Yesterday, we received tomorrow's issue of the New England Journal of Medicine and, yet again, I nearly walked into a tree coming back from the mailbox. This (abstract, full text), folks, is a fascinating medical detective story rivaled only by (and similar to) the discovery that Parkinson's disease could be caused by contaminant from a faulty clandestine synthesis of an analog of the opiate, meperidine. (1979, 1983)
Here's the backstory: in the US, our newly-implemented restrictions on ephedrine and pseudoephedrine OTC drug products are due to the use of these chemicals as starting materials for the illicit synthesis of methamphetamine. However, in Russia and the Baltic states these compounds are used to oxidatively synthesize a related euphoric compound called ephedrone or methcathinone. Methcathinone may sound familiar as it is related to the natural product, cathinone, a stimulant released when smoked as khat (from Catha edulis).
The mystery begins with the appearance of intravenous drug users aged 25 to 40 in Russia, Latvia, and Estonia presenting with symptoms of Parkinson's disease (first report in Russian literature in 2005). This movement disorder has its basis in the brain with the death of dopamine releasing neurons in a neuronal tract called the nigrostriatal pathway. The symptoms includes tremors at rest, inability to initiate muscle movement (akinesia), rigidity leading to jerky or overamplified muscle movement once initiated, and loss of balance (postural instability). Normally, Parkinson's is disease of later age (60 or greater but early-onset Parkinson's disease can be observed in individuals as young as their late 30s (think Michael J Fox).
The differential diagnosis of these cases holds the key to the mystery:
First, many intravenous drug users in the Baltics (and elsewhere) are HIV-infected and parkinsonian syndromes have been observed in HIV-infection and AIDS. However, the incidence of this is quite low and is usually associated with HIV-facilitated opportunistic infections of the central nervous system; moreover, HIV-infection enhances the parkinsonian side effects of some antipsychotic drugs that individuals might be taking for co-morbid schizophrenia or bipolar disorder. But as Stepens and colleagues noted:
We questioned the role of HIV as the underlying cause of the severe parkinsonian syndrome in our patients after encountering the syndrome in patients who were HIV-negative. Among those with the syndrome who were infected with HIV, less than half had progressed to AIDS, although the movement disorders associated with HIV infection are typically seen in patients with AIDS. Furthermore, the movement disorder we observed was remarkably stereotyped and unlike idiopathic Parkinson's disease
There are no data to indicate that methcathinone or the more widely used cathinone cause anything resembling Parkinson's disease. Only one 1998 paper is suggestive that methcathinone can reduce the abundance of the dopamine neuronal transporter but to a much lesser degree than that observed in patients with Parkinson's. But none of the methcathinone users had parkinsonian symptoms. Based on this very limited study, methcathinone use might at the very most predispose individuals to Parkinson's disease.
So, what was going on if the drug itself wasn't the culprit?
In the original Russian report, Levin suggested that the parkinsonian cases might be due to manganese toxicity. In the oxidation of ephedrine to ephedrone, potassium permanganate (KMnO4) is used under acidic conditions but the reaction mixture is then injected directly without first crystallizing the ephedrone/methcathinone away from the permanganate oxidant (it needs to remain in acetic acid to prevent it from degrading back into ephedrine; injecting this stuff must be quite painful). As a result, intravenous users of this preparation are also mainlining a known, heavy metal neurotoxicant that is known to cause Parkinson's disease in welders.
Of the 23 patients in the current NEJM study, 10 were active methcathinone users and 9 of these had blood manganese levels above normal (mean 831 nM, range 201-2102; normal <209). Sadly, those patients who had stopped using methcathinone and had lower manganese levels nevertheless had no resolution of their symptoms, suggesting this syndrome is irreversible. In fact, a couple of the patients failed to respond to conventional antiparkinsonian drugs like levodopa and one who underwent chelation therapy to reduce their manganese burden experienced no changes in their symptoms.
(For my neuroscience and neurology colleagues, the paper includes T1-weighted MRI images that illustrate lesions in the basal ganglia, specifically the globus pallidus, that was present in all active users. (To these colleagues, shouldn't the basal ganglia be called the basal nucleus since it's in the brain?). In addition, there are nuances in the neurological examinations that distinguish the extrapyramidal effects observed in iv methcathinone users that are distinct from patients with idiopathic parkinsonism.).
The bottom line is that a highly oxidizing form of manganese used to synthesize methcathinone (ephedrone) appears to be the root cause an irreversible, parkinsonian syndrome in individuals who inject this illicit drug intravenously.
As methamphetamine and methcathinone/ephedrone are synthesized from the same precursors there is considerable public health concern that while methamphetamine use is certainly debilitating, intravenous methcathinone use could be a far bigger problem if it spreads to larger populations.
Stepens A, et al. A Parkinsonian Syndrome in Methcathinone Users and the Role of Manganese. New Engl J Med 2008; 358:1009-1017. (abstract, full text)
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This is exactly what happens when you outlaw safe ways of getting high.
I dunno, the side affects of methamphetamine abuse are pretty gnarly. The "meth mouth" in particular really grosses me out.
To these colleagues, shouldn't the basal ganglia be called the basal nucleus since it's in the brain?
I hate explaining this unfortunate misnomer to students every year (twice, this year)...and some neuroanatomists do refer to them as basal nuclei (not sure about clinicians, though). The misnomer is particularly egregious, IMO, because "basal ganglia" actually includes nuclei derived from several different embryonic brain regions: caudate, putamen, and globus pallidus from telencephalon, subthalamic nucleus from diencephalon, substantia nigra from mesencephalon.
More than you ever wanted to know, I imagine.
No, no, Barn Owl - that's *exactly* what I was looking for. Thanks!
Carl Spackler: "Cinch bugs...you know...manganese...not a lot of people know what that is."
Wow! I've sent this off to a colleague who researches amphetamine neurotoxicity, and it will go into my next neurotoxicity lecture!
Khat is not smoked, - the fresh whole plant is chewed and then slowly sucked on (in Yemen people have a ball of it under their cheek for hours at time. Cathinone is rather unstable - as it should, alpha aminoketone - and the dried plant is inactive. Smoking would definitely destroy cathinone.
The methcathinone high is not "clean", druggies prefer methamphetamine if they can get it.
Inhaling Mn-oxide dust causes Parkinsonism - but a direct toxicity of methcatinone should not be discounted either.
I've never seen an adequate explanation of meth mouth. We don't have a ton of meth around here, comparatively, but we have enough that I've seen a bit of meth mouth (actually, I've diagnosed HIV in the same patients---high risk behaviors go together).
Anyone have a good explanation?
Good question, Doc. The pathophysiology of meth mouth seems to be multifactorial, probably initiated by the xerostomia and vasoconstriction of methamphetamine's direct action. PharmGirlMD reminds me that pts receiving head and neck radiation have to use Biotene rinse to compensate for decreased saliva production as xerostomia can increase the abundance of oral bacteria. The dental literature I've been able to dig up talks more about signs and symptoms but it seems that cravings for sugary drinks and overall poor dental hygiene further contribute.
That's all I have - anyone else?
@milkshake - thanks for correcting me on khat being chewed and for the insights on cathinone chemistry.
RE meth mouth -
Abel missed an important aspect, though as he mentions, there are a number of contributors, not the least being poor hygiene.
When meth is produced in makeshift labs, the solvents used are usually not pharmaceutical grade. I.e. carborator cleaner is a common source for ether and it's not uncommon for keytone based solvents to also be used. The problem with carb cleaner specifically and some keytone solvents, commonly used in painting an refinishing, is that solvent residue is left behind. The same is true of processes that utilize hydrochloric acid. When the drug is smoked, the residue is turned gaseous and wreaks havoc on the teeth and gums.
Ironically, if speed users brush their teeth when they smoke, they reduce the problem substantially. It is very common for salespeople and professionals who use meth, to carry and regularly use their toothbrush and paste. I suspect that after a certain point, abusers just don't care any more. I have never smoked meth myself, though I did ingest it for a while to see if it helped with my ADHD (it did), but I have used some very powerful enthogens in my day. I have a pretty good idea of how ambivalence towards important things such as hygiene, can become the rule with heavy drug use.
You are all too right about the risky behaviors going together. Of the dozen or so HIV/AIDS victims I know five are ex or current speed junkies. I think it is an important distinction though, that a couple of them were safe sex enthusiasts, before they got heavy into meth use. Heavy drug use is often the cause of other risky behaviors, rather than a partner to them. I still remember the night I took a massive dose of LSD and ended up having sex with a complete stranger, several times, without using protection. I have an uncle who died of AIDS and subsequently made a lot of friends who have HIV/AIDS. Even though I am in a monogamous relationship (kids tend to do that), I carry condoms around and give them out at every opportunity. Even at that time in my life, the notion of having unprotected sex, was just anathema to me. But there it happened, thankfully nothing bad came of it, but it had me freaked for several weeks as I waited for test results to be substantiated.
There is a very explanation of meth mouth: the crystal meth is hydrochloride salt that dissociates as it is smoked. The fumes are rather acidic and diluted HCl is known to have strongly corrosive effect on enamel, on repeated exposure. (The decreased saliva production and poor oral hygiene together with host of meth-dependence mental factors definitely play role also).
Abel, I forwarded this methcathinone-manganese poisoning to our people here at the institute who do Parkinson research and they were pretty interested - they use MPTP to produce parkinsonian mice but MPTP is tricky to dose because the dose margin is so narrow - you end up with mice with very variable degree of basal ganglia damage and it is pretty easy to overdose them and kill them instead. Also since MPTP is absorbed orally and by skin contact, the people who work with the stuff here are quite nervous about their own cummulative exposure. This also makes the animal protocols complicated (all poop and stuff in the cage has to be treated like a neurotoxin-contaminated material). So they would be glad to swich to another model, especially if it could be something safe-to-use and overdose-resistant, like permanganate.
I've read the NEJM paper and will be my new talk at the weekly meeting in Toxicology residency.
Interesting indeed
Very interesting to read. As time goes by and more research done, there will be many similar cases....