"Practically any stimulus capable of causing injury to a tissue or organ can, when applied close to (but below) the threshold of damage, activate endogenous protective mechanisms--thus potentially lessening the impact of subsequent, more severe stimuli." -- Dirnagl et al. 20031

One of the more interesting neurotoxicity research findings over the last 25 years is that exposure to a low dose of a neurotoxin can provide protection against more severe damage from a later dose of the same substance. For methamphetamine, this was first documented in 1985,2 and in 2006, researchers found that "chronic, intermittent exposure" to MDMA in rats blocked severe damage to the serotonin system from a later high "binge" dose (Piper et al. 2006).3 A second research group recently published confirmation that pre-treatment with MDMA provides protection against a later neurotoxic dose (Bhide et al. 2009).4

Background Summary

MDMA causes damage to serotonin neurons at high doses High doses used by humans overlap those shown to be neurotoxic in rats and non-human primates Risk of neurotoxicity very likely increases with re-dosing and stacking multiple doses Risk of serotonergic damage could be highly individual MDMA neurotoxicity in humans probably results in mild, but detectable reductions in some types of verbal memory and possibly an increase in depressive symptoms in some people Research continues to refine the boundaries of MDMA neurotoxicity in humans in terms of dosage and types of problems that result from damage

The MDMA regimens used for both the pre-treatment and neurotoxic doses differed between the two studies. Piper et al. pre-treated adolescent rats with two 10 mg/kg subcutaneous (s.c.) injections of MDMA, four hours apart, every five days for a total of seven injections. Bhide et al. pre-treated adult rats with a single 10 mg/kg dose injected i.p. (into the abdominal cavity) every day for four days. Bhide et al. also administered a single 10 mg/kg pre-treatment dose to a different set of rats.

Piper et al. waited seven days after the last pre-treatment dose and then administered a neurotoxic regimen of MDMA, 10 mg/kg s.c. every hour for four hours to both pre-treated rats and untreated controls. Bhide et al. waited one day after the final pre-treatment and used a similar neurotoxic regimen, administering four 10 mg/kg doses separated by two hours instead of one. Both waited about a week after the neurotoxic doses before sacrificing the animals to autopsy their brains.

The neurotoxic dose regimens resulted in sharp declines in serotonin activity in the rat brains, with as much as an 80% reduction in serotonin reuptake transporter (SERT) binding in some areas. In each study, control rats administered the pre-treatment without a following neurotoxic dose showed modest reductions in SERT binding compared to rats given only saline. However, pre-treatment also completely prevented the severe reductions caused by the later neurotoxic dose regimen in rats that received both. The rats that received a single pre-treatment from Bhide et al. were less protected than those that received the four pre-treatment doses.

These two studies leave open the question of how high a pre-treatment dose needs to be in order to effectively block later neurotoxicity. Since the pre-treatment doses were high enough to be on the edge of neurotoxicity themselves and resulted in slightly reduced serotonin system activity, it may be that prophylactic effects arise only when initial doses are high enough to cause at least a small amount of damage.

Duration of the prophylactic effect is also unknown. Piper et al.'s research shows that the protection lasted at least a week. However, Bhide et al. reported that they did not find pre-treatment protective if they waited four days to administer the neurotoxic dose regimen rather than one day, and they report that "the neuroprotective effect of MDMA preconditioning was relatively transient in nature." The age of the rats or the exact pre-treatment regimen might be factors, but this will have to be studied further to resolve these issues.

The prophylactic mechanisms have not been established, but possibilities include up-regulation of endogenous antioxidant systems in the brain in response to the earlier dose, or neurons reacting less strongly to MDMA after being exposed in the recent past. The protection does not result simply from reduced MDMA effects in general, as physiological responses such as increases in body temperature were not reduced by pre-treatment.

Research into this phenomenon is still in its infancy, but suggests that starting with a lower dose of MDMA might be beneficial, not only to assess individual reaction, but also to possibly train the body and brain to better handle a higher dose later. It may also help explain why those who have used MDMA twice per weekend for months or years at a time do not have as many cognitive deficits as has been predicted from previous rat research: perhaps the body and brain adapt.