No compelling evidence exists that taking a single c.125mg dose of MDMA a few times or so a year is likely to cause any long-term harm to the user’s mental or physical health. Nevertheless, even pharmaceutical-grade MDMA taken at moderate doses in optimal conditions is not a wholly benign drug. The problem isn’t (just) the toxic adulterants used by dance-floor pharmacologists or the botched syntheses of bathtub chemists.
Deceptively, and in contrast to most other recreationally used drugs, ingesting pure MDMA can sometimes leave the user feeling better than normal the next day, albeit tired and slightly spaced-out. Beyond warm memories, this afterglow may in part be explained by MDMA’s residual amphetamine metabolic by-products: MDMA itself has a long, c.8-9 hour elimination half-life from the blood; and its main metabolite’s longer-acting, less stimulating (-)-MDA enantiomer has 5-HT2A activating effects resembling low-grade LSD. But two days or so after taking MDMA, most users experience the serotonin dip. The dip ranges from the almost imperceptible to the markedly unpleasant. The functional deficit the dip reflects may last ten days or more – in some cases possibly weeks or months. A biphasic post-E serotonin profile in the user has been reported: users’ serotonin levels – though hard to measure and interpret – apparently fall 3-6 hours after taking the drug, then recover to nearly normal levels after around 24 hours, and then decline again.
Excessive MDMA intake triggers oxidative damage to the user’s serotonergic nerve cell fine axon terminal lipids and proteins via the production of toxic free radicals. However, the threshold dose for any lasting MDMA-induced toxicity is unknown; and the identity and precise mechanism of the chemical(s) causing the oxidative stress is unclear. The issue is also controversial. Currently the three leading candidates for guilty agent are:
- toxic metabolites of MDMA
- toxic metabolites of dopamine
- impaired cellular energetics
An excellent review of the published scientific evidence on neurotoxicity is offered by Matthew Baggott and John Mendelson on the indispensable Erowid. A role has also been proposed for nitric oxide; increased Ca2(+); and a toxic intraneuronal metabolite of serotonin. Elevation of body temperature can seriously worsen possible MDMA-induced toxicity; and the thermogenic effect of MDMA is magnified in a hot environment like an indoor rave. Certainly, hypothermia-inducing agents are (partially) neuroprotective against Ecstasy damage; and the primary role of dopamine in MDMA-induced toxicity may actually be to elevate body temperature via its increased action on the dopamine D1 receptors rather than its uptake into the depleted serotonergic axon terminals. But consensus on the molecular mechanisms behind MDMA megadose-induced damage remains elusive.
MDMA itself (probably) isn’t the culprit. Experimental microinjection of MDMA, MDA or other amphetamine analogues directly into the cerebrum doesn’t produce the toxicity to the serotonergic axons ascending from the dorsal raphÃ© nucleus that follows high and/or frequent doses of the peripherally administered drug. MDMA can be centrally injected to induce the release of just as much serotonin as the toxic peripherally-administered dose; but there’s still no sign of neurotoxicity. Nor does experimental central MDMA perfusion trigger the toxicity-enhancing higher body temperatures likely from the peripheral route. When MDMA is centrally administered in animal experiments, not even artificially inducing hyperthermia in the victim is enough to produce serotonergic damage. If systemic metabolism of MDMA is indeed necessary for neurotoxicity, the nature of any such possible toxic metabolite(s) is unknown: thioether conjugates of alpha-methyl dopamine have been mooted. Since drug metabolites are normally more hydrophilic than their parent drug, specific transporters are presumably needed to take up the neurotoxic metabolite into the brain; but their identity or even existence isn’t known either. If they do exist, then presumably they are monoamines; otherwise selegiline wouldn’t be protective against MDMA-induced neurotoxicity.
Whatever the mechanism at work, most users eventually stop taking MDMA. They do so after either they find the E-magic wears off, or the unwanted side-effects of heavy E-use begin to outweigh its joys. Even so, some heavy MDMA users claim they don’t experience any long-term adverse effects. Prolonged MDMA administration can even cause a long-lasting increase in the dopamine content of the nucleus accumbens, possibly indicating its disinhibition from normal serotonergic control. The persistent elevation of dopamine function reported in the nucleus accumbens of some MDMA veterans might otherwise be expected to enhance mood, not darken it. Likewise, MDMA users may be less anxious or panic-stricken in response to the normally anxiogenic challenge of a 5-HT2C agonist such as m-chlorophenylpiperazine (m-CPP). Depending on one’s ideological agenda, this diminished response to m-CPP can be described as evidence either of serotonergic “toxicity”, or alternatively as a pointer to the substrate of a long-lasting “therapeutic” effect. Again, MDMA use increases sensitisation to the rewarding effects of euphoriant dopaminergics such as cocaine; and once more, this is not inherently a sign of “brain damage”. However, reports of real and serious health problems from excess E-use are not all prohibitionist propaganda or part of a government-inspired conspiracy to stop young people having a good time. Among heavy “recreational” MDMA users, self-medicating or otherwise, the incidence of depression seems to be more common than healed minds or any enduring therapeutic benefit. The prospect of serotonergic axon terminal degeneration doesn’t sound much fun, even if the axons re-sprout – one way or another. Worryingly, the MDMA-induced pruning of the serotonergic axon tree seen at high-dosage regimens leads to altered patterns of reinnervation by ascending axons projecting especially to forebrain sites. In the process of recovery from a prolonged MDMA-binge, the hippocampus, a brain structure critical for episodic memory formation, may actually be hyperinnervated, but reinnervation of the dorsal cortex is sparser. It has been suggested that the heavy MDMA user who discerns no long-lasting ill effects, and who displays minimal functional impairment, may still be subtly damaging his or her serotonergic “functional reserve”. The disturbing parallel drawn here is with neurodegenerative disorders: clinical signs of Parkinson’s disease, a progressive disorder caused by outright dopaminergic cell death and frequently prefigured by depression, only become apparent after 70-80% of dopamine cells have been lost. It is fiendishly hard to demonstrate MDMA-induced dopaminergic cell damage without virtually killing the victim; in contrived circumstances it can be done. Yet the most notorious attempt to show MDMA-induced dopaminergic neurotoxicity, Ricaurte’s September 2002 paper Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (“Ecstasy”) in Science, actually demonstrated methamphetamine-induced dopaminergic neurotoxicity instead. This unfortunate study, its publication timed to coincide with debate in US Congress over the “Anti-Rave Act”, was retracted in September 2003; but the spectre it raised of a post-E generation of Parkinsonian zombies may prove harder to dispel.
Not even heroic doses of MDMA are likely to kill off serotonergic brain cells, though there have been unconfirmed reports of MDMA-induced apoptosis in mega-dosed rats. Only the most alarmist commentators anticipate a delayed epidemic of demented depressives as a result of serotonergic carnage caused by MDMA abuse. But equally, no alien anthropologist in his right mind who merely read the gruesome scientific literature on MDMA would want to self-experiment with such a deadly neurotoxin. Taking weed-killer, glue sniffing or swallowing rat poison sounds marginally less dangerous. Calling it dystopian pharmacology might seem more apposite. Even listening to glowing, first-person accounts of the MDMA experience is curiously uninspiring when refracted through the lens of our normal Darwinian consciousness. The prospect of love, peace and empathy seems less exciting than a round of Quake 3. We are all prone to mood-congruent thoughts.
In any case, MDMA users themselves may find the magic of the initial drug-induced epiphany tends to fade with frequent use. For many but not all users, a magical drug becomes just a feel-good drug. Adverse side-effects tend to become more troublesome. Higher doses are needed to gain the same effect. Users lament that “the E isn’t as pure as it used to be”; and that the tablets are weaker. Often indeed this is true; but a physiological explanation for so-called “cumulative tolerance” must be sought as well. Enzyme-induction plays a role, though the phenomenon isn’t fully understood. Pharmacodynamic tolerance to a drug is normally reversible, yet some users of MDMA report they never quite recapture the initial ecstatic glory even if they abstain for a year or more. Researchers are still unsure if this fade-off is a symptom of long-term neuroadaptation or serotonergic damage.
Perhaps we shouldn’t be so surprised at the “loss of magic”. The liver (and the brain) is adapted to life on the African savannah. Our vital organs can’t know the difference between the elixir of life and a poison. MDMA has the attributes of both, and in the African bush, the latter is a more realistic outcome. Yet we won’t be trapped in brutish states of consciousness for ever. In the near future, functional analogues of MDMA promise to enhance mental health, add perpetual magic to our lives, and beautify our troubled minds. Empathetic bliss isn’t inherently toxic; though its reactive metabolites may be. In principle, the psychopathologies of everyday life can all be cured. MDMA offers a foretaste of life in post-Darwinian paradise; but it delivers, at best, only a fleeting hint of the magic to come.