Parkinson’s disease is like a storm slowly brewing: first, dark clouds gather in the clear sky, the wind picks up, and the first raindrops fall—signs of the impending storm. Then suddenly: a flash of lightning, a clap of thunder—a call to action and to seek shelter.
Similarly, people often experience symptoms such as constipation, changes in smell, fatigue and other premotor signs for years before being officially diagnosed with Parkinson’s disease. During this time, the brain and nervous system begin to change, ultimately leading to the classic motor symptoms of Parkinsonism. Unfortunately, the damage is irreversible at this point, and standard treatments can only alleviate the symptoms—they do not restore lost function.
But what if there were another option? What if we could treat the premotor phase and prevent the development of Parkinson’s disease?
REM sleep behaviour disorder: an important early warning sign for Parkinson’s disease
Approximately one quarter of people with early-stage Parkinson’s disease are also diagnosed with REM sleep behaviour disorder (RBD). Similarly, people with this disorder have a significantly higher risk of developing Parkinson’s disease later in life.
REM sleep behaviour disorder is a sleep disorder in which sufferers physically act out their dreams—they talk, shout, kick or punch—and may injure themselves or their bed partners. It is usually treated with clonazepam or melatonin, which alleviate the symptoms but do not prevent or slow down the underlying neurodegeneration.
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What is N-Acetyl-DL-Lecuin (ADLL)? A neuroprotective compound
Leucine is an essential amino acid that we obtain through our diet and is important for both muscle health and energy production. Like almost all amino acids, leucine exists in two forms: L-leucine and D-leucine. These are mirror images of each other, similar to how our left and right hands are different but complementary. Although both forms are present in our bodies, they occur in different amounts and have different functions.
L-leucine is the active form that our body relies on. A chemical modification known as “N-acetylation” transforms leucine into the drug N-acetyl-L-leucine (NALL) 1. There is also N-acetyl-DL-leucine (ADLL), a balanced mixture of both forms. This mixture has been used in France for several decades to treat dizziness, presumably by restoring neural communication. Excitingly, studies between 2020 and 2021 showed that N-acetyl-DL-leucine offers neuroprotective benefits and slows the progression of neurodegenerative diseases such as Niemann-Pick type C and GM2 gangliosidosis 2. These promising results prompted researchers to investigate the potential of ADLL in treating Parkinson’s disease.
Vitamin B3 (niacin) and brain protection in Parkinson’s disease – mechanisms and evidence
N-acetyl-DL-leucine (ADLL) in REM sleep behaviour disorder: Could it delay Parkinson’s disease?
In 2021, Professor Dr Wolfgang H. Oertel from Philipps University in Marburg invited a man and a woman—both with REM sleep behaviour disorder and partial loss of smell, but without signs of Parkinson’s or other neurological diseases—to participate in a clinical trial with N-acetyl-DL-leucine (ADLL) 3. They took 5 grams of ADLL daily and kept detailed symptom diaries.
The REM Sleep Behaviour Disorder Symptom Severity Scale (RBD-SS), an 8-item questionnaire, measures the frequency and intensity of dream behaviours, including vocalisations, movements, and injuries. After three weeks of treatment, both participants showed remarkable improvements—they experienced minimal symptoms of REM sleep behaviour disorder and no more aggressive dreams. These positive effects persisted over 18 to 22 months of continuous treatment.
N-acetyl-DL-leucine (ADLL) could protect the brain from Parkinson’s disease
Researchers also performed advanced brain scans on both participants to monitor neurological changes. The DAT-SPECT scan measures dopamine transporter (DAT) levels in dopamine-producing neurons. A decline in the DAT “binding ratio”—a measure of how many healthy dopamine neurons are still functioning—indicates the loss of these neurons, a hallmark of Parkinson’s progression.
–> Is slowing down possible? UDCA in Parkinson’s therapy – opportunities and limitations
The female participant had undergone scans between 2013 and 2019 that showed progressive neurodegeneration. After nearly two years of ADLL treatment, her DAT binding ratio improved to near-normal levels, suggesting that ADLL may protect dopamine-producing neurons. A similar effect was observed in the male participant.
FDG-PET scanning helps identify the Parkinson’s-related pattern (PDRP), which shows specific glucose metabolism abnormalities in the brain associated with Parkinson’s and its earlier stages. Over time, people with REM sleep behaviour disorder show increasingly disturbed brain metabolism/activity—reflected by rising PDRP values—before they transition to Parkinson’s disease.
After one year of ADLL treatment, both participants showed a decrease in PDRP levels, indicating a possible slowing of the disease progression. It is noteworthy that both maintained normal motor and cognitive functions during treatment. FDG-PET scans of 12 untreated patients with REM sleep behaviour disorder over 8 years showed that 4 developed Parkinson’s disease and 1 developed another neurodegenerative disease.
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N-Acetyl-DL-Leucine (ADLL) vs. N-Acetyl-L-Leucine (NALL): Which is better?
ADLL (Tanganil™) has been in use since around 1960, and its established approval and availability have facilitated the use of ADLL in clinical trials and for off-label treatments. Excitingly, animal studies suggest that N-acetyl-L-leucine (NALL) is a promising neuroprotective molecule. Last year, Dr Tatiana Bremova-Ertl from Inselspital, University Hospital Bern in Switzerland, was the first to publish results from a Phase 3 trial of NALL 4. This important study showed that NALL produced significant improvements in neurological symptoms, cognition and overall quality of life in people with Niemann-Pick type C. It was the first placebo-controlled study of NALL to confirm both its efficacy and safety over 12 weeks.
In his study, also published in 2024, Professor Dr. Wolfgang H. Oertel points out one limitation: he used N-acetyl-DL-leucine instead of pure N-acetyl-L-leucine, which was not available at the time. Due to regulations governing off-label treatments with Tanganil™, only two people without placebo control were able to participate in this study. Conducting a larger clinical trial with a placebo group will really help to consolidate the results. This approach reduces random variations and confirms the effect of the drug with greater certainty. Nevertheless, Prof. Oertel’s results show the promising potential of acetyl-leucine in slowing the progression of Parkinson’s disease.
–> For a broader overview: Parkinson’s Basics – Fundamentals explained simply.
N-Acetyl-DL-Leuin (ADLL) & Parkinson’s: Conclusion
ADLL has shown strong, lasting effects on REM sleep behaviour disorder – without side effects – and may even protect the brain from Parkinson’s disease. Although these initial results are encouraging, larger clinical trials are needed to validate its potential as a disease-modifying therapy.
If you or someone you know suffers from REM sleep behaviour disorder, consult a neurologist about the latest research findings. While treatments such as ADLL are still being researched, early detection and monitoring of symptoms can be crucial.
–> Looking beyond ADLL: Thiamine/vitamin B1 in Parkinson’s disease – a potential therapy booster.
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References
- Churchill GC, Strupp M, Factor C, et al. Acetylation turns leucine into a drug by membrane transporter switching. Sci Rep. 2021;11(1):15812. Published 2021 Aug 4. doi:10.1038/s41598-021-95255-5
- Kaya E, Smith DA, Smith C, et al. Acetyl-leucine slows disease progression in lysosomal storage disorders. Brain Commun. 2020;3(1):fcaa148. Published 2020 Dec 20. doi:10.1093/braincomms/fcaa148
- Oertel, W.H., Janzen, A., Henrich, M.T. et al. Acetyl-DL-leucine in two individuals with REM sleep behavior disorder improves symptoms, reverses loss of striatal dopamine-transporter binding and stabilizes pathological metabolic brain pattern—case reports. Nat Commun 15, 7619 (2024). https://doi.org/10.1038/s41467-024-51502-7
- Bremova-Ertl T, Ramaswami U, Brands M, et al. Trial of N-Acetyl-l-Leucine in Niemann-Pick Disease Type C. N Engl J Med. 2024;390(5):421-431. doi:10.1056/NEJMoa2310151