select search filters
briefings
roundups & rapid reactions
Fiona fox's blog
Scientists comment on study in JAMA Neurology looking at carbon monoxide exhalations levels and risk of Parkinson’s disease
Dr Michael A. Schwarzschild, Cure Parkinson’s International Linked Clinical Trials committee member and Professor of Neurology, Harvard Medical School, said:
“Not only does this study reaffirm smokers’ reduced risk of Parkinson’s, it is the first rigorous investigation of a large population to evaluate whether exposure to carbon monoxide itself can predict an altered risk of developing the disease.
“Remarkably, higher levels of carbon monoxide in non-smokers — corresponding to those found in light or moderate smokers — predicted a lower risk of Parkinson’s years later.
Among the important cautions in interpreting these results is the question of whether they will be reproducible in other populations.
Nevertheless, the findings suggest that some potentially good effects can be separated from the many established, overwhelmingly detrimental health effects of smoking.
Importantly, Bueno Lopez and colleagues were able to show that while non-smokers with higher levels of carbon monoxide were at lower risk for Parkinson’s, they were not at increased risk for lung cancer and other known detrimental effects of smoking. This contrasts with smokers who, as expected, had a markedly increased risk of developing lung cancer as well as a reduced risk of Parkinson’s.
The findings highlight the value of trying to find what molecule of the myriad in cigarette smoke could account for a potential — but unproven — preventative effect on Parkinson’s without contributing to the many established dangers of smoking.
This report provides the clearest human evidence even if circumstantial that low-dose carbon monoxide may be beneficial in people with PD — short of randomized, blinded clinical trials.
This study further strengthens the rationale for the trial of low-dose carbon monoxide we have just started in non-smokers with Parkinson’s.
I serve as the Principal Investigator of LoCaMoTE-PD, which is short for “Low-dose liquid Carbon Monoxide (HBI-002) Trial to Evaluate its safety, tolerability, pharmacokinetics, and biomarkers in PD” and is registered with NIH (ClinicalTrials.gov # NCT07005180).”
From our friends at SMC New Zealand
Dr Toni Pitcher, Senior Research Fellow in Parkinson’s epidemiology, University of Otago, Christchurch, said:
“The so-called protective effects of cigarette smoking on Parkinson’s disease risk has sat uncomfortably with the medical community since it was first described in 1959. Surprisingly, the exact mechanism underlying this association remains elusive. Nicotine, perhaps the most obvious candidate to mediate the association has been studied widely, but no firm mechanisms for protection have been uncovered.
The newly published paper by Lopez et. al. provides further evidence for another potential candidate mediating this association – carbon monoxide. This is the first large-scale demonstration that Parkinson’s is also less common in individuals with higher levels of exhaled carbon monoxide in the absence of a smoking history.
Carbon monoxide has anti-inflammatory effects and in the brain helps to counteract cell stress. There is the potential that individuals with higher internal levels of carbon monoxide are more able to fight off inflammatory processes and better maintain brain health.
The challenge now is to replicate these findings in independent cohorts and to better understand how carbon monoxide counteracts the pathology associated with Parkinson’s. Study authors refer to a registered clinical trial testing the safety of low-dose carbon monoxide in people with Parkinson’s, highlighting its therapeutic potential.
Caution is needed however, we know there is no one cause of Parkinson’s and as such there is unlikely to be one ‘cure’ for all. Identifying who will benefit most from a particular therapy remains a challenge within the Parkinson’s field.”
From our friends at SMC Spain
Rosario Sánchez Pernaute, an Ikerbasque Research Professor, director of the Laboratory of Neural Reprogramming and Regeneration (Molecular Brain Lab) and a member of the scientific management team at the Health Research Institute Biobizkaia, said:
Is the research of high quality?
“It is a well-designed study, carried out by a group of experts in epidemiology. The analysis is meticulous. The only point to bear in mind is that the follow-up period is relatively short for diseases such as Parkinson’s disease (PD), which have a late age of onset; consequently, they may be detecting fewer cases than actually occur in that sample.”
How does it fit in with the existing evidence?
“It is consistent with epidemiological studies showing a reduced risk of developing PD among smokers, even to a greater extent than in this study.”
Could findings such as these encourage people to take up smoking or prevent them from giving up?
“No, the health risks associated with smoking are well known and severe. In fact, the study suggests that the protective effect can be dissociated between the effect of carbon monoxide (CO) and that caused by other compounds present in tobacco, such as nicotine, which was thought to be causally linked, albeit without clear evidence. It is also true that this study cannot prove that this is not the case (regarding nicotine or other tobacco compounds), but it does provide evidence of an inverse correlation between CO levels and the risk of developing PD in non-smokers, which is the most significant finding from my point of view.”
What are the implications of these findings for clinical practice?
“At present, they have no direct clinical implications. Strategies are being explored to stimulate the production of endogenous CO as an indirect antioxidant, given its ability to activate heme oxygenase-1 and other antioxidant mechanisms.”
Does the study have any significant limitations that need to be taken into account?
“I believe the main limitation is the relatively short follow-up period for diseases such as PD, which have a late age of onset, and perhaps the fact that only a single measurement of exhaled CO was taken, which may not be representative of actual exposure over time.”
From our friends at SMC Spain
Salvador Ventura, a Professor of Biochemistry and Molecular Biology at the Autonomous University of Barcelona and a researcher with the Academy of Excellence programme, said:
“The study is epidemiologically sound: a prospective design, over half a million participants and 12 years of follow-up. But for me, its significance lies not where it might seem at first glance. Confirming that smoking is associated with a lower incidence of Parkinson’s is not a decisive finding, because that observation has been on the table for decades. What is striking is the subgroup of people who had never smoked: even amongst them, higher levels of exhaled carbon monoxide are associated with fewer subsequent cases of the disease. And here, the measurement is objective, with adjustments made for foreseeable exogenous sources, ranging from passive smoking to the domestic use of solid fuels.
However, an association does not imply a protective effect. Carbon monoxide could be involved in some protective mechanism or it could simply be a marker of other biological processes or exposures that do influence the risk. The study does not distinguish between the two.
The mechanism is plausible. We produce carbon monoxide endogenously via the heme oxygenase pathway, and there are experimental findings linking it to the response to oxidative stress and to neuroprotective effects, reducing the aggregation of α-synuclein in animal models.
The message to the public must be unequivocal. These findings do not justify taking up smoking or delaying giving up smoking; the study itself finds, as might be expected, higher rates of lung cancer, cardiovascular disease and mortality amongst smokers. Nor do they justify deliberately exposing oneself to a gas that causes severe poisoning.
Furthermore, there remains a limitation that is easily overlooked. The fact that something is associated with a lower incidence of the disease says nothing about whether administering it would slow its progression in someone who has already been diagnosed. These are two distinct questions, and this research addresses only the first. Before discussing clinical applications, the observation would need to be replicated in other populations and safety and efficacy demonstrated in controlled trials. This is a hypothesis worth exploring, but so far there is no reason to change clinical practice or tobacco control policies.”
Ana Isabel Rodríguez Pérez, co-principal investigator of the Cellular and Molecular Neurobiology of Parkinson’s Disease Group at the Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS-USC) and senior lecturer at the University of Santiago de Compostela, said:
“The study by Bueno-López and colleagues provides a new clue to understanding why smokers have a lower risk of developing Parkinson’s disease. After following more than half a million participants from the China Kadoorie Biobank for around 12 years, the authors confirm this association and present a very interesting finding: amongst people who had never smoked, those with higher levels of exhaled carbon monoxide (CO) also had a lower risk of Parkinson’s.
This result suggests that the reduced risk of Parkinson’s associated with smoking may not be due to tobacco itself, but rather that CO could contribute, at least in part, to explaining this relationship. This possibility is particularly interesting because for years it has been suggested that nicotine might be responsible for this effect, but clinical trials conducted to date have not demonstrated that it slows the progression of the disease.
The study stands out for its large number of participants, its long follow-up period and the control for numerous factors that could influence the results (passive exposure to tobacco smoke, use of solid fuels in the home, physical activity and socio-economic status). Furthermore, the results are consistent with previous studies carried out in animal models, which demonstrate that, although CO is highly toxic at high concentrations, at low and carefully controlled doses it can activate antioxidant, anti-inflammatory and neuroprotective mechanisms.
In any case, and very importantly, this study does not prove that smoking protects against Parkinson’s disease and offers no reason to take up smoking or to continue smoking. In fact, the study itself confirms that smoking increases the risk of lung cancer, cardiovascular disease, stroke and premature death.
The research has some limitations: as it is observational, it shows an association but does not prove a cause-and-effect relationship; furthermore, CO was measured only twice and its origin cannot be determined with precision. Although these results do not, for the time being, change clinical practice, they open up the possibility of exploring low-dose CO as a therapeutic strategy, an option that is already beginning to be evaluated in patients with Parkinson’s disease.”
José A. Morales-García, a research scientist specialising in Parkinson’s disease at the Complutense University of Madrid, says:
“This is a very interesting observational study because of its scale – more than 500,000 adults aged between 30 and 79 followed for around 12 years – and, above all, because it offers a possible explanation for an association we have known about for decades: smokers have a lower risk of developing Parkinson’s disease.
What is new is that the authors have directly measured exhaled carbon monoxide (CO) and found that, even amongst people who have never smoked, higher levels of CO are associated with a lower risk of Parkinson’s. This raises the possibility that the supposed protective effect of tobacco may be related to CO and not necessarily to nicotine. It is an interesting hypothesis, moreover, because the potentially neuroprotective effects of CO had already been observed in experimental models.
The study is robust due to its large sample size, its prospective design and the objective measurement of CO, but we must be cautious in our interpretation. As this is an observational study, it demonstrates an association, not a causal relationship. Therefore, these results do not in any way imply that smoking is beneficial or that one should smoke to prevent Parkinson’s disease. Smoking remains a major cause of cancer, cardiovascular disease and mortality. Furthermore, the study participants are from the Chinese population, with genetic and environmental characteristics, consumption habits and patterns of exposure to smoke and pollution that may differ from those of other populations. It is therefore prudent not to extrapolate these results directly to other populations until studies are available that replicate the association in different contexts.
From a clinical perspective, the most interesting aspect is that these results support research into the potential therapeutic use of very low, controlled doses of CO. It is a promising avenue, but one that is still experimental and has no immediate clinical application.”
‘Smoking, Exhaled Carbon Monoxide, and Risk of Parkinson Disease’ by Clara Bueno Lopez et al. was published in JAMA Neurology at 16:00 UK time on Tuesday 8th September.
DOI: 0.1001/jamaneurol.2026.3037
Declared interests
Dr Michael A. Schwarzschild: “I have no financial conflict of interest with this research or the company that is sponsoring the trial. I have no involvement in the report itself, and no relationship with its authors. I have no COI with any commercial interest related to the subject of the report of commentary.I am a PI of a grant from a foundation (Farmer Family Foundation) to my institution (Massachusetts General Hospital), which supports a clinical trial of HBI-002 called LoCaMoTE-PD. I also serve as PI of this trial LoCaMoTE-PD (https://clinicaltrials.gov/study/NCT07005180). I am member of Cure Parkinson’s iLCT, which in 2023 prioritized a carbon monoxide-containing drug HBI-002.”
Dr Toni Pitcher: “No conflicts of interest.”
Rosario Sánchez Pernaute: “She declares that she has no conflicts of interest.”
Ana Isabel Rodríguez Pérez: “She declares that she has no conflicts of interest relating to this study.”
José A. Morales-García: “He doesn’t declare conflicts of interest.”
For all other experts, no reply to our request for DOIs was received.