Prodrome Science™ — Webinar Series
Why does L‑DOPA work at all — and what does that tell us about what is still intact in the Parkinson’s brain? Dr. Dayan Goodenowe on dopamine, what long‑term dopamine therapy asks of the brain, and the biochemistry of membrane repair.
Excerpt — full video on Dr. Goodenowe’s website.
Dr. Goodenowe presents the complete Parkinson’s webinar — the dopamine pathways in full, the published impulse-control case reports, the MPTP protection and regeneration studies, the neuroimaging, and an extended Q&A on medication interactions and biomarkers.
Watch on DrGoodenowe.com ↗1 hour 16 minutes · Free to watch · Opens in a new tab
Parkinson’s is one of Dr. Goodenowe’s longest-running research subjects — and, he says, one of his pet peeves. “I’ve done a lot of work in Parkinson’s,” he opens. “A lot of people have seen my lectures on autism and dementia and the work we do in concussions, but actually a large volume of work in Parkinson’s and the animal models of Parkinson’s have been done.” Of all his webinars, this is the one where the research he presents is most his own.
The lecture starts from an observation so ordinary that almost nobody stops to examine it: L‑DOPA works. It has worked since the early 1970s. And according to Dr. Goodenowe, the reason that matters is not the drug — it is what the drug’s effectiveness proves about the brain taking it.
L‑DOPA is not an exotic molecule. In Dr. Goodenowe’s framing it is “actually a supplement, quite frankly, used as a drug” — a direct biochemical precursor that dopamine neurons absorb and convert. And that, he argues, is the whole point: “The only reason L‑DOPA can work is that if the dopaminergic system is actually there for it to work from.”
By the time most people are diagnosed, roughly 80% of the dopamine-producing cells in the substantia nigra — a pea-sized structure deep in the midbrain — are already gone. Dr. Goodenowe’s reading of that: if L‑DOPA still produces a response, then the physical infrastructure the drug acts through must still be present. “If the physical structure wasn’t there, L‑DOPA couldn’t work. So clearly at diagnosis, L‑DOPA working means there’s physical structure there. All it needs is to be juiced up a little bit — which is why deep brain stimulation works.”
His analogy for what the substantia nigra does is worth keeping: it is “the reins on your team of horses.” Movement, in his description, is not something we switch on. It is something already primed that we release with precision. “Your arm is already ready to move and you’re keeping it from moving. It’s the ability to release that movement that gives you fine tuning.” Lose the reins and you lose the fine control — which is why a resting hand won’t stay still, and why standing upright, a background function rather than an active one, becomes work.
The core of the lecture is a caution about what happens when you flood a complex system to fix one part of it. The nigrostriatal pathway — the motor circuit — is what Dr. Goodenowe calls “the bright shining object”: the pathway everyone watches because it produces the visible symptom. But dopamine runs at least three other routes: the mesocortical system (cognition, motivation, memory, learning), the mesolimbic system (emotion, perception, reward), and the tuberoinfundibular system (hormone regulation, including prolactin).
“When we dump a bunch of dopamine into the human brain,” he says, “we’re dumping it on all these systems simultaneously. And the brain kind of has to adjust and adapt and figure out what’s going on.” Treatment becomes a titration problem: “How much dopamine can I give to restore nigrostriatal without messing up the rest of my brain?” Adding to the difficulty, the same molecule has opposite effects depending on which receptor subtype it reaches — some activate the receiving cell, some suppress it, and they are distributed differently across the brain.
This is, in our view, the most practically important section of the webinar, and the part most worth the time of anyone living with Parkinson’s or caring for someone who is.
Dr. Goodenowe reads out a published case from a Canadian physician. A man diagnosed at 42 with a right-sided resting tremor, rigidity, and bradykinesia. A lifetime non-smoker. No history of gambling or alcohol problems. Over the following years his medication was escalated in the ordinary way — a MAO‑B inhibitor added, then a dopamine agonist, then rising doses of levodopa/carbidopa. At 52 he developed pathological gambling, and the agonist was discontinued. The gambling stopped. His motor symptoms worsened, so his levodopa was increased and held stable.
Then, at 56 — fourteen years in, with no change to his medication — the gambling returned. “At any opportunity he would use online applications and websites, requiring that his wife had to hide all electronic devices,” Dr. Goodenowe reads. The man lost more than $10,000 in a single sitting. His personality changed; he became aggressive and irritable. Over eleven months he lost $180,000 and had to refinance his home.
And it is not an isolated case. According to Dr. Goodenowe, around 30% of Parkinson’s patients on dopamine agonists develop impulse control disorders — pathological gambling, hypersexuality, compulsive spending — with a lesser rate on levodopa alone. The lesson he draws from the case report is the one clinicians should be saying out loud more often: these disorders can appear without any medication change at all, in a susceptible person, and any drug that perturbs dopamine homeostasis — agonist or inhibitor — can trigger them.
“Dumping the brain full of dopamine is not just a completely benign situation,” he concludes, “and it really cannot go on forever.” If you take one thing from this webinar to your own neurologist, we would suggest it is this.
He raises a second cost of long-term levodopa that gets less attention: the load it places on the body’s methyltransferase system. “Highly reproducible — as soon as people get on L‑DOPA, within six weeks their homocysteine levels are usually up by several points.” According to Dr. Goodenowe, this is why anyone on levodopa should be paying attention to methyl B12, choline, and methylfolate, and why he considers homocysteine the biomarker to watch in Parkinson’s specifically.
Dr. Goodenowe’s own research enters here, and the mechanism he proposes is specific. Dopamine, he explains, is useless inside a neuron unless the cell can actually release it — and release happens by membrane fusion, the process by which a vesicle merges with the cell wall and empties its contents into the synapse. That fusion, according to work he cites from 1995, depends on the plasmalogen content of the membrane: “Seventy-five to a hundred percent of the ethanolamine portion needs to be plasmalogens. Anything less than that, membrane fusion is decreased.”
Which reframes what L‑DOPA can and cannot do. “If you’re going to put dopamine in the system, whether it’s L‑DOPA or anything else, that dopamine is going into the presynaptic neuron — but it can’t actually get released into the synapse unless the machinery of the cell is working.” In his framing, L‑DOPA supplies fuel; plasmalogens are part of the engine.
He presents three converging lines of evidence. In post-mortem human frontal cortex, Parkinson’s brains show markedly lower plasmalogen levels than controls. In a long-running Chicago cohort of roughly 1,262 people, higher blood plasmalogen levels were associated with substantially lower Parkinson’s incidence — “a 50% reduction… for one standard deviation” — and the association held for measured motor function, not just diagnosis. A separate study in Osaka, Japan, with Dr. Sakoto, found the same pattern.
Worth noting alongside this, and Dr. Goodenowe raises the question himself before moving to the animal work: these are observational findings, and he asks aloud, “well, is this just causal?” It is a fair question to sit with. Parkinson’s has a prodromal phase measured in decades — Dr. Goodenowe spends several minutes of this same lecture showing symptoms detectable up to ten years before diagnosis. If the earliest stages of the disease process themselves deplete plasmalogens, the same association would appear without plasmalogen loss being the cause. Observational data cannot separate those two possibilities; that is what the animal work below is for.
The animal model has one of the strangest origin stories in neurology, and Dr. Goodenowe tells it well. In the early 1980s, a group of young people in California were synthesising designer heroin. The chemistry went wrong, producing a contaminant called MPTP. Within days, people in their twenties were checking into hospital with full-blown Parkinsonism — and nobody knew why.
The detective work that followed established the mechanism. MPTP crosses into the brain, gets converted to MPP+, and is then recognised and absorbed by the dopamine transporter specifically. “It was like candy for dopamine neurons,” Dr. Goodenowe says. Once inside, it wrecks the mitochondria. That selectivity — a toxin that dopamine neurons pull in preferentially — is what made it a reproducible model. There are, by his estimate, some 5,000 research papers on it.
Dr. Goodenowe’s group used it to ask two questions. First: does pre-treating with plasmalogen precursors protect against the toxin? He reports that it does — dopamine transporter levels dropped with MPTP alone and were fully restored at a 50 mg/kg dose of precursor, with the serotonergic system protected as well. Second, and in his words the bigger question: “Can we rescue dopaminergic neurons when they’ve already degenerated from the toxins?” Applying the precursors after the toxin, he reports significant regeneration of the terminal fields — not the cell bodies themselves, but the branching projections those cells send into the striatum.
That distinction matters to his argument. “We’re not measuring where the cell bodies are lost. What we’re showing is that we’re growing the terminal fields” — the goal being that the surviving 20–30% of cells can do more of the work. In a further primate study, animals given plasmalogen precursors alongside L‑DOPA showed reduced L‑DOPA‑induced dyskinesia, which he frames as the ideal outcome: “We want L‑DOPA to work, we just don’t want it to have the nasty side effects.”
A note on how far this evidence reaches: MPTP is an acute, single-mechanism toxin that kills dopamine neurons within days, and it is well known not to reproduce the Lewy body pathology that defines idiopathic Parkinson’s. It models a chemical injury to the dopamine system rather than the slow disease most people have. Protecting a mouse against MPTP is a real result, and it is not the same as preventing or reversing Parkinson’s in a person.
Asked directly in the Q&A for peer-reviewed placebo-controlled studies in humans rather than animal models, Dr. Goodenowe answers plainly, and we think his candour is worth quoting rather than paraphrasing:
“We’ve done one human trial, formally with Dr. Jordan in Santa Monica. It wasn’t a placebo controlled trial, it was an open label, dose escalation trial.”
He explains that placebo-controlled designs are difficult with multi-agent protocols, describes a delayed-start crossover design as his preferred alternative, and says his research centre in Temecula will be running larger trials. “We will do some small placebo trials,” he adds. As of this webinar, the human evidence for these protocols is open-label and case-based — which Dr. Goodenowe states himself, without being pressed.
The webinar opens with a testimonial from Heather about her husband Ian, who has Parkinson’s. Before Moose Jaw, she describes left-sided weakness, balance problems, a shuffling gait, feet that “wouldn’t work occasionally,” falls, needing help to stand, deteriorating concentration, and a fading sense of taste and smell. “I was never out of arm’s reach of Ian,” she says, “in case he needed extra support or he had a trip.” She looked at the stairs on arrival and thought they would never manage them.
Six weeks later, by her account, he was climbing those stairs in the morning unassisted. But the change she leads with is not physical. “The first thing we noticed was his animation… he just got this lovely cheeky man back that we’ve had for years and we had lost before we went.” Their own neurologist, she says, saw the difference immediately.
Ian has since come off levodopa. This is the part that needs reading carefully, and Dr. Goodenowe is more careful about it than a short summary can convey. Heather is explicit that they consulted their neurologist before changing anything. And asked in the Q&A why anyone would stop a drug that helps, Dr. Goodenowe’s answer is not what the question anticipates:
“You want to keep taking your L‑DOPA while your brain is regrowing, and you just gradually take it back… as you build your endogenous system and you need less and less L‑DOPA, you slowly bring it back. But no, you still use it — you want to have a good functioning life.”
He calls levodopa “a miracle drug and a necessary one,” and goes further: “If we can make L‑DOPA nontoxic… then yeah, you could take L‑DOPA your whole life. Who cares if it works? Do it.” The reduction he describes is gradual, medically supervised, and follows improvement rather than causing it. It is not a recommendation to stop.
Heather’s own summary of the six weeks is the line that stays with you: “I went to Moose Jaw with a 77-year-old husband with Parkinson’s, and I’ve come home with a 77-year-old husband.” As with every case study on this site, this is one person’s experience, reported by his wife, on a protocol combining several interventions at once. It is a story, not a trial. Dr. Goodenowe would say the same — and does, in the passage quoted above.
Dr. Goodenowe is candid that this work spans different levels of evidence, and it is worth being clear about which is which. The observation that L‑DOPA’s effectiveness implies surviving structure is a reasoned argument. The impulse-control data and the homocysteine effect are published findings in humans. The plasmalogen associations in Chicago and Osaka are observational epidemiology. The protection and regeneration results are animal and primate work. The human protocol evidence, by his own account, is open-label and case-based, with controlled trials planned.
That range is normal for research in progress. It is also why this page links to the full webinar rather than summarising it away — so you can see the studies, the imaging, and the Q&A for yourself, and take the questions that matter to you to your own physician.
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