In July 1982, a 42-year-old addict in a San Jose, California jail became paralyzed—unable to move or talk. His symptoms, caused by a bad batch of synthetic heroin, were indistinguishable from those associated with Parkinson's disease, a degenerative nerve disorder that strikes the elderly. NOVA traces the story of a "designer" drug which could lead to a major medical breakthrough.
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00:00It began with the emergency admission of a bizarre medical case.
00:15George, I'm just going to flash a light in your eyes.
00:20What I saw when I went in the patient's room was remarkable.
00:25I had never seen anything like it before in my life.
00:28Here was this man, apparently in his forties, who was frozen.
00:34The key to this mystery would not be found in any medical textbook,
00:38but would lead instead to the underground drug world of California.
00:41Ironically, from that seedy world has come a major medical breakthrough,
00:45bringing hope to millions of sufferers of a devastating brain condition
00:49known as Parkinson's disease.
00:51The Case of the Frozen Addict, next on NOVA.
00:58Major funding for NOVA is provided by this station
01:01and other public television stations nationwide.
01:06Additional funding was provided by the Johnson & Johnson family of companies,
01:10supplying health care products worldwide.
01:15And by Allied Signal, a technology leader in aerospace, electronics,
01:19automotive products, and engineered materials.
01:47In San Jose, California, something strange happened on July 16, 1982.
01:53One of the prisoners at the local jail awoke to find that he couldn't move or talk.
02:0110-15-1, 10-49, VMC, ER, in the ambulance.
02:06Frozen like a pillar of salt, he was rushed to the Valley Medical Center.
02:14Nothing like it had ever been seen before, and arguments broke out as to what it was.
02:21Let's take a look at that.
02:23George, if you can hear me in there, what I want you to do
02:26is to try to follow my finger very carefully with your eyes.
02:30Keep your finger just glued, your eyes glued on my finger here as I move it about.
02:35A little bit of saccadic pursuit.
02:37But he can do it. He can do it.
02:39I'd only seen one case that was close to that,
02:41a case of a very, very rare disease called Wilson's disease,
02:43but this wasn't even like that.
02:45So I could see why the arguments had broken out.
02:48The first real question that confronted us at that point
02:51was whether this man was mentally normal inside.
02:54Since there was no way to communicate, we didn't know.
02:57Noticing that he could move his hand just a little,
03:00Doctors Langston and Ballard had an idea.
03:04See if you can write the answers to some of our questions on this pad of paper.
03:10He could. As George Carrillo wrote,
03:12I can't move right, I know what I want to do, it just won't come out right.
03:17By question and answer, a case history was built up.
03:20And in that history was a revealing statement.
03:23George Carrillo was a heroin addict.
03:26As would become clear, he was the victim of a bad batch of drug
03:29that had done irreparable damage to his brain.
03:32But his tragedy would open a new chapter in medical research.
03:41George Carrillo was just the first.
03:44His girlfriend Juanita, also a heroin user, was having even worse problems.
03:49To a neurologist, the symptoms were very familiar.
03:53They were textbook descriptions of a very common disease of the elderly.
04:00These patients, of course, manifested all of the signs of Parkinson's disease.
04:05However, this was a difficult diagnosis to swallow.
04:09Parkinson's disease usually occurs over the age of 50.
04:12It comes on very gradually.
04:14In fact, it's so slow, it's almost imperceptible.
04:17Most patients have had symptoms for one to two years
04:20before they actually go to a doctor.
04:22That's how slow it is.
04:24In this case, these were younger people.
04:27The girlfriend was in her early 30s.
04:30And it came on almost overnight.
04:32Parkinson's disease doesn't do this, yet this looked like Parkinson's disease.
04:37We had a first-class medical mystery on our hands at that point.
04:43The mystery was only just beginning.
04:48That Friday, Dr. Phil Ballard left for a weekend break.
04:54He headed some 40 miles south to Santa Cruz,
04:57where he'd been invited to a dinner party.
05:02In this unlikely setting, he was to stumble on the next clue.
05:06At the party was another neurologist, Dr. Jim Tetreault,
05:10and soon the two of them started to talk about their cases.
05:13What Ballard heard that night was remarkable.
05:16Jim Tetreault told him of a bizarre case of two brothers
05:19from nearby Watsonville that had just been referred to him.
05:22Like George and Juanita,
05:24they were frozen with all of the symptoms of Parkinson's disease.
05:30David and his brother had been found by their mother
05:33lying frozen in their apartment.
05:35And there was another remarkable thing about them.
05:38They were both heroin addicts.
05:40Here we now had a totally different family,
05:43different geographical location,
05:45and the key, both these brothers were heroin users.
05:49That identified the heroin that was the only common link between these cases.
05:55At that point, we went for the heroin and started trying to get samples.
05:59Langston also held a press conference
06:01to warn there was some very dangerous heroin on the street.
06:04Basically, it's a profound slowing of all motor function.
06:07The patients are not able to talk, move, feed themselves, eat.
06:12Mentally, we think they're okay inside.
06:15This was the first of many encounters with the media.
06:18It's interesting to me how the involvement of the media, the press,
06:22really helped break this case.
06:24The first thing that happened
06:26was that we got a call the next morning from a public health nurse.
06:30And she said, you know, I saw you on TV last night, Channel 4 or something,
06:35and you were talking about this Parkinson's-like condition,
06:38and I'm seeing a young woman in her home.
06:41And this young woman was in a psychiatric unit for three weeks
06:48with a diagnosis, I think, of hysteria, hysterical paralysis.
06:51But she said, you know,
06:53she sounds just like what you described on TV last night.
06:56Do you think she could be another case?
06:58We said, well, did she use heroin?
07:00And the answer was yes, and we said, get her in.
07:02And we saw her that afternoon.
07:04That was our fifth case.
07:06And in some ways, this was the most tragic young woman.
07:09This was her first summer using drugs IV,
07:12and we all know kids experiment.
07:14She got this stuff.
07:16And she is probably the most affected.
07:18This was Connie.
07:21And after Connie came still other cases, like Toby.
07:26By the end of July, there were a total of seven.
07:29How many other drug users out there on the California streets were at risk?
07:36California had always had more than its fair share of drug problems,
07:40but in recent years, police had come across a disturbing new trend.
07:45What am I being arrested for?
07:47Selling fentanyl.
07:48Selling what?
07:49Food.
07:50All right.
07:51Man, that is wrong, brother.
07:53Drugs were turning up on the street, packaged and sold as heroin
07:56that were not derived from the opium poppy nor from any other natural product.
08:01They came instead from underground laboratories.
08:04Here, entirely synthetic versions of hard drugs were made,
08:07some hundreds of times more powerful than heroin.
08:10And it was all quite legal,
08:12Since the drug's molecular structure was different from any outlawed drug,
08:16they could be made, sold, and used with impunity.
08:19They were to become known as designer drugs.
08:22The heroin that George and the others took was not real heroin.
08:26It was a synthetic designer imitation.
08:28But what exactly was it?
08:30Langston collected samples and sent them out to chemists all over California,
08:34like Stanford University's Ian Irwin, with a plea.
08:37Find the guilty chemical.
08:42All substances have unique chemical fingerprints by which they can be identified.
08:49Using a mass spectrometer to analyze the compound,
08:52Irwin obtained the mystery substance's fingerprint.
08:58He then fed it into a computer in Washington
09:01where the fingerprints of many known chemical substances were stored.
09:04He was looking for a match.
09:06As expected, it wasn't heroin.
09:09But it didn't match with any of the 40,000 known chemicals on the computer.
09:29The compound was apparently completely unknown.
09:33While Langston and his team puzzled over the mystery designer drug,
09:37unknown to them, a local police investigation was closing in on a designer drug chemist.
09:42This man was the key to the operation.
09:45A suspicious list of chemicals fell into his possession.
09:49For the police, this was a big break,
09:51because in reality he was an undercover narcotics agent,
09:54better known today as Deputy Sheriff Dave Weidler.
09:5748065, got it.
10:00Dave Weidler turned the list over to the county crime lab.
10:08What would a local resident want with such large quantities of chemicals?
10:12Forensic scientist Jim Norris had to decide one thing.
10:16Was this the basis of a designer drug operation?
10:19The key suspect was well known to them,
10:21ever since a notorious incident in nearby Saratoga 18 months before the incident.
10:27when his residence mysteriously caught fire.
10:29Police and fire officials discovered he'd been experimenting on a vast scale
10:33making designer narcotics, but they were powerless to arrest him.
10:37Now it seemed as if he might be at it again,
10:39and all Norris could do legally was stage a fire inspection.
10:42But the suspect was ready for them.
10:45The owner of the laboratory, when confronted by the fire department,
10:49first said that he was attempting to make hand lotion
10:52and also attempting to make a new type of snow cone.
10:55The chemicals that had been purchased were not appropriate
10:59to make snow cones or hand lotion.
11:02Most of them were very poisonous, highly flammable,
11:05and also very expensive.
11:07He had spent nearly $10,000 to buy just the chemicals.
11:13Then the police started to hear about the frozen addicts
11:16who were turning up at Dr. Langston's clinic at the Valley Medical Center.
11:20They wondered, could there be a connection?
11:22We knew that Dr. Langston had seized some samples
11:27from patients who had been admitted,
11:30and we asked Valley Medical Center to give us those samples
11:35so that we might conduct a further legal investigation.
11:38I got a call, a start-again call from police, different police groups,
11:42and one in particular was Jim Norris of the local narcotics agency.
11:45And I remember that conversation.
11:48And I remember that conversation quite well because he said,
11:51Dr. Langston, we understand that you have some samples of this synthetic heroin.
11:56And I said, yes.
11:57And he said, well, we'd really like some of that.
12:00We need some of that for analytic purposes in our lab.
12:02And I said, it was being very nice.
12:04And I said, well, I'd really like to loan you some,
12:07but, you know, we just have a very small amount left
12:10of what we think is the critical sample, so I'm afraid I can't do that.
12:13And I remember there was a pause on the phone,
12:16and Jim said, Doctor, you don't understand.
12:20Either you can give us the sample,
12:23or I'm coming over there with some of my men,
12:26and we're going to take a sample.
12:28At that point, I realized I'd better negotiate,
12:31and I think we wound up splitting it.
12:33The second thing I remember about that conversation,
12:36and to this day it amazes me,
12:39is when I said, do you have any idea who this fellow is making this stuff?
12:44And his remark was almost casual.
12:46He said, oh, yeah, we know who this guy is.
12:48We've known about this guy for two years.
12:50He said he was associated with this house that mysteriously blew up in Saratoga.
12:54And I said, well, why isn't he behind bars?
12:57And he said, we can't touch him.
12:59And after he explained that to me,
13:01that was the first time I'd heard about designer drugs,
13:03these new synthetics that are altered so they're beyond the reach of the law.
13:07He said, our only hope is to get this guy on his income taxes,
13:10and I was just floored.
13:13Norris couldn't identify the sample,
13:15nor could pharmacologist Gary Henderson,
13:17the inventor of the term designer drug.
13:19For years, Henderson had been warning
13:21of the terrifying potential of synthetic narcotics.
13:24Tiny design changes to a molecule like this
13:27can make it thousands of times more potent than morphine.
13:30It was not only dangerous, but perfectly legal.
13:33Now, the real important thing from the legal standpoint
13:36is if you simply put another group here, for example,
13:40regardless of what it does to the activity,
13:43under the old drug laws, it was a new chemical
13:46and therefore not restricted.
13:49It could have all the properties of heroin.
13:51It could look like it, act like it, taste like it,
13:54produce all the effects and side effects.
13:56But because it was a new chemical and not listed on any drug list,
14:00it was strict legal.
14:05As the search for the unknown substance continued,
14:08the reputation of the frozen addicts was deteriorating.
14:13David, can you stand up? Let's try to stand up.
14:27Can you stand up for me?
14:34That's a considerable amount.
14:38Rigidity.
14:52You don't know? Well, give it a try here.
14:55I'll give you a little bit at a time.
14:58They were by now invalids,
15:00quite unable to wash or feed themselves.
15:02You want water with that?
15:08What?
15:12So bad was their condition that Langston decided to put them
15:15on the treatment given to sufferers of Parkinson's disease,
15:18the drug L-Dopa.
15:20Nobody was sure if it would work,
15:22but the effect was miraculous.
15:24They came back to life.
15:26Can you hop on your right foot?
15:28On your left foot?
15:32Can you put your hands above your head?
15:35Okay.
15:37Langston realized that he might be on to something big.
15:40What had begun as a drug tragedy might help unravel
15:43one of the world's major brain diseases
15:45affecting one person in a hundred over the age of 60.
15:50Okay.
15:52Can you touch your fingers to your nose?
15:56L-Dopa replaces dopamine,
15:58a naturally occurring brain chemical
16:00without which we would all freeze up.
16:04Okay.
16:06Without dopamine, the thought of lifting an arm
16:08can't be translated into the act of lifting an arm.
16:14If enough of the cells making dopamine die,
16:17people get Parkinson's disease,
16:19the characteristic tremor,
16:21increasing rigidity,
16:23and leading eventually to complete disablement.
16:28Langston realized that in the frozen addicts
16:30this process was speeded up hundreds of times.
16:33Something in the synthetic heroin had passed into the brain
16:36and, avoiding every other structure,
16:38had destroyed just that small area of brain
16:40that makes dopamine, the substantia nigra.
16:45To understand this toxin might be
16:47to begin to understand Parkinson's disease.
16:52The next clue as to what that toxin was
16:54would come from the crime lab.
16:57For one of Jim Norris' colleagues,
16:59a toxicologist, Hallie Weingarten,
17:01the idea that a toxic chemical
17:03could cause a Parkinsonian state stirred a memory.
17:07Buried away in her files
17:08was an obscure article written in the late 70s.
17:15As the article revealed,
17:17George Carrillo wasn't the first victim
17:19of a bad synthetic drug.
17:21There had been an almost identical case six years before.
17:25For William Langston,
17:26this article provided the missing clue,
17:28for in this case,
17:29the victim had known the formula of the drug he had taken.
17:33The article told the tragic story of Barry Kidston,
17:36a 23-year-old student from Bethesda, Maryland,
17:38with a long history of drug abuse.
17:41In the summer of 1976, he bought a chemistry set
17:44and in the basement of his parents' house
17:46began making his own narcotics.
17:49After six months of doing this, he hurried a batch.
17:52On injecting himself, his body froze.
17:54He couldn't speak.
17:55He developed the symptoms of Parkinson's disease.
17:59Barry was referred to
18:00the close-by National Institute of Mental Health,
18:03where, after treatment with L-DOPA,
18:05he was able to tell investigators
18:06just what he had tried to make.
18:08He wanted to get a drug related to Demerol.
18:13That was his favorite drug of abuse,
18:15which he'd been able to get fairly readily
18:19when he was overseas.
18:21And he wanted to avoid clandestine sources of supply.
18:27So he decided,
18:28after looking through the scientific literature,
18:30that this looked like an easy compound to make.
18:33It should give him the same effects as Demerol
18:37or a heroin-like high
18:40without running up against the law.
18:45He was going to do this all in his own basement.
18:48It was certainly an ambitious undertaking,
18:50certainly much more ambitious
18:51than most undergraduates would begin to do
18:56in their school laboratory.
18:58The drug Barry was trying to make was called MPPP.
19:02Chemically quite different from heroin,
19:04it produced the same kind of high
19:06and was easier to make.
19:07Was this the toxin that had given Barry Parkinson's disease?
19:13Yeah.
19:18Markey injected MPPP into rats
19:21to see if they would come down with the disease.
19:27And lo and behold, the rats froze up.
19:31For Markey and his colleagues back in 1977,
19:34it looked as if they were on the verge
19:36of an important discovery.
19:43But an hour or so later, the rats started to unfreeze.
19:50The effect was temporary,
19:51whereas Barry's condition was permanent.
19:54It was not Parkinsonism.
20:00This was a serious setback for the team of scientists
20:03now working on this unique case.
20:05But there were other possibilities.
20:09I've started putting it together here,
20:11and you can see from the drawings that he's made.
20:14Using Barry's detailed notes and Barry's own equipment,
20:17Markey tried to duplicate in his NIMH lab
20:20just what Barry had done.
20:26Markey reasoned that Barry must have made a mistake.
20:29Use too much heat or acid in this reaction
20:32and there is a danger of making side products.
20:34Was this what Barry had done?
20:37As Markey tried to forget all his scientific training
20:39and do sloppy chemistry, he got a lucky break.
20:42He noticed that trapped in the glassware,
20:45buried in the grease, there was a small amount of powder,
20:48the last remaining trace of Barry's last synthesis.
20:57Knowing the formula Barry had used,
20:59this tiny amount was enough for Markey to analyze
21:01in a mass spectrometer.
21:04It showed that Barry had indeed made a sloppy synthesis.
21:07In addition to the drug he was trying to make, MPPP,
21:11he had also made a side product, MPTP.
21:14Could this be the toxic chemical?
21:16For some reason, the researchers never tested pure MPTP in rats.
21:21Then one day in September 1978,
21:23Barry came to the grounds of the NIH,
21:26sat down under a tree, took an overdose of cocaine and died.
21:31His parents gave permission for an autopsy
21:33and results removed any skepticism.
21:36The substantia nigra of his brain was extensively damaged.
21:40The substantia nigra of a normal brain looks like this.
21:44Barry's was like a Parkinsonian brain.
21:46All the black pigment was missing.
21:49Thus in 1978, four years before George Carrillo took the bad heroin,
21:53researchers had uncovered a clear link
21:55between a synthetic drug and a Parkinsonian state.
21:59Why then did no one hear of their discovery?
22:03The research was destined for obscurity.
22:06First the prestigious New England Journal of Medicine
22:08rejected the article on technical grounds.
22:13Then the Journal of the American Medical Association
22:15insisted that one of the seven authors drop out
22:18as a condition of publication.
22:22Because no one would drop out,
22:23it was eventually placed in the first volume of a brand new journal,
22:27Psychiatry Research, published in Holland,
22:29and it remained largely unread.
22:32But three years later when Langston read this remarkable article,
22:35he was struck by a powerful thought.
22:37Was it possible that the California designer drug maker
22:40had tried the same synthesis as Barry and made the same mistake?
22:48Langston read the formulas Barry Kidston had used
22:51and called the phone to chemist Ian Irwin,
22:53who realized immediately that the same chemical synthesis was involved.
22:58Like Barry, the California designer chemist was trying to make MPPP.
23:03And like Barry, he had used too much heat and made MPTP as well.
23:08In fact, he had done the synthesis so badly
23:10that some of the samples were almost 99% side product,
23:14almost pure MPTP.
23:20Langston strongly suspected that MPTP,
23:23which hadn't been tested in rats, was the toxin.
23:26But he wanted to know more.
23:29Because Barry Kidston had based his experiments
23:32on some long-forgotten articles written in the 1940s,
23:35Langston went to Stanford University to read them for himself.
23:42But someone had been there first.
23:45All the articles had been razored out.
23:48It was really an eerie feeling because I had the sense
23:51I was crossing paths with this individual,
23:53this person that was now a part in our imagination that I'd never seen.
23:58That shock started turning to anger after I went to additional journals
24:03because every single one that had a relevant article
24:06had been razor-bladed out.
24:13The scientists back at NIMH, having heard about the California tragedy,
24:17were back in the game.
24:19Whereas Barry had been an isolated case,
24:21now there was a virtual epidemic.
24:23Anxious to make up for lost time,
24:25they set about finding out what they had missed.
24:29When Markey had previously tested MPPP in rats,
24:32it produced a temporary paralysis, but not Parkinsonism.
24:36Now he tried injecting pure MPTP
24:39to see if it would cause a permanent Parkinsonian state
24:42and kill cells in the substantia nigra.
24:46To many people's surprise, it had absolutely no effect whatsoever.
24:50To this date, nobody has produced Parkinsonism in a rat.
24:54For one of Markey's colleagues, Stan Burns, this came as no surprise.
24:58From the outset, he reasoned that rats were so physiologically different from humans
25:02that it would never work.
25:04To test if MPTP was toxic, you had to use an animal like a human,
25:08another primate, for example, a monkey.
25:11Burns was right.
25:13In monkeys, the effect of MPTP is dramatic.
25:16They freeze up.
25:18And their Parkinsonism can be reversed with L-DOPA.
25:29From Barry Kidston to the California addicts,
25:32they had all been struck down by the same substance,
25:35a simple molecule produced by a piece of sloppy chemistry, MPTP.
25:40So here we've got a simple molecule that, like a Nike missile,
25:45goes right in past all the organs in the body,
25:48skips all other areas of brain,
25:50and hones right in on this same area that is damaged in Parkinson's disease.
25:55This has a lot of implications.
25:59The first implication was that now scientists had an animal model
26:03for what had always been an exclusively human disease.
26:07Research could move forward for the first time in years.
26:11This was a godsend.
26:13I mean, it was even better than you would dream of
26:15in the sense of a chemical that you give systemically
26:20that only destroys the group of cells that are responsible
26:24for the clinical manifestations of Parkinson's disease.
26:27I was not so much on a hunt for what was the causative agent
26:33to explain the cases in heroin abusers.
26:36I wanted to find the chemical
26:39that would reproduce Parkinsonism in monkeys in particular
26:45because that would be a wonderful tool.
26:51Obviously, you can't do a lot of experiments on humans.
26:55In fact, you can do very few experiments on humans.
26:58So that limits you tremendously in being able to study the disease
27:01and do basic research.
27:03In fact, in many ways, I think basic research in Parkinson's disease
27:06was almost dead in the water when this came along.
27:09I mean, where do you look? What do you do?
27:12MPTP opened a whole new era in Parkinson's disease research.
27:17Scientists from all over the world started jumping on the bandwagon.
27:21The first thing that happened was that the price of MPTP
27:24for experiments shot up.
27:27In 1982, the Aldrich Chemical Company sold 5 grams for $11.
27:32But two years later, it was 860 times more expensive.
27:38It's now extraordinarily expensive.
27:40In fact, a bottle of MPTP that was given to us
27:43by Aldrich Chemical Company
27:45so we could do some toxicology studies on it,
27:48by our current estimate, is worth $210,000.
27:52We still have it. We should have it in the safe.
27:55The other kind of interesting figure that Ian worked out, our chemist,
27:59is that currently, neuroscientists working with MPTP
28:03are paying approximately five times
28:07what addicts on the street paid to get this back in 1982.
28:12Now, the secret of MPTP was out.
28:15Could Langston keep up?
28:17He was a clinical neurologist in a county hospital
28:19with almost no basic research experience and no funding.
28:23Remarkably, he found himself on the crest of a wave of interest,
28:27both in the designer drug phenomenon
28:29and the search for a cure for Parkinson's disease.
28:32For years, this had been a moribund research field.
28:35Now, the various Parkinson's foundations rallied around
28:38to fund the new wave of research.
28:42For patients like those in the Oregon chapter
28:45of the American Parkinson's Disease Foundation,
28:47there was hope for the first time of real progress.
28:50In meetings and in newsletters, the message was one of optimism.
28:53I think it's a very exciting time for research in this disease.
28:57For all of us, it's had a tremendously invigorating effect
29:01on basic research in this country.
29:03And for patients with Parkinson's disease and their families,
29:06that's good news. Thank you very much.
29:15Parkinson's disease is a disease of aging.
29:18The older one is, the more likely one is to get it.
29:22It involves, in general, we would say,
29:25one person in a thousand of the general population.
29:28But since it's a disease that increases with age,
29:31over the age of 40, it's one in 200.
29:35Over the age of 60, it's one in 100.
29:38And over a lifetime, there's a chance in 40
29:42of developing the disease if you live to a normal expectancy.
29:47Dr. Andre Barbeau pioneered L-Dopa therapy back in the 1960s.
29:52People called it a miracle drug.
29:55It has the power to transform even an invalid like Connie,
29:58who without medication has no voluntary control over her movements.
30:02We'll probably do that again a little later when hopefully the medicine works.
30:05Now what I want you to do is try to reach out and touch my finger.
30:10Let's try to make it a little easier.
30:12Try to just take this hand and just reach up and touch my hand.
30:15Can you do that with your fist? Just get your arm up there.
30:19Do your best. Try to get your right arm up there.
30:22Are you trying? Okay, so you can't really do that right now.
30:25I can see the tremors getting a little worse.
30:27Let's try it on the other side.
30:29Just try to hit my hand like a boxer. Can you do that?
30:33Let's try to hit my hand.
30:35L-Dopa gives her back what most people take for granted,
30:38voluntary control of her body.
30:40You couldn't even do that a while ago, could you?
30:42Actually, that's quite fast.
30:46Good. Now let's try it with this hand, okay? Same thing.
30:49Tip of my finger to your nose. Very good.
30:53But the miracle has a price.
30:56Several of them have to take medication every two to three hours
31:00just to be able to move.
31:02Some of them even get up at night and take it.
31:04Even that is not a guarantee that they're going to be all right
31:08because with time you get these serious side effects.
31:13Connie was plagued with uncontrollable writhing movements,
31:16a common L-Dopa side effect which leads to dramatic weight loss.
31:21David has suffered from this also.
31:23At times, David's had terrible problems with this
31:26and actually has lost a lot of weight, haven't you, David?
31:28Yeah.
31:29About how much weight have you lost because of that?
31:31About 40 pounds.
31:32Forty pounds.
31:33They've actually been disabling at times
31:35and that's been our big enemy in trying to get him balanced.
31:38It's a typical problem you see with Parkinson's disease.
31:40You get side effects if you go up enough to be effective.
31:43You go down and the patient frees up.
31:45George, the original case, has another common L-Dopa side effect.
31:48Are you having any problem with the hallucinations now?
31:51Are those coming?
31:52Yeah, I'm having them now.
31:53You're having them right now?
31:54Yeah.
31:55Can you tell me what they're like?
31:56They're real creepy, man.
31:59I feel like a big snake's coming to get me.
32:01Like what?
32:02Like a snake's coming to get me.
32:03Like a snake's coming to get you?
32:04Yeah.
32:05That's the one you often have.
32:06It sounds very frightening, is it?
32:08It is.
32:09For the cases caused by N-type hallucinations,
32:12and for millions of ordinary Parkinson's sufferers,
32:15L-Dopa isn't a final solution.
32:17In fact, it can be a therapeutic trap.
32:23For the new worldwide research initiative,
32:25one pressing goal was to find alternative therapies
32:28that would allow people to move without debilitating side effects.
32:32Then a staggering development occurred
32:34that was to send some researchers in a completely different direction.
32:38One day, Langston received a letter from a pharmaceutical chemist in New Jersey
32:42who had read about the discovery of MPTP in the press.
32:50He reported that MPTP was not new.
32:53He had worked with a compound for years back in the 1970s
32:57on the laboratory bench.
32:59Then at 37 years old, he noticed that things started to go wrong.
33:03His tennis game began to fall apart.
33:05His serve continually went into the net.
33:08He developed early signs of what he now realized might be Parkinsonism.
33:12Langston was horrified.
33:14This was shortly after all these calls
33:16and knowing all these scientists were getting it,
33:18and I thought, what have we done?
33:20You know, we've set the world off on using MPTP in labs,
33:23and here this stuff can cause a disease, you know, just from exposure.
33:27So I thought, what have we done?
33:29And here this stuff can cause a disease, you know, just from exposure.
33:33So I felt quite panicked that we might have done something
33:38that could be quite harmful,
33:40so we immediately rushed a letter out in the New England Journal of Medicine
33:44describing this chemist and his case
33:47and really warning people that if you're using MPTP, be careful.
33:52Then at NIMH, Stan Burns heard from a Danish chemist
33:56who languished for nine years in a psychiatric ward
33:59with a diagnosis of catatonic schizophrenia.
34:02When the MPTP story broke in the press,
34:06the ex-wife of this chemist read one and said,
34:11read the description and said,
34:13that's what happened to my ex-husband.
34:16She called the doctor involved who had taken care of him and said,
34:20I wonder whether he wasn't exposed to the same chemical.
34:24They went back at the pharmaceutical firm,
34:27and lo and behold, that's exactly what he had his hands on
34:30the few weeks before he developed it.
34:33And so it's really to the credit of the ex-wife that he was diagnosed
34:37and that that case then became apparent.
34:41This perfectly sane individual only worked with MPTP for two or three weeks.
34:47It was turning out to be a very toxic chemical.
34:52Exposure by inhalation, by skin contact, and probably by any route.
34:57I mean, if you swallowed it, if you injected it,
35:00any systemic exposure of the body,
35:03it goes to the brain cells and it kills them off.
35:06The very first man to encounter this toxic substance was its discoverer,
35:10the now retired author of the missing articles from the 1940s,
35:13Dr. Albert Ziering of Hoffman La Roche.
35:16Langston called him to see if he'd had any health problems.
35:19He was in excellent health and a very bright man, a very lively man.
35:23And as we were chatting about MPTP and his early experience with it when he made it,
35:27I remember he paused in the conversation and said,
35:30you know, I vaguely remember getting a report back that MPTP was toxic.
35:38And I said, well, how could that be?
35:40He said, well, normally we make these compounds and we send them off,
35:43you know, to another part of the company.
35:47I then went to the head of the research division of this company,
35:51and he was helpful, although it took some pushing.
35:56And eventually I was able to get him to read a report to me that was filed in 1960.
36:03And in fact, MPTP back in the 50s had actually been tried out experimentally in animals.
36:09The first report was on rats, and an MPTP didn't do much in rats.
36:14We now know it doesn't do much in rats.
36:16However, they then took it to primates.
36:19They actually gave it to a total of six monkeys.
36:22And in higher doses, those monkeys froze up, became rigid, unable to move, and died.
36:30More remarkably, they then tried this out in humans, six humans.
36:36And in what I consider the crowning irony of this story,
36:42and this is a story full of ironies,
36:44is that this drug was being tried as a treatment for Parkinson's disease.
36:49While being given MPTP, two of the six people died, and Hoffman LaRoche discontinued testing.
36:56Since the 1960s, other drug companies have tested MPTP in animals
37:00for everything from heart disease to blood pressure.
37:03Did they realize its toxicity?
37:06Only the ones who expensively tested it in monkeys,
37:09but surprisingly, under FDA regulations, that's not required.
37:13I recently learned that current policy requires testing only in rats.
37:18You can theoretically take a new drug, test it in rats, and go straight to human trials.
37:25With MPTP, this disastrous Parkinsonian state that it causes
37:30would have been missed completely because rats don't get it.
37:34So if just as happened back in the 50s,
37:38you would have missed it completely by skipping over primates.
37:41And I think there's a real message here.
37:43And the message is that drugs, before they're tried in humans,
37:47should be tested for toxicity, not only in rats, but in primates.
37:51And I think people are starting to look at this.
37:53If there's a moral, it's that men are not mice.
37:59Drugs affect different animals quite differently.
38:02A dose of morphine that would kill a man would merely put a dog to sleep.
38:08MPPP, which temporarily paralyzes a rat, gives a human a heroin-like high.
38:16On the other hand, the side product MPTP, which gives humans Parkinson's disease,
38:21leaves a rat totally unaffected.
38:23If you're going to study Parkinson's disease,
38:25and you're going to take out of the MPTP story an animal model,
38:29you have to work in primates.
38:31And the reason you have to work in non-human primates
38:33is because it's qualitatively similar.
38:36It's the same as in the patients with Parkinson's disease.
38:39So the findings with research are going to be easily transferable
38:45to considering the human situation.
38:47When you get to lower animal species,
38:50and I'd use the example of dogs or canines,
38:53the motor system isn't the same.
38:55And no longer are the symptoms and signs qualitatively the same.
39:00The one-half million Americans with ordinary Parkinson's disease
39:03have never injected or snorted synthetic drugs,
39:06nor worked at a chemical bench.
39:08How did they get the disease?
39:10The cause of Parkinson's disease has always been something of a mystery.
39:14So far, no virus has ever been found.
39:17Recently, a very large study was completed
39:20investigating whether it was a genetic inherited disease.
39:24Identical twins have identical genes.
39:27If Parkinson's disease was a genetic inherited condition,
39:30then if one twin developed it, you'd expect the other two as well.
39:34Yet in a vast study of affected identical twins,
39:37all but one pair were like the Brown sisters.
39:40One sister got the disease, like Mary on the right.
39:43The other, with identical genes, did not.
39:48If Parkinson's disease isn't genetic or caused by a virus,
39:52that leaves the environment.
39:55It is revealing that before James Parkinson described the disease in 1817,
40:00there are few convincing accounts of the condition.
40:03That means it could be a disease of the industrial age.
40:12It's known that prolonged exposure to manganese
40:15causes Parkinsonism among miners,
40:17and changes in mineral content of water and soil
40:20may explain why in certain Pacific islands, like Guam,
40:23the incidence was until recently five times that of the USA.
40:29Yet when you discount specific causes like these,
40:32for the vast majority of cases worldwide across all cultures and races,
40:36there is no obvious cause.
40:38Clinicians refer to it as idiopathic, meaning unknown Parkinson's disease.
40:43Could that unknown be something in the environment?
40:47Probably. For most people, it's a disease.
40:49It's something out there in the environment.
40:51Somewhere, someplace.
40:53Now, if you link this with the almost simultaneous discovery
40:57of a very simple molecule
40:59that can get in through inhalation or exposure to the skin,
41:04you've got a pretty powerful hypothesis there
41:07that, in fact, it is environmental
41:09and that those of us that get it are getting exposed to something out there.
41:13MPTP is a pyridine.
41:15Now, that's a chemical name.
41:17But pyridines are all over the place.
41:19They're very common.
41:21To the best of my knowledge,
41:23no one has ever made a methodical search in the environment
41:26looking for MPTP or MPTP-like compounds.
41:31Out there in our everyday world,
41:33are there toxins which can account for most cases of Parkinson's disease?
41:37It's a controversial theory that has divided the scientific establishment.
41:41Its proponents say that, if true, it might work like this.
41:46From cradle to grave, our brain cells die off through natural causes
41:50at the rate of a few percent every decade.
41:52To get Parkinson's disease,
41:54eight-tenths of the cells in the substantia nigra must die.
41:57So aging alone can't account for the disease.
42:01Humans who get Parkinson's disease, therefore,
42:03must lose additional brain cells by some other means.
42:07They might suffer a serious external environmental attack at some stage,
42:11which kills off, say, about half of these nigral cells.
42:14Then normal aging finishes the job.
42:17When the 80% threshold is reached, the disease begins.
42:21So aging is involved,
42:23but ultimately the cause of the disease is something in the environment.
42:27I think the environmental cause for Parkinson's disease
42:31is one of the most exciting prospects to come about
42:36in the last few years out of the MPTP research.
42:41I believe that it's going to be something very subtle
42:45because the epidemiology of Parkinson's disease
42:48is that it's found really worldwide over many cultures,
42:52and that's been well documented.
42:54So that it must be some substance which is common
43:01in the fact that our own bodies are producing it
43:04or is a product of our diet,
43:09something that we can convert to an MPTP-like substance,
43:12something in intermediary metabolism, something that we make.
43:17While people speculated about the cause of Parkinson's disease,
43:20something quite unexpected happened.
43:23Several of the research labs working on MPTP uncovered a bombshell.
43:27It turned out that surprisingly,
43:29MPTP wasn't quite the villain everyone had assumed.
43:32MPTP by itself wasn't even toxic.
43:36The problem lay in the brain's complex waste disposal system
43:40where unwanted toxins are pounced upon by special enzymes
43:43and rendered harmless.
43:46At least, that's what usually happens.
43:49When MPTP enters the brain,
43:52one enzyme in the system does something disastrous.
43:55It takes this harmless molecule
43:57and transforms it into a highly toxic one, MPP+,
44:01so toxic, in fact, that a chemical company
44:03had already synthesized it as an herbicide, Ciproquat.
44:07Ciproquat, or MPP+, was test marketed about ten years ago as an herbicide.
44:13It's chemically related to Paraquat,
44:16which is a much better known herbicide.
44:21The California street drug that had caused Parkinson's disease
44:24was not itself toxic.
44:26It became toxic because the MPTP in it
44:29was transformed in the brain into an herbicide.
44:33Herbicides and pesticides have been extensively used in North America
44:36for over 40 years.
44:38If such widely used chemicals are related in some way to Parkinson's disease,
44:42the implications are, to say the least, alarming.
44:45Dr. Andre Barbeau in Canada decided to take one region, Quebec,
44:49as a test case to see if the incidence of Parkinson's disease
44:52could be linked with any toxins in the environment.
44:55Firstly, to many people's surprise,
44:57he found that far from being uniform,
44:59the disease varied sevenfold across nine different regions.
45:04It was highest in Region 3, the main agricultural area,
45:07the so-called breadbasket of Quebec.
45:11Then Barbeau plotted the use of pesticides in Quebec
45:14and the map was identical.
45:16Where there were pesticides, there was Parkinsonism.
45:20This didn't prove pesticides were responsible.
45:23Anything in the agricultural landscape might be to blame.
45:30The data showed another striking correlation.
45:34The 15 hotspots that had by far the highest amount of Parkinson's disease
45:38were all near pulp and paper mills,
45:41so a number of toxins may be involved.
45:45It may be the pesticides themselves.
45:47I'm not ruling that out, but I'm not saying that is the cause.
45:51It may be the nature of the soil.
45:54In the pulp and paper industry,
45:56there are about 30 different compounds being used.
45:59Some of it may get to the environment, may be toxic.
46:02We're now sorting this out.
46:04We're working with the pulp and paper industry
46:07and we're working with the agricultural department
46:10and the environmental departments
46:12to identify in a very specific control area
46:16all the pollutants that have been used over the last 100 years.
46:22One argument that is often given
46:24is that pesticides have only been around for 40 years.
46:27This is not true.
46:29People were using what we call in French verres de Paris,
46:32which is arsenic compounds, for hundreds of years.
46:38Pesticides are just one possible cause.
46:41In our industrial world, MPTP-like substances
46:44are used throughout the chemical industry
46:46and are found in many foods and beverages
46:48and even in chewing gum and cigarette smoke.
46:51Dr. Barbot's results have been met
46:53with a mixture of intense interest and skepticism.
46:55Scientists await further studies to confirm his dramatic findings.
46:59I think the analogy here is that of fishing versus hunting.
47:03People have been looking for 100 years or more
47:06for the cause of Parkinson's disease, but they were fishing.
47:09They were looking at everything. They weren't focused.
47:12We now are hunting, specifically looking for chemicals,
47:16one or more chemicals in the environment
47:18that might play a role in Parkinson's disease.
47:21Dr. Barbot's data that I presented is quite dramatic.
47:25Results in other areas of research, just as dramatic as Barbot's,
47:29were coming in from labs all over the world.
47:32A major breakthrough was made by scientists in San Francisco
47:36investigating the deadly transformation of MPTP in the brain.
47:40They actually identified the guilty enzyme
47:43that caused MPTP to become the lethal MPP+.
47:49It was a very common enzyme known as MAO.
47:55If you could block this enzyme, then MPTP would remain harmless.
48:01And such a blocking drug was available, pargylene.
48:06Scientists rushed to try the obvious experiment.
48:09When you give MPTP to an animal, usually within hours,
48:13they're, look, Parkinsonian.
48:15They're slowed, quiet, don't move, clearly affected.
48:20One dose of pargylene, which is an MAO inhibitor,
48:24before MPTP, and these animals are doing handsprings an hour later.
48:29It's so dramatic.
48:31Secondly, when you look at their brains,
48:33whereas the nigral neurons would be gone, dead, wiped out,
48:37they're totally normal.
48:39It completely prevents cell death.
48:41Quite dramatic.
48:43In the excitement, it emerged that a similar enzyme-blocking drug
48:46called Deprinil had been given to patients
48:48with Parkinson's disease in Europe.
48:54It had fewer side effects, and it seemed to help.
48:59Deprinil seemed to be slowing the progress of the disease.
49:02In fact, in that article, they actually concluded
49:04they were preventing nigral cell death.
49:07So here we have the real disease now
49:10that is being slowed, apparently, by MAO inhibitor therapy,
49:14and we have MPTP Parkinsonism.
49:17These two together generated some real excitement.
49:20Is there the hope now, for the first time,
49:23we might be able to alter the course of the disease?
49:26If we could, this comes none too soon,
49:28because we're at a stage now where many neurologists
49:31are quite disillusioned with L-DOPA,
49:33other medications that stimulate dopamine receptors,
49:36because of all these side effects.
49:38It just seems like you conquer one and another one comes along.
49:41It's gotten to be a very challenging problem in neurology.
49:44A new therapeutic strategy, altering the course of the disease,
49:48could be very exciting, particularly with Parkinson's disease,
49:52because the disease is so mild when people first come in.
49:56If you could halt it at that point,
49:58you could give them an almost normal life.
50:01As Dr. Langston's group got the go-ahead late last year
50:04for a Deprinil trial,
50:06scientists at the University of British Columbia in Vancouver
50:09announced a remarkable technical breakthrough.
50:11They had developed a method of detecting Parkinson's disease
50:14before there were any clinical symptoms at all.
50:17This California drug user has no clinical symptoms,
50:20yet deep inside his brain there may be scars
50:23from the one dose of MPTP he took back in 1982.
50:28A mildly radioactive chemical is injected
50:30that will enter the brain and spread out along the dopamine pathways,
50:34provided those pathways are undamaged.
50:38The positron emission tomography, or PET scanner,
50:41is able to track the passage of this chemical
50:43by photographing dozens of brain sections
50:46from the bottom to the top of the brain.
50:52In a normal brain, the top section looks like this.
50:55But in a Parkinsonian brain,
50:57much less radioactive chemical gets through to this key motor area.
51:01But would such a dramatic contrast show up in this MPTP case?
51:06He may have no symptoms yet,
51:08but his PET scan shows he is well on the way to getting the disease.
51:15We can see Parkinson's disease before it develops clinically.
51:20If we then have a way of halting further cell death,
51:24and we could intervene at that time,
51:26we could literally start people on therapy
51:29before they ever got the disease and no more Parkinson's disease.
51:34The way it would work in reality and the things that would be required
51:37would be the PET scan would have to be turned into a screening tool.
51:40Right now it's just a basic research tool.
51:42I'm told the technology is there.
51:44It's not practical yet, but it could be done possibly.
51:48And one of these new therapeutic strategies
51:50to slow the progress of the disease would have to work.
51:54But if both of those occur, and maybe we're in the 21st century now,
51:57I don't know yet, but if both of those work,
51:59then people could routinely go in at a certain age.
52:02Say you go in for your EKG, heart tracing at age 40.
52:06You go in for your PET scan for your striatal dopamine at age 50.
52:10If it's normal, great.
52:12If it's down and you're on your way, you start Deprinil, and that's it.
52:17But what of people who are too late for Deprinil,
52:20who already have the disease in an advanced form,
52:23who've already lost the cells in the substantia nigra?
52:26What can be done for them?
52:28Perhaps one day even this might be curable.
52:31At Yerkes Primate Center, they've been trying to reverse Parkinsonism
52:35by surgically replacing the damaged substantia nigra
52:38with new dopamine-producing cells.
52:40These three monkeys have all got MPTP Parkinsonism.
52:45But after brain grafts, they move almost normally.
52:48It's much too early to know if it'll work in humans,
52:51but research is moving rapidly ahead on all fronts.
52:55I would say in the next 5 or 10 years,
52:57there are guarantees of new information
53:00in our understanding of Parkinson's disease
53:02which are going to come from those studies.
53:04They're almost predictable.
53:06Also, the perspective, how clinicians view Parkinson's disease
53:10and its treatment, it's already changed.
53:12There are things now that are clearly due to the severity of the disease
53:16and not to chronic L-DOPA treatment,
53:18which in the past were blamed on chronic L-DOPA treatment.
53:23It will change the way drugs are given.
53:25It will change the way people understand the pathophysiology of the disease,
53:28the functional disturbance.
53:30It will alter and has altered the view about which chemical substances
53:36that are disturbed in the disease
53:38are important in terms of symptomatic treatment.
53:41If medical research has thrived,
53:43so has the California designer drug business.
53:46Underground labs have spawned a whole series of designer heroines,
53:49some of very high quality.
53:51And as fast as one is made illegal,
53:53new ones are designed.
53:57Authorities are now worried about designer versions of other drugs,
54:00like cocaine.
54:04Last September 27th,
54:06California passed state legislation
54:08outlawing the drug family that struck down George
54:11and another series based on the fentanyl molecule.
54:15Meanwhile, in Washington,
54:16federal hearings were held last summer
54:18and the mood was passionate.
54:20Try to imagine never being able to move normally again.
54:24Never being able to raise your arm when you wanted to.
54:27Never being able to walk to the dinner table.
54:30Your life permanently and forever changed.
54:32That's what it does.
54:35A designer drug bill now exists in draft form
54:37and may soon become law.
54:40And what of the suspect the San Jose police had their eyes on?
54:44After the fire inspection,
54:45he and his colleagues fled.
54:47He is now in jail in Texas,
54:49not for making designer heroin,
54:51but for manufacturing an illegal street drug, PCP.
54:55A lawyer, he continues to deny his responsibility
54:58in the MPTP affair.
55:01But in a final twist of irony,
55:03before his arrest,
55:04he actually developed early signs of Parkinsonism
55:06and went to see Dr. Langston.
55:09The men spent two days together as doctor and patient.
55:16For the designer drug victims,
55:18there is little immediate hope.
55:27They live on a narrow ledge between being completely frozen
55:30and having terrible side effects.
55:39But for the millions of sufferers of Parkinson's disease
55:42around the world,
55:43the future has never looked brighter.
55:45All because of the case of the frozen addict.
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