Let’s talk snus use

# # # # Environmental factors that influence the risk of developing Parkinson’s have long fascinated researchers as the offer the opportunity to generate testable hypotheses about what could be causing/influencing the condition. These environmental factors are typically explored via epidemiological studies that look at the behaviour and environmental interactions of large groups of people, including some who have developed Parkinson’s.  Recently, one such study has been reported and the results point towards a curious influencer: Snus In today’s post, we will discuss what snus is, we will review the results of the new study, and consider the implications for Parkinson’s. # # # #

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Lund. Source: Northabroad

One of the most fortunate experiences of my life was being invited to do my PhD research in a small academic city called Lund in Sweden. I will be forever grateful to the people of Sweden for offering this opportunity and to Matt Maingay whose kind words paved the way for me.

I loved my years in Lund. I worked like a dog (7 days per week, volunteering for everything, last one to leave the lab – that sort of stuff), and my time there had an incredible impact on my life (for one thing, I met my wife in Lund).

Lund. Source: Themayor

During my time in Sweden, it was also a real pleasure to learn about the country, the people, and the culture. I sampled as much of it as I could – from trying to learn the language to visiting ‘mythical’ Landonia (a stunning coastal micronation made entirely of driftwood):

Landonia – wondrous! Source: Wikipedia

There were a couple of features of Swedish life, however that I struggled to adopt. First, eating Surströmming was not for me (not once, but twice I tried). Surströmming is lightly-salted, fermented Baltic Sea herring, and the key word there is “fermented“. It is an acquired taste, that’s all I will say.

Surströmming. Source: Rove

Second, I never developed a habit for snus.

What is snus?

Snus (pronounced snoose) is a moist powder smokeless tobacco product that is either taken raw or in a small teabag-like sachets:

Snus. Source: Harvard

Both are placed inside the lip (between the lip and gums – see the photo at the top of the post) for extended periods. It is loaded with nicotine and, as a result, rather addictive.

I tried it a few times. Tremendous head rush, over activation of saliva glands, and (again) an acquired taste – wasn’t really my thing.

But some of my friends in Sweden really love it.

Interesting. Why are we discussing this? What does it have to do with Parkinson’s?

Well recently a manuscript was made available on the OPEN ACCESS preprint depository website called BioRxiv, that suggests that use of snus could reduce the risk developing Parkinson’s.

Before we go any further, I should say that I am about to be break one of the unwritten rules of science communication (…yet again).

Until a research report has been through the peer-review process you probably should not be discussing the results in the public domain. But in this particular case, the research is rather interesting and relevant to what we discuss on this website.

I should also add that this is not the first time we have discussed manuscripts on BioRxiv (Click here, here, here, and here to read other SoPD posts on Biorxiv manuscripts).

Regular rule breakers we are here at the SoPD.

Ok, that said, let’s move on.

In this new manuscript, the authors wanted to conduct a case-controlled cohort study involving 929 people with PD and 935 matched population-based controls from
southern Sweden. They were looking for any environmental factors that could be having a direct causal effect on the risk of developing Parkinson’s.

Here is the manuscript:

Title: Novel Insights on Genetic and Environmental Factors in Parkinson’s Disease from a regional Swedish Case-Control Cohort
Authors: Brolin K, Bandres-Ciga S, Blauwendraat C, Widner H, Odin P, Hansson O, Puschmann A, Swanberg M
Database: MedRxiv; Posted June 23, 2021.
Doi: https://doi.org/10.1101/2021.06.18.21259024

In their study – which was supported by MultiPark – information about the exposure to environmental factors was obtained using questionnaires. The participants also had their DNA analysed to determine any genetic basis for possible associations.

The results of the study pointed towards many well known aspects of the condition (for example, a male predominance was observed in the cohort with a sex ratio of 2:1) and towards associations with recognised risk factors (such as, a family history of PD, which was over-represented within the PD cohort (20% of cases compared to just 11% among the control group)).

Parkinson’s symptoms were more commonly observed in the patient cohort than the control group – see some of them listed in the image below:

Source: medRxiv

But the study got interesting when the researchers explored factors that could possibly increase or decrease the risk of developing Parkinson’s.

In the image below, the environmental features listed on the left hand side. The respective odds ratio (OR – a statistic that quantifies the strength of the association between two events) is represented by a number (in the middle) and a bar relative to 0 difference on the right side of the image. Basically, the further to the left each horizontal bar is for each environmental feature, the greater the reduction in risk of developing PD, and the further to the right, the greater the increase in risk of developing PD:

Source: medRxiv

As expected, coffee drinking was associated with a lower risk of developing Parkinson’s (in a dose dependent manner), with a dose-dependent shift of the horizontal bar to the left side of the image. Meanwhile exposure to pesticides was the strongest risk factor (you seeing this, Syngenta? I’m just saying…Yet. Another. Study), with the horizontal bar on the bottom of the image shifting to the right side (note the difference in OR measures across the bottom of the image).

Smoking was also associated with a reduced risk of Parkinson’s – a well recognised association (Click here for a previous SoPD post on this topic), but curiously, snus had a stronger odd ratio than smoking – meaning that people who snus-ed rather than smoked, had a lower risk of developing Parkinson’s.

In Sweden, it has been estimated that 18% of men use snus and only 7% smoke on a daily basis (among Swedish females, 5% use snus and 7% smoke on a daily basis).

One of the interesting details in this study was that after adjusting for confounding variables, smoking only had a weakly inversed association with Parkinson’s. If you previously smoked, you have a slightly lower risk of developing PD, and this increases with the number of cigarettes/day, but there was a stronger relationship in non-smoke related tobacco products.

This finding suggests that cigarettes contain chemicals that are dangerous, not only to your health, but also to the beneficial effects of tobacco-based products on reducing the risk of developing PD. It also starts to help researchers zero in on the potential candidate molecules underlying the inverse association (nicotine is the obvious one, but it could be something else or certain combinations of compounds).

Was this the first time this association has been reported for snus?

No, there have been previous reports, such as:

Title: Moist smokeless tobacco (Snus) use and risk of Parkinson’s disease.
Authors: Yang F, Pedersen NL, Ye W, Liu Z, Norberg M, Forsgren L, Trolle Lagerros Y, Bellocco R, Alfredsson L, Knutsson A, Jansson JH, Wennberg P, Galanti MR, Lager ACJ, Araghi M, Lundberg M, Magnusson C, Wirdefeldt K.
Journal: Int J Epidemiol. 2017 Jun 1;46(3):872-880.
PMID: 27940486               (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers looked at data from The Swedish Collaboration on Health Effects of Snus Use, which includes data from 348, 601 men. They found 1199 cases of idiopathic Parkinson’s in the data. And when they rant the numbers, the investigators found that non-smoking, snus-using Swedish men had 60% lower risk of developing Parkinson’s compared to men who had never used snus before.

And this is supported by the findings of an older study:

Title: Smokeless tobacco use and the risk of Parkinson’s disease mortality.
Authors: O’Reilly EJ, McCullough ML, Chao A, Henley SJ, Calle EE, Thun MJ, Ascherio A.
Journal: Mov Disord. 2005 Oct;20(10):1383-4.
PMID: 16007624

In this prospective study involving a cohort of 95,981 men who never-smoked, the researchers found that smokeless tobacco use was also inversely associated with Parkinson’s (with an age-adjusted risk of 0.22 (0.07-0.67)).

So how could this “protective” association work? What is the biology behind it?

This is not clear. Nicotine an the obvious candidate though.

The levels of nicotine concentration in blood from snus use are similar compared with smoking, but without combustion and yields of toxicants in tobacco smoke (Click here to read more about this).

Nicotine has received a lot of research attention since the inverse association between smoking and Parkinson’s was first identified. Numerous preclinical studies in models of Parkinson’s, demonstrate that nicotine has neuroprotective properties (Click here and here to read good reviews on this topic). Parkinson’s UK has a good blog on nicotine as well – click here to read that.

Recently a large clinical trial exploring the disease-modifying potential of transdermal Nicotine patches in individuals with Parkinson’s was conducted. This Phase II study – called the “NIC-PD” study – involved 160 participants who were recently diagnosed with Parkinson and did not yet require any dopamine-based medication.

They were randomly assigned (1:1 ration) to two groups: One group of participants were treated with a nicotine patch (up to 28 mg/day) and the other group received a daily placebo patch. For one year the participants were treated with these patches, and then the treatment (or placebo) was stopped, and the participants were followed for another eight weeks (what is called a wash out phase – Click here to read more about the details of this study).

What was the result of the study?

The results have not been published yet, but they were presented at the Movement Disorder Society meeting 2018 in Hong Kong.

The primary endpoint of the study (the predetermined measure of efficacy) was the change in score of a clinical rating scale (called the UPDRS parts I-III) between a baseline assessment and then a final assessment at 60 weeks (52 weeks treatment + the 8 weeks washout).

At the end of the study, 101 participants were still involved and analyzed for the primary endpoint. The researchers found that there was a 3.5 mean UPDRS score increase in the placebo group (n=54), while the nicotine treated group (n=47) had a 6.0 increase in mean UPDRS score.

This result suggested that contrary to the inverse association discussed above, “nicotine may exert an accelerating effect as evidenced by worsened UPDRS scores compared to placebo” (Source).

That is to say, after diagnosis of Parkinson’s, nicotine might make progression of the condition worse.

What???

The result was surprising.

But as one of the study’s investigators Prof Karl Kieburtz told the Michael J Fox Foundation in an interview about the study, “Based on these results, there is no evidence for the use of nicotine in PD to slow clinical progression. If you smoke, consider quitting” (Source).

So instead of smoking should I start snus-ing?

No.

Firstly, it is difficult to get hold of snus in many parts of the world. It’s use is banned in many parts of the world, and travelling Sweds have to be careful where they take it.

Source: Wikimedia

In addition, snus use is associated with other serious health risks.

According to a report commissioned by the Norwegian Ministry of Health and Care Services into the health risks from snus use, it was found that:

• Use of snus probably increases the risk of oesophageal and pancreatic cancer.
• It is possible that snus use also increases the risk of cancer of the stomach and rectum.
• Use of Swedish snus probably increases the risk of high blood pressure and lethality after myocardial infarction and stroke.
• It is also possible that use of Swedish snus increases the risk of non-affective psychosis.
• High consumption (> four boxes of snus per week) of Swedish snus among men probably results in a large increase in the risk of type 2 diabetes and metabolic syndrome.
• The use of Swedish snus probably increases the risk of premature births.

Despite these (and other health risks) almost 20% of adult men and just over 5% of adult women in Norway use snus on a daily basis. And it is most common among young adults (aged 16-24 years): 25% of men and 15% of women in this age group use snus daily.

So I shouldn’t touch snus?

As we discussed above, associations studies are useful in identifying factors that could be influencing the risk of or progression of Parkinson’s. But as the findings of the NIC-PD study demonstrates, we need to be careful in how we interpret the findings of such studies. Just because something reduces the risk of PD before diagnosis, does not mean that it will naturally slow progression afterwards.

These types of studies are best considered “hypothesis-generating” efforts for researchers to explore new ideas. It would be interesting to really zero in on the various active chemicals in snus and try to identify which of them might be having the effect, and then trying to better understand the biological of that effect. Such knowledge could give key insights into the nature of Parkinson’s.

So what does it all mean?

Data presented in an non-peer-reviewed manuscript indicates that “snus use” is an environmental factor that has an inverse association with the risk of developing Parkinson’s in Sweden. This finding corroborates previous association studies, and suggests that smokeless tobacco products could contain chemicals worthy of further investigation.

Exactly how such an enquiry would be made is a topic for further discussion. Tobacco contains a wide range of chemicals which could be playing a role in influencing risk. Isolating the important agent(s) could be challenging, but – as we discussed above – would probably provide us with some useful insights into the biology underlying Parkinson’s.

So please do not rush out and snus. Let’s see what the scientists can do with this information first.

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