Ecstasy (MDMA) and Mental Health: Nerves or Neurosis ?

Dr. Karl L. R. Jansen MB.ChB., M.Med.Sci., D. Phil. (Oxon), MRCPsych
e-mail: K@BTInternet.com

The use of Ecstasy (methylenedioxymethamphetamine, MDMA) has been linked with a wide range of psychiatric sequelae such as anxiety, panic attacks, depression, insomnia, depersonalisation, derealisation, cognitive deficits, flashbacks, hallucinations and other perceptual disorders, and paranoid delusions and other forms of psychotic phenomena (Jansen, 1997; McCann et al., 1996; McGuire, Cope and Fahy, 1994). The list is extensive, diverse and non-specific, raising questions about the possible causes of these observations, and appropriate methods of treatment.

A key issue is whether the symptoms are primarily due to neuronal changes affecting the nervous tissue of the brain, as suggested by those conducting animal experiments, or by the psychological effects of the drug upon the mind.

It is now 10 years since the introduction of Ecstasy into the U.K., in 1987, and it is timely to consider the current state of this controversy and the resulting implications for future research.

First synthesised in 1912, there was little interest in Ecstasy until the mid-1970's when the drug was explored as an aid to psychotherapy. In this context, the key effects were feelings of empathic understanding for others and a release of emotions. By the early 1980's, Ecstasy had moved off the couch and into the community, and in the 1990's recreational use became widespread, as did reports of psychiatric sequalae (McGuire, Cope and Fahy, 1994). It was also reported that large doses of MDMA repeatedly injected into animals resulted in a partial loss of serotonin in a dose dependent fashion, and could permanently damage serotonergic nerve terminals (Battaglia et al., 1988). Serotonin deficits were also reported in some human Ecstasy users (Review: McCann et al., 1996; Ricuarte et al., 1990), but the relevance to humans taking one or two tablets occasionally was questioned (Grob et al., 1992). MDMA was shown to be more toxic in the primate than in the rat, with some investigators reporting extensive destruction of nerve terminals at doses only twice the usual human dose (Molliver et al., 1989; Ricuarte et al., 1988). Persons taking large quantities of MDMA in a binge pattern of use were thus at risk. As reduced serotonin levels have been linked to mood changes, it was suggested that heavy users might develop depression and anxiety in the future, a 'neurological timebomb'.

Attempts to explain adverse sequelae focussed upon these chemical issues while the 'mind' aspect was largely ignored, despite the fact that MDMA is a powerful releaser of emotions and could be expected to have an effect upon the 'psychodynamic equilibrium'. Psychotherapy can involve bringing repressed material into waking consciousness, and the weakening of blocks and defences. MDMA was given to patients by some psychotherapists for this purpose (Greer and Tolbert, 1990). The consequences of the removal of defences against disturbing material in a non-psychotherapeutic, possibly harmful context where the thoughts and feelings cannot be worked through or contained could be anxiety, depression, insomnia, depersonalisation and nightmares - symptoms which have in fact been linked with the use of MDMA.

That psychological causes need to be considered is supported by the observation that in a significant number of cases there appears to be no clear link between the duration of use or the dosages taken, and the probability of developing psychological symptoms (e.g. Wodarz and Boning, 1993). Persons who report persisting symptoms which are still present months after the consumption of MDMA may date the symptoms from one dose taken on a particular occasion, and may have quite limited drug histories. The general absence of detectable behavioral changes in animals following chronic, high dose administration of MDMA, after a wash-out period, must also be considered. The animals can have very dramatic changes in serotonergic terminals in the brain without demonstrating any behavioural changes, and without developing symptoms consistent with animal models of depression before their death (McCann et al., 1996). A brief period of low mood after taking Ecstasy may be due to low serotonin levels, but this 'come-down' is not what is usually implied by the term 'psychiatric sequelae.'

These observations may be explained by the finding that MDMA damages one type of serotonin terminal ('thin' fibres) and not those of a second system ('thick' fibres) (Molliver et al., 1989). It may be the relatively undamaged 'thick' fibres which continue with the regulation of mood, appetite, sleep, and other key serotonergic functions. Serotonin levels are low for a week in this second system, but the structural changes are generally not seen (Molliver et al., 1989). This matches the weekly cycle of what has actually been observed in humans.

Problems with the Data

Discovering the causes of psychiatric sequelae following MDMA use is hampered by the predominance of single case studies and short, uncontrolled series. Although at least 40% of pills sold as 'Ecstasy' contain other drugs, including hallucinogens, there is rarely any evidence that the drug taken was actually MDMA. These short reports also often minimise the role of poly drug use, which is almost universal amongst persons who take Ecstasy (Meltzer, 1994), and often provide no information about the 'set and setting' : the personality, past experiences (including previous drug experiences) mood, motivations, attitudes and expectations, the environment and other people present. Many 'bad reactions' to LSD, psilocybin and mescaline were shown to be due to a 'bad' set and setting (Grinspoon & Bakalar, 1981; Strassman, 1984), rather than persisting neurochemical changes which do not occur with this group of drugs.

It is known from earlier studies with the 'psychedelic hallucinogens' that people with poorer premorbid adjustment, a history of psychiatric illness, drug-taking in an unsupervised setting, poly drug use, and self-therapeutic and/or 'peer-pressure-submission motive' are more likely to suffer complications (Strassman, 1984).

It is also important to recognise that, among the large group of drug users within the general population, a proportion will become mentally ill regardless of any drugs they have taken (Brabbins and Poole, 1996). Drug use may also be a symptom of impending or actual mental illness as a result of 'self-medication' or impaired judgement.

In human studies, serotonin reductions have been detected by comparison with a control group (Ricuarte et al., 1990). These are not prospective studies. It is possible that the 'reduction' is in fact due to preexisting differences. Those who take large quantities of psychostimulants may have genetically determined 'under-functioning' of serotonergic and/or dopaminergic systems, increasing the likelihood of depression and anxiety, and creating an inner drive to take drugs which provide temporary relief.

It is unknown whether or not Ecstasy can specifically induce a relapse of preexisting schizophrenia, beyond the increased risk of relapse attached to any substantial emotional stressor. Ecstasy experiences can be very emotional events, and for this reason alone one might expect to see an association with increased risk of relapse. Ecstasy releases dopamine in a similar manner to amphetamine and cocaine (Nichols and Oberlender, 1989) and as such might be expected to increase the risk of psychotic illness in a similar manner to other psychostimulants.

With respect to 'flashbacks', the likelihood that such phenomena are in fact due to persisting changes in the brain is considerably reduced by the observation that a wide array of drugs, with radically different mechanisms of action in the brain (e.g. LSD and ketamine), have also been linked to flashbacks. Ketamine use is as likely to result in flashbacks as LSD use (Siegel, 1978; Jansen,1993; Strassman, 1984).

There is some evidence to suggest that the use of Ecstasy may be associated with a condition where there is a higher level of internal imagery but no actual perceptual disorder. A psychological model for explaining this phenomenon suggests that perforations have been made in the defences which usually separate conscious from unconscious processes (Jansen, 1997). Consistent with a psychodynamic explanation, the imagery, which is both random and semi-meaningful, is intensified by anxiety-generating situations. Flashbacks, also described in Ecstasy users (McGuire & Fahy, 1992) may be a related phenomenon. Some flashbacks may be a form of post-traumatic stress disorder as they are more likely after traumatic drug experiences. Other flashbacks may be a form of psychological 'conversion disorder', where anxiety with a neurotic basis is 'converted' into psychological symptoms, just as it may be converted into physical symptoms such as a 'paralysed' arm.

Conclusions

Further studies are required to establish the true causes of the psychiatric sequelae which have been reported to follow the use of MDMA. While alterations to monoaminergic nerve terminals may play a significant role, many of the disorders which have been reported may also be related to psychological events rather than neurotoxicity. The implication is that some of these patients may profit from referral to psychotherapy, in addition to the more usual practice of prescribing serotonin active antidepressants.

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