MDMA and harm

John Fitzgerald, Department of Pharmacology, University of Melbourne

MDMA (methylenedioxymethamphetamine or Ecstasy was placed on a restricted schedule in 1985 by the Drug Enforcement Agency in the USA. Similarly, MDMA has been placed on a restricted schedule in Australia. The reasons fpr restricting access to the drug were that it was thought to be neurotoxic, it had high abuse potential and it had no medical use. Since that time there has been a great deal of pharmacological research into both its neurotoxicity and its abuse potential.

In this report, the actions of MDMA will be compared to those of some other neurotoxins and to the stimulant actions of amphetamine. In light of the harm minimization initiatives of the Australian national Campaign Against Drug Abuse 9Rolfe, 1989) this report will discuss new information about MDMA use in the community, its potential for harm and will arrive at a recommendation for keeping MDMA on a restricted schedule.

Pharmacology and harm
MDMA is known to reduce brain content of the neurotransmitter serotonin and to damage serotoninergic nerve terminals in the rat and primate brain selectively (for reviews see Peroutka, 1990). Repeated low doses (2.5 mg/kg twice a day for four days) selectively reduce the activity of serotonin synthesizing enzymes (Ricaurte et al., 1988). Larger doses result in neurodegeneration of serotonin containing cell bodies and nerve terminals in several regions of the brain (Battaglia et al., 1987). Other drugs which, like MDMA can be considered as amphetamine derivatives, such as para-chloramphetamine (Sanders-Bush et al., 1974), methamphetamine (Ricaurte et al., 1980; Hotchkiss & Gibb,1980) and the prescribed appetite suppressant, fenfluramine (Steranka & Sanders-Bush, 1979; Appel et al., 1989) have been reported to have similar neurotoxic effects, in similar dose ranges.

The availability of fenfluramine as a presciption drug has been used by some investigators to highlight an apparent contradiction in the scheduling of MDMA as a restricted substance (Barnes, 1989; Grob et al., 1990). There are, however, distinct differences between the two drugs. MDMA, unlike fenfluramine, is readily self administered by laboratory animals (Lamb & Griffiths, 1987; Beardsley et al.,1988) and humans (Chait et al., 1986), and in behavioural studies, its effects are similar to both hallucinogens (Oberlander & Nichols, 1988; Callahan & Appel 1988) and amphetamine (Glennon & Young, 1984; Kamien et al., 1986). MDMA and fenfluramine are similar in that they both release the neurotransmitter serotonin. MDMA, however, is quite a potent releaser of the neurotransmitters dopamine and noradrenaline (Fitzgerald & Reid, 1990), while fenfluramine has little or no dopamine-releasing activity (Hannengeisser etal., 1976) . The dopamine-releasing action of MDMA is very similar to that of amphetamine.

MDMA is different from amphetamine in its selective neurotoxicity; however, in several behavioural and neurochemical models, MDMA has a greater similarity to the stimulant d-amphetamine than to hallucinogenic amphetamine derivatives (Sadzot et al., 1989; Spanos & Yamamoto, 1989). A particularly clear demonstration of the similarity of MDMA to amphetamine was reported by Dimpfel et al. (1989), who found that MDMA altered the normal pattern of brain electrical activity (EEG) in a manner closely resembling that of amphetamine.

The conclusion from these laboratory observations is that MDMA has a balance of both stimulant and hallucinogenic effects, with a greater similarity to amphetamines with stimulant activity than those with hallucinogenic properties. This similarity places it in a category of substances that may have abuse potential. It is possible therefore that MDMA does have the potential to be harmful, not just because of the neurotoxicity data, but because of the propensity for it to be self administered.

Harm minimization and the legal status of MDMA
The profile of activity of MDMA derived from studies in pharmacological laboratories is very different from that coming from those who use MDMA both recreationally and therapeutically. It is the unique actions of MDMA reported by users that prompt arguments about the harm associated with the illegal status of MDMA.

The arguments to change the legal status of MDMA are: firstly, that at the current use levels, MDMA poses a low health risk to the user; secondly, users may be suffering because of the illegal status of the drug; thirdly, that there may be costs to society because of its illegal status; and finally, that MDMA may have significant therapeutic value.

While many medical researchers claim MDMA to be a widely abused drug, evidence of this has not appeared in the traditional indices of illicit drug abuse. In the US, deaths due directly or indirectly to MDMA intoxication appear to be rare (Dowling et al., 1987) and there have been only two reported deaths related to MDMA in Australia (State Forensic Science Laboratory ISFSLS, personal communication) and a death in New Zealand tenuously attributed to Ecstasy abuse (Ellis & Schimmel, 1989).

Manifestations of neurotoxicity resulting from recreational use of MDMA have not been found in studies of recreational MDMA users (Peroutka et al., 1987; Price et al., 1989) and behavioural deficits associated with reductions in brain monoamines have not been reported (Peroutka et al.,1988). The long term effects (if any) of MDMA may be difficult to detect as many MDMA users are polydrug users (Beck et al., 1989) and other confounding factors will be involved (Grob et al., 1990). In 1988, of the 30 or 40 MDMA users seen at St Vincent’s Hospital Clinical Pharmacology Unit in Sydney, none reported MDMA to be their main drug problem (Monaghan, 1988). MDMA use in the Netherlands is also thought to "fit into the light trend" (Barendregt, 1990) of recreational use.

In the only comprehensive work performed to date describing MDMA use in the community, Beck et al., (1989) report several factors that limit the use of the drug, including extrinsic factors such as availability and price, as well as intrinsic factors such as the development of tolerance and the enhancement of unwanted side-effects over time. These intrinsic factors are a disincentive to frequent use and would make addiction to MDMA most unlikely (Chesher, 1990;Peroutka, 1989).

While Beck et al., (1989) located a subset of heavy or binge users, most user groups in their study had relatively well controlled MDMA use. It is difficult to say whether this was a consequence of the snowball sampling, or simply that the majority of MDMA users are not abusing the drug.

No information suggests at present that MDMA users are suffering harm because of the illegal status of MDMA. There are few risks to the user associated with HIV transmission as intravenous use of MDMA is fairly rare (Beck et al., 1989).

Criminalization of a substance can lead to a reduction in the purity of the street drug. This may not be the case with Ecstasy, as samples analyzed in the US have been found to be relatively free of contaminants (Renfroe, 1986; Follow Me,1989), although in the Netherlands only 60% of Ecstasy samples tested actually contained MDMA (Barendregt, 1990). The MDMA content of confiscated samples of MDMA in Victoria in 1990 ranged from 80 to 120 mg, indicating a fairly high purity (SFSL, personal communication). The high purity of confiscated street MDMA has been reported in most states of Australia over the period 1986-1990 (SFSL, personal communication). The high cost of MDMA may well be related to its illegal status; however, the socioeconomic profile of the users in the study by Beck et al. (1989), would suggest that perhaps their disposable incomes could accommodate these prices. Predictably, the illegal status of MDMA has decreased its availability, however, the high price of MDMA may well stop other less sophisticated user groups from using MDMA (Newmeyer, 1986).

There is little to indicate whether there are significant costs to society due to the illegal status of MDMA. The number and size of MDMA seizures across Australia has increased over the period from 1987 to 1990, from two seizures in 1987 (amounting to 126 capsules), to five seizures in the first six months of 1990 (totalling 800 grams of over 90% pure powdered MDMA, 145 tablets and six capsules). This may well indicate heightened police activity, however the number of seizures is quite small in comparison to other illicit drugs, and may indicate that the use of MDMA is quite isolated and on a small scale, possibly in user groups that are less accessible to police investigations.

In terms of the harm associated with its criminality, the above indicators suggest that MDMA has a fairly low profile as a recreational drug.

Several reports from some US psychotherapists suggest that MDMA is a valuable psychotropic drug when used therapeutically, by enhancing interpersonal communication and personal insights (Greer & Tolbert, 1986; Grinspoon and Bakalar, 1986). The therapeutic effects of MDMA have yet to be demonstrated in a rigorous manner, and may never be revealed due to its restricted status (Beck et al., 1989). Preliminary studies from psychotherapists in Switzerland may well provide further insights.

The "New Age" users reported by Bech et al., (1989) to use MDMA therapeutically, to date, have not been reported as a prominent user group in Australia. Until ethnographic evidence details the user groups in Australia, we don’t know whether there is a large group of people using MDMA therapeutically who are disadvantaged by its illegal status.

Conclusions

There are two possible changes in the legal status of MDMA being discussed: decriminalization, and/or the placement of MDMA on a schedule where it can be prescribed for medical purposes. Each of these options must take into account MDMA’s potential for harm and alternatively, the harm caused by its illegality.

The pharmacological profile of MDMA has greater similarity to that of amphetamine than to the amphetamine derivatives fenfluramine and para-chloramphetamine, that have neurotoxic actions at serotoninergic neurones. This suggests that MDMA may have a higher potential for abuse than fenfluramine and para-chloramphetamine.

Perhaps MDMA does have the potential for moderate harm; however, in any debate on harm minimization, the pharmacology of the drug is not considered in isolation. On the one hand, it is known that MDMA can be used in a controlled way by young professionals (Rosenbaum et al., 1990). But on the other hand, it is not known whether there are other social milieus that use MDMA in an uncontrolled manner.

There are several groups in Australia currently exploring the patterns of MDMA use in three major cities. As yet, results are still preliminary, but if anything can be gleaned from the American experience of MDMA, we can expect great variability in user groups and the levels of use. To determine the true potential for harm resulting from MDMA use, we must find out who is suffering most at present from its illegal status and alternatively, who is most likely to suffer if the legal status of MDMA is altered.

To justify decriminalization of MDMA, we require evidence that there is a substantial amount of harm to the community caused by its illegal status. At present, because of both a lack of information and because of its low profile as a recreational drug, there are no indicators suggesting that the community is suffering because of its illegal status. It is for these reasons that changing the legal status of MDMA does not seem to be warranted.

References

Appel N.M., Contrera J.F & Desouza, E.B. 1989 Fenfluramine selectivbiy and differentially decreases the density of serotonergic nerve terminals in rat brain. J. Pharmacol. Exp. Ther., 249, 928-943.

Barendregt, C. 1990 Dutch conference on MDMA, The International Journal on Drug Policy, 1, 8.

Barnes, D.M. Neurota xicity creates regulatory dilemma. Science. :t43, 29-30.

Battaglia, G.A., Yeh, Kuhar, MJ. & Desou . Methylenedioxymethmethylenedioxyamph terminals in rat brain: neurodegeneration b paroxetine-labelled s Pharmacol. Exp. Thq

Beardsley. P M., Balst Self administration of methylenedioxymetha rhesus monkeys. Dru .Y, O’Hearn, E., rVIUIIIVF " ,v,.C.,a, E.B. 1987 3,4-mphetamine and 3,4-tamine destroy serotoninquantification ofmeasurement of [3H]rotonin uptake sites. J.q !r., 242, 911-91–.t er, R.L. & Harris, L.S. 1988R mphetamine (MDMA) byl g & Alcohol Dependency, 18,149-157.

Beck, J., Harlow, D., McDonnell, D., Morgan, PA., Rosenbaum, M. & Watson, L. 1989 Exploring Ecstasy: A description of MDMA users. Report to the National Institute –n Drug Abuse. Institute for Scientific Analysis, San Francisco, California.

Callahan, RM.& Appel, J.B.1988 Differences in thestimulus properties of 3,4-methylenedioxyamphetamine and 3,4- methylenedioxymethamphetamine in animals trainedt0o discriminate hallucinogens from saline. J. Pharmacdt. Exp. Ther., 246, 866-870.

Chait, L.D., Uhlenhuth, E.Bi. & Johanson, C.E. 1986 The discriminative stimulus and subjective effects of d-amphetamine, phenmetrazine and fenfluramine in humans. Psychopharmacology, 89, 301-306.

Chesher, G. 1990 Designer drugs-the "whats" and the "whys". Medical Journal of Australia, 153, 1 57-161 .

Dimpfel, W., Sp�ler, M. & Nichols, D.E. 1989 Hallucinogenic and stimulatory amphetamine derivatives: fingerprinting DOM, DOI, DOB, MDMA, and MBDB by spectral analysis of brain field potentials in the freely moving rat (Tele-Stereo-EEG). Psychopharmacology, 98, 297-303.

Dowling, G.P, McDonough, E.T & Bost, R.O. 1987 ‘Eve’ and ‘Ecstasy’ A report of five deaths associated with the use of MDEA and MDMA. Journal of the American Medical Association, 257, 1615-1617.

Ellis, P 1989 Ecstasy abuse. New Zealand Medical Journal, 102, 358.

Fitzgerald, J.L. & Reid, J.J. 1990 Methylenedioxymethamphetamine ( MDMA) has di¤erential effects on monoamine release in rat brain slices. European Journal of Pharmacology, (In press).

Follow Me 1989 Ecstasy... or agony?, Dec/Jan., 84

Glennon, R.A. & Young, R. 1984 Further investigations of the discriminative stimulus properties of MDA. Pharmacology ot Biochemical Behaviour, 20, 501- 505.

Greer, G. & Tolbert, R. 1986 Subjective reports on the effects of MDMA in a clinical setting. Journal of Psychoactive Drugs, 18, 318-327.

Grinspoon, L. & Bakalar, J.B. 1986 Can drugs be used to enhance the psychotherapeutic process? American Journal ot Psychotherapy, 40, 393-404.

Grob, C., Bravo, G. & Walsh, R. 1990 Second thoughts on 3,4-methylenedioxymethamphetamine (MDMA) neurotoxicity. Archives ot General Psychiatry, 47, 288-9.

Hannengeisser, M.H., Hunt, PF & Raynaud, J.R 1976 Comparative actions of fenfluramine on the uptake and release of serotonin and dopamine. European Journal ot Pharmacology, 35, 35-43.

Hotchkiss, G.A. & Gibb J.W. 1980 Long term effects of multiple doses of methamphetamine and tryptophan hydroxylase and tyrosine hydroxylase activity in rat brain. J. Pharmacol. Exp. Ther., 214, 257-262.

Kamien, J.B., Johanson, C.E., Schuster C.R. & Woolverton, W.L. 1986 The effects of (+j-methylenedioxymethamphetamine and (_)-methylenedioxymethamphetamine in monkeys trained to discriminate (+)-amphetamine from saline. Drug & Alcohol Dependency, 18,139-147.

Lamb, R.J. & Griffiths, R.R. 1987 Self-injection of d,1-3,4-methylenedioxymethamphetamine (MDMA) in the baboon. Psychopharmacology, 91, 268-272.

Monaghan, D. 1988 MDMA in the wards. Connexions, Jan/Feb, 19-21.

Oberlander, R.A. & Nichols, D.E. 1988 Drug discrimination studies with MDMA and amphetamine. Psychopharmacology, 95, 77-86.

Peroutka, S.J. 1989 ‘Ecstasy’: a human neurotoxin? Archives ot General Psychiatry., 46, 191.

Peroutka, S.J. 1990 Ecstasy: the clinical pharmacological and neurotoxicological effects of the drug MDMA. Norwell, MA. Kluwer Academic Press.

Peroutka, S.J., Pascoe, N. & Faull, K.F 1987 Monoamine metabolites in the cerebrospinal fluiri of recreational users of 3 4-methylenedioxymethamphetamine (MDMA ‘Ecstasy’) Res. Comm. Subst. Abuse, 8,125-138.

Peroutka, S.J., Newman, H. & Harris, H. 1988 Subjective effects of 3 4,-methylenedioxymethamphetamine in recreational users. Neuropsychopharmacology, 1, 273-277.

Price, L.H., Ricaurte, G.A., Krystal, J.H.& Heninger, G.R. 1989 Neuroendocrine and mood responses to intravenous L-tryptophan in 3,4-methylenedioxymethamphetamine (MDMA) users. Preliminary observations. Archives ot General Psychlatry, 46, 20-2.

Renfroe, C.L. 1989 MDMA on the street. Journal of Psychoactive Drugs, 18, 363-366.

Ricaurte, G.A., Forno, L.S., Molliver, M.E., & Langston, J.W. 1988 (_)3,4-methylenedioxymethamphetamine selectively damages central serotonergic neurons in non-human primates. Journal of the American Medical Assoclation, 260, 51-55.

Ricaurte, G.A., Schuster, C.R. & Seiden, L.S. 1980 Long-term effects of repeated methylamphetamine administration on dopamine and serotonin neurons in the rat brain: a regional study. Brain Res., 193, 153-163.

Rolfe, J.L. 1989 Drug control: legal alternatives and consequences. Current situation in Australia National & State policy context. Drug Rehabilitation & Research Fund. Melbourne.

Rosenbaum, M., Morgan, R & Beck, J.E. 1990 Ethnographic notes on Ecstasy use among professionals. The Internatlonal Journal on Drug Pollcy, 4,16-19.

Sadzot, B., Baraban, J.M., Glennon, R.A., Lyon, R.A., Leonhardt, S., Jan, C.R. & Titeler, M.1989 Hallucinogenic drug interactions at human brain 5-HT2 receptors: implications for treating LSD-induced hallucinogenesis. Psychopharmacology, 98, 495-9.

Sanders-Bush, E., Gallagher, D.A. & Sulser, R 1974 On the mechanism of brain 5-hydroxytryptamine depletion by p-chloramphetamine and related drugs and the specifity of their action. In Costa, E., Gessa, G.L. & Sandler, M. (eds) Advances in Biochemical Pharmacology 10,185. Raven Press.

Spanos, L.J. &Yamamoto, B.K. 1989 Acute and subchronic effects of methylenedioxymethamphetamine [(_)MDMA] on locomotion and serotonin syndrome behavior in the rat. Pharmacology of Biochemichal Behaviour 32, 835-40.

Steranka, L.R. & Sanders-Bush, E. 1979 Long term effects of fenfluramine on central serotonergic mechanisms . Neuropharmacology,18, 895-903.