Iravani MM, Jackson MJ, Kuoppamaki M, Smith LA, (2003) 3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates

Iravani MM, Jackson MJ, Kuoppamaki M, Smith LA, (2003) 3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates. J Neurosci 23 (27):9107-9115.

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In this study, researchers sought to discover whether MDMA could reduce or eliminate problems that can arise from long-term treatment with medications intended to treat Parkinson’s disease (PD). These treatments increase motor activity and reduce the slow movements associated with PD, but in turn they can cause dystonias (abnormal movements) and chorea (flicking or waving arm movements). The researchers used MPTP-treated marmosets (non-human primates) as a model for Parkinson’s disease, and they used drugs that influenced serotonin and dopamine receptors to try to tease out what neurotransmitter systems are involved in the dyskinesia-abating actions of MDMA.

Marmosets without damaged dopamine cells showed less movement immediately after receiving 12 mg/kg MDMA, and marmosets with brain dopamine cells damaged by MPTP showed an increase in movement followed by a decrease in movement. Motor activity levels in MPTP-treated marmosets given a regime of anti-Parkinson medication intended to provoke dyskinesias showed as much movement as marmosets without dopamine cell damage, and dyskinesias were attenuated or eliminated without reducing improved motor activity, with effects lasting about 4 hours.

MPTP-treated marmosets given MDMA and another drug that activates dopamine D2 and D3 receptors had fewer dyskinesias than expected, but they still had increased motor activity. On the other hand, pre-treatment with a selective serotonin uptake inhibitor (SSRI, or Prozac-type drug) interfered with the anti-dyskinesic effects of MDMA. Several drugs that reduce action at (antagonize) specific serotonin receptors (5HT1A, 5HT1B and 5HT2A/2C receptors) also reversed MDMA’s anti-dyskinesia effects. Wondering whether MDMA might reduce dyskinesias by activating 5HT1A and 5HT1B receptors (two other serotonin receptors), the researchers gave MPTP-treated marmosets with drug-induced dyskinesias another drug that directly activated (was an agonist at) these receptors. However, the 5HT1A/1B agonist produced abnormal posture and trembling gait, changes not seen after MDMA.

The researchers concluded that MDMA could reduce unwanted motor abnormalities arising from other drugs intended to treat the slow and difficult movements that occur with Parkinson’s disease. After considering the results of altering serotonin and dopamine receptors, the researchers hypothesized that MDMA acts by altering serotonin function, including serotonin release and 5HT2 receptors (many psychedelic drugs act on 5HT2A receptors). However, the anti-dyskinesic effects of MDMA almost certainly involve actions on the dopamine system as well, and probably require the presence of dopamine, since MDMA alone only temporarily improved MPTP-treated marmosets. The researchers also consider the possibility that MDMA, or its metabolites (such as HMMA) reduce dyskinesias by acting on other neurotransmitter systems, such as that for arginine vasopressin, but these hypotheses have not yet been tested.

It is important to note that MDMA metabolism in marmosets has not been compared with metabolism in humans or in other non-human primates, and that the higher dose used in this study (12 mg/kg) is higher than typical human doses. A recent study in rhesus monkeys found that blood MDMA levels after 10 mg/kg injection (of the S-(+) form of MDMA) are ten times higher than levels in humans ingesting 40-125 mg (approximately 0.6-1.8 mg/kg) MDMA (humans usually ingest racemic MDMA, consisting of both forms). Hence study results should be interpreted with caution, as it may be that MDMA is ineffective at controlling dyskinesia when given at doses that more closely approximate amounts used by humans. However, the same anecdotal account that stimulated interest in MDMA as a treatment for L-DOPA provoked dyskinesia suggests that typical human doses of Ecstasy are capable of dramatically reducing dyskinesia.

Other studies in rats have examined MDMA and related drugs (MDE, MDA and MBDB) as potential treatments for Parkinson’s disease or dyskinesias arising from medication for Parkinson’s disease (Banjaw et al. 2003; Lebsanft et al. 2003; Schmidt et al. 2002). These studies also suggest that entactogens can treat motor problems similar to Parkinson’s disease. However, these studies used different models than the study in marmosets, with some models finding that MDA was even better than MDMA in one model, whereas another model found that MDMA, followed by MDE, were best at treating Parkinson’s-like movements in rats.

Given that MDMA and other related entactogens strongly activate the sympathetic system (i.e. increase blood pressure and heart rate), and given the potential for daily MDMA use to harm brain serotonin cells, and possibly heart valve cells (see Setola et al. 2003), it is unlikely that MDMA or other entactogens will be used to reduce dyskinesias in people with Parkinson’s disease. However, these findings might lead to a drug that can reduce dyskinesia and can be administered daily.