids); and (b) other factors related to the behavioural and psychological aspects of reward and
Role of funding source
This review was assisted through funding from the Australian Government Department of Health and Ageing. Louisa Degenhardt is the recipient of an Australian NH&MRC Senior Research Fellowship (ID #510279). The funding bodies had no role in the design, interpretation or write up of this paper.
Contributors
L.D. led the writing and suggested structure. L.D., R.B. and L.T. all provided substantial input into the content, argument and conclusions of the paper.
Conflict of interest
None.
Acknowledgements
Many thanks to Natasha Sindicich, Bianca Calabria, Chiara Bucello, and Eva Congreve of the National Drug and Alcohol Research Centre, University of NSW, for their assistance in conducting literature searches and locating difficult to access papers for use in this review. This review was assisted through funding from the Australian Government Department of Health and Ageing and the Australian National Health and Medical Research Council.
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