“Frozen Addicts” – An Unusal Twist on Drug-Induced Parkinsonism

The term “frozen addicts” was coined by Californian neurologist Dr William Langston after he had encountered an outbreak of akinetic rigid Parkinsonism in 6 drug users in Santa Clara County California:
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The story actually starts in 1947 with Hoffman-La-Roche chemist Dr Albert Ziering, who first synthesized synthetic opioid  Desmethylprodine 1,3-Dimethyl-4-phenyl-4-propionoxypiperidine (MPPP).  The drug was never developed or marketed.

The story continues with chemist Barry Kidston, who in the 1970s synthesized MPPP using Dr Ziering’s recipe and a home chemistry set.  However, a few days after injecting himself with a sample from a newly synthesized batch of drug, Kidston became frozen, unable to speak or walk.  He was taken to the hospital by his parents, misdiagnosed with catatonic schizophrenia, and treated with electroconvulsive therapy for months.  He was ultimately diagnosed him with Parkinson’s disease, and improved with L-dopa treatment.  Soon after, researchers analyzed the tainted drugs, and concluded that it was comprised of both MPPP and a similar compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).  Kidston died of cocaine overdose shortly afterwards.  His autopsy showed loss of dopaminergic cells in the substantia nigra, the hallmark of Parkinson’s disease.  The case was written up in the Journal Psychiatry Research in 1979.

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In July 1982, a 42 year old named George Carillo was hospitalized in San Jose frozen like a statue in a bent twisted position.

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Then a neurologist in Watsonville, only 30 miles away, reported 2 drug-addict brothers in their 20s  both with advanced symptoms of Parkinson’s.

Ultimately seven addicts came down with these same symptoms.

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A sample of tainted heroin was ultimately analyzed, and one of the toxicologists involved remembered reading about the Kidston case in Psychiatry Research.

William Langston, the neurologist who first treated Carillo, looked the case report up and found that Kidston had prepared drugs based on a 1947 paper by Albert Ziering.  But when Langston he went to the Stanford University library to read that original paper, he found that it had been cut out of the journal.  Some enterprising college chemist was cooking up MPPP and selling it as heroin, but like Kidston had made a mistake in his recipe and produced MPTP instead.

Once inside the brain, MPTP is metabolized into 1-methyl-4-phenylpyridinium which is toxic to dopamine producing neurons in the substantia nigra.

Since then MPTP has been used to develop an animal model of Parkinson’s disease, and this has allowed researchers to investigate surgeries to repair the injured region of the brain, new techniques using electrical stimulation, and more recently stem cell replacement of damaged cells.

These Frozen Addicts have also posed a question that we have yet to answer. If a street-drug impurity can trigger on form of Parkinson’s, could other “idiopathic” cases also have a chemical source? Recent studies have found that ingestion of the pesticide Rotenone can bring on Parkinson-like symptoms in mice. Loss of motor control, stiffening of muscles, and even loss of facial expression have been noted among the rare side effects of the high blood pressure medication, Reserpine, and the heartburn drug, Metoclopramide.

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