A History of L-Dopa, the Dopamine Building Block

The Story of a Natural Substance Used as a Pharmaceutical

In creating a new module of my Nervous System in Chronic Illness online course, on the topic of “All Things Dopamine” [see bottom of this post for more info on this], I looked back at the history of the development and use of L-Dopa as a pharmaceutical, and felt it was worth sharing what I found here too.

This article should be of interest not only to folks with chronic conditions that are associated with [apparent] Dopamine deficits, in which Dopamine supplementation may have a role, from Parkinson’s Disease, Restless Leg Syndrome. Dystonia, ADHD to Fibromyalgia and Ehlers Danlos Syndrome, but also to those healthy individuals seeking optimization of Dopamine as a “bio-hack”.

Fibromyalgia as a Dopamine Deficiency Condition

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L-Dopa (also known as Levodopa) is a natural substance which we create in our our bodies and brains, but which we can also ingest from food. Broad beans and mucuna pruriens are very high in the substance, for example, from which it can be extracted as a supplement.

L-Dopa is the immediate precusor to Dopamine, in the Dopamine biosynthesis chain:

PHENYLALANINE (from food) -> TYROSINE (from food or made in body from Phenylalanine) -> L-DOPA (from food or made in the body from Tyrosine) -> DOPAMINE.

[As intriguingly pointed out by

Roman S Shapoval

of

The Power Couple by Roman Shapoval

substack, L-Dopa is also a precusor for Melanin].

Back in the 1960s and 70s, L-Dopa was trialed as a drug for conditions in which people are immobilized or catatonic, such as Parkinson’s. The movie “Awakenings” was based on a true story of Oliver Sacks trying L-Dopa with catatonic survivors of the 1919–1930 epidemic of encephalitis lethargica.

A very good account of the history of L-Dopa is given in the science article in Nature “Levodopa: The Story So Far”, from which the below quotes are taken.

“L-DOPA burst onto the clinical scene in the late 1960s as a miracle drug, unlocking or awakening patients immobilized for years or decades by the crippling and progressive neurodegenerative disease. Its debilitating side effects became apparent with equal swiftness. These include disturbing dyskinesias or uncontrolled movements and equally disturbing on–off effects in which the effect of the drug suddenly stops, freezing patients almost mid-sentence.”

This initial success, followed by devastating consequences, is as depicted in the film “Awakenings”.

“But L-DOPA turned out to be a most difficult molecule to control therapeutically, thanks to its inconveniently short biological half-life, physicochemical cussedness and poorly understood pharmacodynamic interaction with disease progression. Neurologists still fight to find the balance between clinical effectiveness and side effects in individual patients. For all that, L-DOPA remains the gold-standard treatment, and many experts assert that life expectancy [but not health span] on current treatment regimens is close to that of the normal population.”

“With L-DOPA, a good two-thirds of patients develop mild or severe dyskinesias following several years of therapy, after which the disturbing on–off phenomenon also kicks in. Ideally, L-DOPA would be packaged and delivered in a form that avoided these side effects, but the molecule turned out to be a pharmacologist’s nightmare. It looks small and innocent, but has an incompliant chemistry and unhelpful metabolism.”

I have suffered from terrible levels of dyskinesia for years from being habitualized on L-Dopa drugs. The good news I have been able to reverse and largely ameliorate this, by taking the steps

The Antidote to Suffering in the Modern World

which have allowed me to reduce the drug burden I was taking without detriment to symptom severity, resulting in now having significantly less dyskinesia. So all is not lost for folks who have already developed this devastating side-effect.

“For one thing, it [L-Dopa] is removed rapidly by enzymes in the blood where it has a half-life of around an hour. It was relatively easy to improve on this by judicious use of enzyme inhibitors. L-DOPA is converted to dopamine by the aromatic amino-acid decarboxylase enzyme in the blood. This [blood] source of dopamine causes peripheral side effects like nausea and reduces the amount of L-DOPA available to cross into the brain. Since the late 1970s, L-DOPA has been given together with carbidopa, or another inhibitor of this enzyme, stretching its half-life in the blood to 90 minutes.”

It is interesting to me, that the addition of the decarboxylase enzyme inhibitor only has a relatively moderate increase in extended half-life of L-Dopa in the blood. I suspect the main reason the enzyme inhibitors were added was to make a natural substance into a patentable drug, and it may not have that much of the advertised profound effect, especially once one has been habitualized to L-Dopa for years. Indeed, my own experience [and that of some other folks with PD], is that taking one capsule of Biovea brand natural supplement, Mucuna Dopa, which does not contain an enzyme inhibitor, gives me an effect which is indistinguishable from that of taking one 125 mg capsule of Madopar [both have 100 mg of L-Dopa as the active ingredient].

Even more intriguingly, researchers found, in another science article in Nature, “Gut bacterial tyrosine decarboxylases restrict levels of levodopa in the treatment of Parkinson’s disease”, that folks with a PD diagnosis, after some years on the drugs, have a type of bacteria in their gut which produce a high level of a variant of the decarboxylase enzyme that the inhibitors don’t work on, and hence ameliorating much of their effect.

“Bacterial tyrosine decarboxylases efficiently convert levodopa [L-Dopa] to dopamine, even in the presence of… inhibitors of human decarboxylase. In situ levels of [L-Dopa] are compromised by high abundance of gut bacterial tyrosine decarboxylase in patients with Parkinson’s disease”

Returning to the history article, the author points out that even now, over half a century later, the mechanism of action and issues with L-Dopa as a drug are still poorly understood.

“Why this should promote dyskinesias is not certain, but a prevailing theory holds that it is because the dopamine-depleted brain becomes more sensitive to external dopamine in compensation and thus overreacts to the dopamine generated from L-DOPA. The on–off effects are also not entirely understood because the off times do not always coincide with low blood levels of L-DOPA.”

I believe this latter observation is, based on experience, because too much L-Dopa can cause freeze just as much as too little - a classic U shaped response curve.

As further evidence that the mechanism of action, and unwanted effects, are still far from being understood, more recently, L-Dopa has been found to be a kind of neurotransmitter itself, and may also have a direct effect on PD symptoms, beyond just being converted to Dopamine.

Also L-Dopa has recently been found to interact/bind with iron, resulting in neurotoxic effects:

“Findings demonstrate that levodopa [L-Dopa] and the protein siderocalin combine in the presence of iron to create a complex that may cause a cellular iron overload, leading to an imbalance between free radicals and antioxidants, as well as neuroinflammation in the brain, triggering dyskinesia, fluctuations in mobility and freezing episodes.”

This is especially relevant to folks with a Parkinson’s or Alzheimer’s diagnosis, whose brains show excess levels of iron.

(It is somewhat unnerving to me, therefore, that the capsules of the L-Dopa based drug Madopar actually contain iron in the printer ink and colouring of the capsules (and titanium too)]).

This article is based on an extended version of the section “L-Dopa: A History” of a new module on Dopamine which I building for my online course on the Nervous System. In this module, “All Things Dopamine”, I am gathering together everything I’ve learned and researched about Dopamine all in one place [in effect, it will be a pragmatic e-book on the topic]. I will be building out this module rapidly in the upcoming days and weeks.