Comments on Sotnikova et al. 2005
Research into MDMA and related drugs as potential treatments for Parkinson’s disease (PD), an often-debilitating movement disorder, began with the chance discovery by a former stuntman in England with young-onset PD. He found that when he took ecstasy, not only did he no longer experience the dyskinesias, or uncontrolled twitching, from one PD medication, but that he could move normally again for as long as the drug’s effects lasted. Soon after this discovery, teams of researchers in Germany (Banjaw et al. 2003; Lebsanft et al. 2003; Schmidt et al. 2002) and England (Iravani et al. 2003) began studying the effects of MDMA and related substances in animals. These studies simulated some of the symptoms of PD with a dopamine receptor antagonist and by damaging dopamine cells in one hemisphere in rats (Banjaw et al. 2003; Lebsanft et al. 2003; Schmidt et al. 2002), and by administering the dopamine neurotoxin MPTP to marmosets, a type of primate (Iravani et al. 2003). This research found that MDMA at doses close to or a little higher than those used by humans (2.5 to 10 mg/kg in rats, 12 mg/kg in marmosets) alleviated movement difficulties or stopped behavior associated with damaged dopamine neurons. These findings are especially interesting given that around the time this research first began, researchers in the US claimed to have found that MDMA caused PD-like symptoms in monkeys (Ricaurte et al. 2002), a claim that has since been retracted upon learning that they had administered methamphetamine, and not MDMA (Ricaurte et al. 2003). It is possible that MDMA produced some of these benefits through its dopamine-releasing actions or through indirect control of dopamine via 5HT2A receptor activity, as noted by Dr. David Nichols of Purdue University. However, while drugs that reduced 5HT2A receptor activity reduced the effectiveness of MDMA, Iravani’s team also found that 5HT1B antagonists and an SSRI also reduced its effectiveness, and MDE had better effects than the stronger dopamine releaser MDA. In the most recent study, it now appears that mice genetically engineered to lack the dopamine transporter (DAT knockout, or KO mice) and given a drug to stop dopamine synthesis still improve after receiving MDMA.
Sotnikova and colleagues (the researchers at Duke University) examined a large array of drugs with potential anti-PD activity. They were interested in finding out whether a newly discovered brain receptor, the “trace amine receptor” or TAR, plays a role in PD or its treatment. Their results suggest that drugs acting on the TAR can reduce freezing and improve movement in mice with little or no dopamine in their brains, though these findings do not rule out the importance of other neurotransmitter systems.
This study is an improvement on the studies in rats, because the researchers used a model of PD more closely resembles PD in humans, and because they conducted a far more thorough assessment of motor effects in their dopamine-deficient mice. However, except when they combined one enantiomer, or form, of MDMA (S-(+)-MDMA) with L-DOPA or carbidopa, the doses of MDMA the researchers found eliminated the movement disorders in DAT knockout mice were quite high, often above the LD50 for mice (meaning, the dose where 50% of animals die). And, in fact, normal mice died when they received the same doses of MDMA that helped the mice without dopamine move. In the studies where S-(+)-MDMA was given along with carbidopa or L-DOPA to DAT knockout mice, the researchers gave 5 and 10 mg/kg S-(+)-MDMA, and found that this form of MDMA and the conventional PD treatments acted together to reduce rigidity and increase movement in the mice without dopamine transporter. The researchers at Duke University and the German team both found that related compounds such as MDE and MDA also had anti-PD effects, but the Duke team’s research suggests that these effects are not related to its being an entactogen, since the putative entactogen alpha-ethyltryptamine did not help DAT knockout mice move normally.
It is notable that Tim Lawrence has “young-onset” PD, not the usual variety. This means that he is less subject to the risks that older people might face, and that his condition may not be the same as “normal” PD. It seems unlikely at present that MDMA itself will serve as a treatment for PD for a variety of reasons, but it is nonetheless surprising that it can reduce some of the side effects of PD medication, and that these effects might not be associated either with its effects on serotonin or dopamine.