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Is nicotine really as safe as e-cigarette supporters make out?

A core platform of the massive promotion of e-cigarettes has been the argument that because these products involve no combustion but only vapourisation, they must be substantially less dangerous than smoked tobacco. Few – including me – would disagree with that. There’s no carbon monoxide with vaping and none of the deadly pyrolysis products generated by the partial decomposition of carbon matter and flavouring chemicals in tobacco when it is burned.

But as toxicologists have pointed out, the long-term consequences of inhaling an average of 200 and up to 600 times a day a soup of vaporized flavouring and other chemicals approved for ingestion but not inhalation will not be known for many years.

‘As safe as coffee’?

The widely publicised “95% less dangerous than smoking” figure in the Public Health England report on the safety of e-cigarettes can be nothing but a fingers-crossed guess. Questions have also been raised about the panel that came to that figure and potential conflicts of interest.

A fundamental appeal of e-cigarettes is they are a “clean” nicotine delivery system. But there is also a widespread effort underway to depict nicotine as a benign drug.

Three prominent advocates for e-cigarettes, psychologists Robert West and Peter Hajek (who together have registered a patent for a nicotine delivery invention) and Professor John Britton, Chair of the Tobacco Advisory Group of the Royal College of Physicians, are among many who have made public statements suggesting nicotine is as close to benign as one could imagine.

Professor Robert West has said:

E-cigarettes are about as safe as you can get. We know about the health risks of nicotine from studies in Sweden into the use of snus, a smokeless tobacco. Nicotine is not what kills you when you smoke tobacco. E-cigarettes are probably about as safe as drinking coffee. All they contain is water vapour, nicotine and propylene glycol

Professor Peter Hajek has said:

Nicotine itself is probably safer than caffeine […] The case for regulating e-cigarettes as a pharmaceutical product is on a par with regulating coffee

And Professor John Britton:

Nicotine itself is not a particularly hazardous drug […] It’s something on a par with the effects you get from caffeine.

But there is extensive research in stark contrast to these statements. Earlier this year, the Lancet published a systematic review of tobacco use and psychosis. It has long been known that people with psychosis (including schizophrenia) have high smoking rates (although citation bias has caused studies reporting extreme rates to dominate discussion and public accounts of this issue). The traditional explanation of their higher smoking has always been that people with psychosis self-medicate with nicotine to relieve boredom or distress.

However, the Lancet review considered whether smoking might somehow play a role in the development of psychosis. The authors found that in five longitudinal prospective studies, the risk of psychotic disorder was increased modestly by daily smoking. The open access review discusses why nicotine is the plausible factor in smoking that is likely to be explanatory.

Last month a new study was published by the American Journal of Psychiatry examining the association between maternal blood cotinine levels (a metabolite of nicotine) drawn twice during pregnancy and subsequent diagnosis of schizophrenia in all children born in Finland from 1983-1998.

Finland has long had highly advanced record linkage for all citizens, and 98% of all mothers who had live births across this 16 year period gave serum samples. Some 977 cases of diagnosed schizophrenia in this birth cohort were identified and these were matched with controls (without schizophrenia) for date of birth (within one month), sex, and residence in Finland at the time of case schizophrenia diagnosis.

The study found heavy maternal nicotine exposure was related to a 38% increased odds of schizophrenia in offspring and these findings were not explained by maternal age, maternal or parental psychiatric disorders, socioeconomic status, or other covariates.

Senior staff at the US government’s Office on Smoking and Health have summarized evidence on nicotine’s role in many health problems including impaired foetal brain and lung development, and altered brain development in adolescents.

Other authors have focused particularly on concerns about the importance of avoiding nicotine exposure in pregnancy, including via nicotine replacement therapy.

In the US, e-cigarettes are now more commonly used by high school students than are cigarettes. Messages about nicotine being virtually risk free may be encouraging this rapid uptake.

What about cancer and nicotine?

Nicotine is not classified as a carcinogen, but there is considerable evidence it functions as a tumour promoter or “enhancer” and that it might contribute to the progression of tumors already initiated.

As many tumours are indolent and do not progress, tumour promoters are of great concern. In April 2014, the International Agency for Research in Cancer (IARC), widely acknowledged as the world’s leading agency for developing consensus on the carcinogenicity of chemicals and environmental pathogens, published a list of high and medium priority candidates for assessment as carcinogens between 2015-2019.

Nicotine was one of the high priorities with the notation stating there is an association between exposure to nicotine via electronic nicotine delivery systems and DNA damage and other pathways of carcinogenesis.

The sort of data IARC would have been referring to have been summarised in recent reviews that found the number of cancers reportedly connected to nicotine is on the rise.

These include small-cell and non-small-cell lung carcinomas, as well as head and neck, gastric, pancreatic, gallbladder, liver, colon, breast, cervical, urinary bladder and kidney cancers.

So why is it approved in nicotine replacement therapy?

It is well known many smokers find nicotine replacement therapy unsatisfactory in that it does not supply them with sufficient nicotine to overcome their cravings.

In 2006 I spoke to a senior researcher who had previously worked for a major pharmaceutical company at the forefront of nicotine replacement therapy. I asked her why companies did not produce higher nicotine delivery products which would stand a better chance of substituting for cigarettes.

She told me pharmaceutical companies were acutely aware nicotine was not a benign drug, and they were highly sensitive to the risks involved in trying to get higher delivery nicotine replacement therapy approved for use, and had collectively decided not to go down that path. The US Food and Drug Administration would have almost certainly rejected such applications, she said.

Could it be part of the business model for nicotine replacement therapy that the dosage which might actually succeed in helping many smokers quit would not be as profitable as the dosage levels that saw high failure rates and many smokers having to repeat attempts with current and newer formulations?

The IARC’s planned assessment of nicotine’s status as a possible carcinogen or cancer promoter will be an important milestone in the emerging picture of e-cigarettes and their risks and benefits to public health.

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