Ambroxol: cough medicine to first Parkinson's trials

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Screening in 2009 by Gustavo Maegawa, Don Mahuran and colleagues; the 2020 trial by Sarah Mullin, Anthony Schapira, Thomas Foltynie and colleagues at University College London.

What happened

• 2009. Screening 1,040 FDA-approved drugs for ones that help GCase (the enzyme in landmarks 16 and 35) singled out ambroxol, a mucus-thinning drug. It acts as a chaperone, steadying the enzyme, though in the test tube it also inhibits GCase at neutral pH.
• 2020 (Phase 2 on the registry, "AIM-PD"). Open-label, no placebo, one centre (UCL), January 2017 to April 2018. 23 people entered, 18 finished and 17 were analysed (8 with GBA1 mutations, 9 without). Dose rose to 1.26 g a day, for 186 days. No serious adverse events; ambroxol entered spinal fluid (+156 ng/mL, P<.001). GCase protein in spinal fluid rose 35% (95% CI 40 to 137 ng/mol, P=.002), but its measured activity fell 19% (95% CI -0.115 to -0.002 nmol/mL per hour, P=.04); the paper's abstract does not explain the fall. Alpha-synuclein in spinal fluid rose 13% (P=.01) and the motor score (MDS-UPDRS Part III) improved by 6.8 points (95% CI -10.4 to -3.1, P=.001), but without a placebo group neither can be credited to the drug.
• 2025 (Parkinson's dementia, Phase 2; NCT02914366). Single-centre (Canada), 52 weeks, 55 randomised to ambroxol 525 mg, 1,050 mg or placebo. The high-dose group (22) and placebo (24) were compared: no difference on the ADAS-Cog-13 or the clinician's global impression, though GCase was higher at week 26 (P=.05). More gastrointestinal side effects on ambroxol (12% vs 5% of events).
• Controlled trials in Parkinson's. Two are covered in their own files: the 65-person AMBITIOUS trial in GBA1 carriers, reported only as a preprint with no benefit (landmark 320), and the 330-person Phase 3 ASPro-PD, started in 2025 (landmark 321).
• Other registered ambroxol trials (small, none with a reported result).
  • GREAT (Phase 2/3, University Medical Center Groningen; NCT05830396): planned 80 people with a GBA mutation, ambroxol 1.8 g a day or placebo for 48 weeks, main measure off-medication MDS-UPDRS Part III at 60 weeks (protocol: BMC Neurol 2024;24). The ClinicalTrials.gov record has not been updated since May 2023 (status "unknown", estimated start May 2023, end July 2025), but the EU trial register (CTIS 2024-514976-41-00) shows it started on 23 September 2024 and is recruiting. No results found.
  • High-dose pilot (Phase 1/2, Agyany Pharma; NCT06193421): open-label, about 40 people newly diagnosed with GBA1 Parkinson's, started 24 Oct 2023. Status "unknown", last updated Feb 2024. No results found.

Why it moved us toward a cure

Ambroxol was one of the drugs picked by the Cure Parkinson's Trust's repurposing committee (landmark 119). It is the leading test of whether strengthening the lysosome's recycling can slow Parkinson's, in line with the loop in landmark 35. The 2020 pilot justified the controlled trials in landmarks 320 and 321.

Outcome

Open. It led to controlled trials, but the dementia trial was null and the GBA-carrier trial (AMBITIOUS) was negative; the Phase 3 is still running. Other GBA-directed drugs failed, venglustat (2023) and BIA 28-6156 (2026), but ambroxol is a different kind of drug (dead ends).

Sources

• Maegawa et al., J Biol Chem 2009;284:23502–23516, DOI 10.1074/jbc.M109.012393
• Mullin et al., JAMA Neurol 2020;77(4):427–434, DOI 10.1001/jamaneurol.2019.4611 (NCT02941822, PMID 31930374) · Alzforum therapeutics page
• Silveira et al., JAMA Neurol 2025;82(8):797, DOI 10.1001/jamaneurol.2025.1687 (abstract read via Europe PMC), also via NeurologyLive
• GREAT NCT05830396 · GREAT protocol, BMC Neurol 2024, DOI 10.1186/s12883-024-03629-9 · CTIS record for GREAT · Agyany NCT06193421 (status and design read from the registry on 19 Oct 2026). AMBITIOUS and ASPro-PD sources are in landmarks 320 and 321.
• Not yet verified: any result from GREAT or the Agyany pilot; whether the Agyany pilot is still running (registry stale since Feb 2024); GREAT's current enrolment; the page range of the Silveira paper.