In the late 70s and early 80s, heroin was in short supply due to conflict in and around Afghanistan and Turkey. Demand was still high -- this is heroin we're talking about, after all -- so the underground supply chain turned to synthetic opioids as a substitute. Fentanyl was popular; while its synthesis was expensive and difficult, as a common OR anesthetic it could be "diverted" from most any hospital. Morphine and the rest of the common opiates were (as always) popular too. Meperidine (Demerol), a synthetic opioid, could also used when nothing else was available, but its effect was shorter lived and produced worse side effects than the alternatives.

Sometime in 1983, a chemist happened upon an analogue of meperidine with the chemical name 1-methyl-4-phenyl-4-propionpiperidine, commonly abbreviated MPPP. Known by some as "Super Demerol", MPPP's duration and feel were comparable to heroin, and it was an immediate success on the street. Unfortunately its synthesis was extremely sensitive, and by-products that would be impossible to find without a multi-thousand dollar GC-MS rig. Since clandestine drug chemists don't generally have access to such cool toys, they had no idea the reactions had produced anything but the desired product. One of the most common side-products of MPPP synthesis was MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, and batches of "synthetic heroin" containing it hit the street in force.

And addicts started dropping off like flies.

Hours, days, or weeks after first shooting MPTP contaminated product, symptoms started appearing: inability to move properly, tremors, stiffness of the limbs, difficulty speaking. In other words the exact same symptoms as in advanced Parkinson's Disease, showing up in users of ages starting from their late teens. PET scans and autopsy revealed damage to the same area, too -- the MPPP/MPTP users had in every way come down with acute Parkinson's.

As it turned out, the MPTP was being converted to MPP+ (1-methyl-4-phenypyridinium) by monoamine oxidase, and MPP+ is extremely toxic to the dopaminergic neurons in the substantia nigra. Those neurons stimulate the basal ganglia which in turn are responsible for conscious control of movement -- when they're knocked out, the person can no longer move his body properly. Doctors figured this out by examining effects of MPP+ on animals, and correlated the damage to natural dopamine neuron death in Parkinson's sufferers, which they hadn't understood before. Either way the cell death happened, though, it was permanent and the deterioration would eventually build up enough to cause death. In short, both the junkies and the Parkinson's patients were screwed.

MPTP toxicity is the reason for a somewhat common misconception about ecstasy, that it will cause Parkinson's. I assume the confusion is caused by the abbreviation MPTP being close (uhh, in that they both start with an M) to MDMA, the chemical abbreviation for ecstasy. Fortunately, the chemicals have virtually zero structure in common, and MDMA does exactly nothing to harm dopamine neurons in the substantia nigra. Toxicity in serotonin neurons is of course another matter entirely :-)

During the seventies, a student living in Massachussetts by the name of Barry Kidston became curious about hard drugs, and wanted to experiment with them. Being a chemistry major, Barry decided to synthesize the drugs himself rather than put himself at risk by traveling to bad neighborhoods to purchase them. Barry became particularly interested in a synthetic analog of Demerol known as MPPP.

Barry set up a laboratory in the basement of his parents' home, and was able to synthesize and use MPPP for several months without incident. However, on one occasion he was forced to hurry through the steps of manufacture for a batch of MPPP, and something went wrong in the process.1 When Barry injected the product, it produced a pronounced unexpected burning sensation, and three days later, he began to experience bradykinesia (a severe slowing of movements) severe enough that he had to be admitted to a hospital. After unsuccessful attempts to treat him with neuroleptics, a neurologist diagnosed Parkinson's disease, and he was put on L-Dopa, which improved his symptoms.

The National Institute of Health was notified about this rare case, and a team was sent to Kidston's home to investigate the etiology of his condition. Fortunately, some of the poisonously mis-synthesized drug was still present in the glassware he had used to cook it, and the NIH decided to perform testing on two of the compounds they found: MPPP, and MPTP, an unexpected by-product.

These compounds were tested in rats, and MPTP did cause the rodents to exhibit Parkinsonian-like symptoms for a few hours. However, the researchers were unable to reproduce the permanent condition that afflicted Barry. This was unfortunately just a case of bad luck. Later research has shown that rats are specifically resistant to the toxic effects of MPTP.

In 1982, six young people in the Bay Area of California suddenly manifested a Parkinson-like syndrome. Doctors were baffled by these cases - the patients were too young, and the symptoms manifested too abruptly to be true Parkinson's disease. It was later determined that these patients were all addicts that had taken a synthetic heroin then going by the name of "China White", which a local drug dealer had been manufacturing in his garage. This turned out to be - you guessed it - a MPTP-contaminated batch of MPPP.

From these two separate incidents, scientists were able to determine that MPTP was the responsible agent. Studying of the action of MPTP on the brain, scientists determined that the action of MPTP's metabolite MPP+ is very similar in effect to that of paraquat, a pesticide, which has led to the investigation of pesticides and other environmental factors as influences in the development of Parkinson's disease. It was eventually discovered that MPTP causes Parkinsonianism in primates, and the syndrome is frequently studied in these creatures as an animal model of the human disease.

1By taking painstaking steps to duplicate Barry's equipment, environment, and procedure, a scientist was able to determine that a minor overheating of the reactants during one step of the process caused MPTP to be synthesized.

An unfortunate footnote: Barry Kidston did recover temporarily as a result of the L-Dopa therapy, but as tolerance began to set in, he became depressed, and one day sat down under a tree and took a fatal dose of cocaine. It is suspected this overdose was intentional, but no note was left behind.

For more information these cases and the discovery of MPTP's effects on the human brain, see The Case Of The Frozen Addicts, Langston and Palfreman.

While the development of the animal model of Parkinsonism was a very important step for western medicine, a high price was paid for it by these addicts and their families. The addicts involved did not die as a result of their poisoning, but were instead rendered totally immobile and helpless. While L-Dopa is a successful treatment in the short term, tolerance does begin to accrue and then the symptoms return. The addicts struck down by this poison were suddenly in the grip of full-blown Parkinsonianism, unlike the gradual onset that occurs for more naturally occurring cases. Therefore, when the L-Dopa treatments ceased being effective in these cases, the patients were returned to a totally helpless state, unable to communicate, and requiring professional care to allow them to eat and go to the bathroom. This is in contrast to sufferers of more moderate Parkinson's sufferers, such as Muhammed Ali (whose affliction can only truly be called moderate in this context). I have friends who have battled heroin addiction, and I can understand how the travails that addicts inflict on themselves can be very amusing (how dumb do you have to be to overdose twice in two separate McDonalds bathrooms), but the anguish they often bring upon themselves makes their plight very sad, also.

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