A Cheap And Popular Cough Medicine May Have a Protective Effect On Parkinson's Brains

A study tested the use of ambroxol, a common cough medicine, in people with dementia caused by Parkinson's disease. The idea was to see if it would help protect the brain by increasing an enzyme involved in clearing toxic proteins. The drug was safe and increased this enzyme in the brain, but it did not improve memory or reasoning. More research, with more people and over longer periods, will be needed to determine whether this medication can actually help treat dementia caused by Parkinson's disease.

Parkinson's disease is primarily known for affecting movement, such as tremors, stiffness, and slowness, but in many cases, it also progresses to memory and reasoning problems, leading to dementia. This is called Parkinson's disease dementia (PDD).

Researchers already know that a substance called β-glucocerebrosidase, which helps clear waste from brain cells, plays an important role in this. When there is a genetic variation that affects this substance, the risk of developing dementia caused by Parkinson's disease increases.

Additionally, higher levels of this enzyme may help reduce the buildup of a protein called α-synuclein, which is linked to brain damage in Parkinson's.

With this in mind, scientists decided to study ambroxol, a common medication used to relieve coughs, but which also acts as a "chaperone," helping the enzyme β-glucocerebrosidase function better and reach its target.

The aim of the study was to determine whether ambroxol is safe for patients with dementia caused by Parkinson's disease and whether it can somehow improve or slow the progression of cognitive problems (memory and thinking).

This study was conducted as a rigorous, randomized, double-blind, placebo-controlled clinical trial. This means that participants were randomly assigned to receive the medication or a placebo (a substance with no effect), and neither the patients nor the doctors knew who was receiving which, to avoid biasing the results.

The study involved patients over 50 who had had Parkinson's disease for at least a year and who already showed mild or moderate signs of dementia. All were on stable treatment and accompanied by a partner (such as a family member or caregiver). The study lasted about a year.

The participants were divided into three groups: one took a low dose of ambroxol (525 mg per day), another took a high dose (1050 mg per day), and the third group received a placebo. Throughout the study, researchers monitored the patients to see if the medication caused side effects, if it was well tolerated, and if it helped with aspects such as memory, cognition, and general well-being.

In total, 55 people participated in the study. As expected, the group taking ambroxol experienced more mild side effects, mainly in the digestive system, such as gastric discomfort. However, the effects were considered tolerable.

When the scientists analyzed the data, they saw that ambroxol did indeed increase levels of the enzyme β-glucocerebrosidase in the blood and fluid surrounding the brain, indicating that it was achieving its target.

Despite this biological advance, ambroxol did not show a clear improvement in memory or cognitive symptoms compared to placebo. In other words, although there was an increase in the desired enzyme, this did not yet translate into a visible clinical benefit for patients over the course of the study.

In summary, the study showed that ambroxol is safe and achieves its biological purpose in people with Parkinson's-associated dementia. However, there is still no evidence that it improves cognitive symptoms. Further research, with more people and over longer periods, will be needed to determine whether this drug can actually help treat dementia in Parkinson's disease.

READ MORE:

Ambroxol as a Treatment for Parkinson Disease Dementia

A Randomized Clinical Trial

Carolina R. A. Silveira,  Kristy K. L. Coleman, Kathy Borron, Rommel G. Tirona, Charles A. Rupar, Guangyong Zou, Robert A. Hegele, 

Cheryl Wellington, Sophie Stukas, Elizabeth C. Finger, Robert Bartha, Sarah A. Morrow, Jennie L. Wells, Michael J. Borrie, Don Mahuran, Penny A. MacDonald, Mary E. Jenkins, Mandar S. Jog, George Dresser, Susan Fox, 

Richard Camicioli, Brian Feagan, Daniel A. Mendonça, Michael Mayich, Manas D. Sharma, Sachin K. Pandey, and Stephen H. Pasternak

JAMA Neurol. Published Online: June 30, 2025

doi: 10.1001/jamaneurol.2025.1687

Abstract: 

Carrying a variation in the gene for β-glucocerebrosidase is a major risk factor for Parkinson disease dementia (PDD), and raising β-glucocerebrosidase levels lowers α-synuclein in cell and animals. Ambroxol is a chaperone for β-glucocerebrosidase, which increases the levels of β-glucocerebrosidase. To examine the safety and tolerability of ambroxol in PDD, test the efficacy of ambroxol in improving or slowing the progression of cognitive deficits, and acquire pharmacological data. This was a 52-week, phase 2, double-blind, placebo-controlled, randomized clinical trial conducted from February 2015 to June 2023. The study took place at a single center and was referral based. Included were patients with PDD who were older than 50 years, had Parkinson disease for at least 1 year before cognitive impairment, had mild to moderate dementia, were taking stable medications, and had a study partner. Ambroxol low dose (525 mg per day), high dose (1050 mg per day), or placebo. Safety and tolerability outcomes were adverse events. Primary efficacy outcomes were the Alzheimer Disease Assessment Scale–cognitive subscale, version 13 (ADAS-Cog-13) and Clinician’s Global Impression of Change (CGIC). A total of 75 patients were screened, and 55 were randomized. Thirty-one individuals received ambroxol, with 8 patients (mean [SD] age, 78.8 [3.4] years, all male) in the low-dose group and 22 patients (mean [SD] age, 70.7 [7.6]; 19 male [86.4%]) in the high-dose group. One patient was excluded from the high-dose group due to a diagnosis of progressive supranuclear palsy. A total of 24 patients (mean [SD] age, 72.7 [6.3] years; 19 male [79.2%]) were included in the placebo group. Participants receiving ambroxol (23 of 193 adverse events [12%]) showed more gastrointestinal adverse events than those receiving placebo (9 of 172 adverse events [5%]). Statistical analyses compared ambroxol high dose vs placebo. There was no evidence to suggest differences between groups on primary or secondary outcomes. Mean (SD) ambroxol high-dose concentrations were 7.48μM (3.17μM; 95% CI, 6.08-8.87μM) in plasma and 0.73μM (0.07μM; 95% CI, 0.64-0.81μM) in cerebrospinal fluid at the end of titration. Mean (SD) β-glucocerebrosidase levels were higher at week 26 (ambroxol, 12.45 [1.97] nmol/h/mg; 91% CI, 11.54-13.36 nmol/h/mg); placebo, 8.50 [1.96] nmol/h/mg; 91% CI, 7.65-9.34 nmol/h/mg; P = .05) in the ambroxol group compared with placebo. Results of this randomized clinical trial reveal that ambroxol was safe, well-tolerated, and demonstrated target engagement. However, the effect of ambroxol on cognition was not confirmed.

Trial Registration  ClinicalTrials.gov Identifier: NCT02914366