E-cigarettes and Harm Reduction: An Evidence Review, the latest in a series of reports it has published since 2007 endorsing e-cigarettes for harm reduction. In this report, the RCP minimizes the adverse health effects of nicotine (beyond addiction), concluding that “There is little evidence of a long-term harmful physiological effect of nicotine that is not confounded by those of other constituents of tobacco smoke [page 8].”
As with the RCP’s conclusions about health risks and the e-cigarettes and stopping smoking, the conclusion is based on a small fraction of the available evidence, while ignoring the much larger body of relevant work showing that that nicotine by itself has many important adverse effects on the body.
Cardiovascular effects
Here is what the RCP has to say about the cardiovascular effects of nicotine:
There is little evidence of a long-term harmful physiological effect of nicotine that is not confounded by those of other constituents of tobacco smoke. [page 8]
[I]ncreases in heart rate have been observed among people who smoke following acute exposure to nicotine replacement therapies (for example, nicotine patches), cigarettes and nicotine-containing e-cigarettes.12,13 However, some evidence suggests that increases in heart rate are far greater when exposed to cigarettes compared with e-cigarettes in studies of acute exposure to nicotine.14 This effect is also seen in circadian studies of heart rate during ad lib vaping and smoking, which found people experienced both a higher heart rate and higher nicotine levels while smoking.15 Acute nicotine exposure also has an impact on blood pressure, whereby nicotine increases systolic blood pressure12,16,17 and diastolic blood pressure (diastolic blood pressure increases to a lesser extent than systolic blood pressure).7,15 Compared with placebo, nicotine replacement therapy (NRT) has also been shown to lead to palpitations and arrhythmia during 3–24 weeks of use,18 while arterial and aortic stiffness have been found to occur after acute exposure to cigarette smoke and e-cigarette aerosol, in some, but not all, studies.16,19,20,21 [page 9]
Contrast the RCP’s conclusion that of the World Heart Foundation in its January 2024 “Nicotine and Cardiovascular Health: When Poison is Addictive – a WHF Policy Brief“:
While various health harms are due to the many other toxicants found in tobacco smoke, nicotine itself is far from innocuous. A large body of evidence indicates that nicotine, as well as ENDS [electronic nicotine delivery systems, including e-cigarettes], are associated with an increased risk of cardiovascular disease and other adverse behavioural and health effects.
The WHF policy brief summary of “PHYSIOLOGICAL AND CLINICAL EFFECTS OF NICOTINE ON THE CARDIOVASCULAR SYSTEM” goes into more detail on wh and how nicotine adversely affects the cardiovascular system than the RCP report:
Nicotine is a major component in all tobacco products and plays a vital role in their harmful cardiovascular effects. Nicotine exerts its effects via stimulation of the nicotinic acetylcholine receptors (nAChRs) located in the central nervous system, at inter-ganglionic junctions of the autonomic nervous system, and on target organs throughout the body as part of the parasympathetic autonomic nervous system [73]. As a result of the global expression of these receptors, their stimulation causes broad physiologic effects, such as free radical production, inflammation, vascular wall adhesion and atherosclerosis (Table 2) [91–96].
Primary effects on cardiovascular physiology include sympathomimetic properties, catecholamine stimulation, and accelerated endothelial dysfunction [97]. Acute use of nicotine causes sympathetic activation and catecholamine release leading to elevations in heart rate, vascular tone, systemic blood pressure, myocardial contractility, and myocardial oxygen demand [98]. Nicotine effects on vascular tone can result in coronary vasoconstriction that can contribute to decreased myocardial oxygen supply and coronary artery spasm [99]. Endothelial dysfunction (impaired function of the cellular lining of arteries leading to arterial narrowing) is one of the major pathogenetic effects of nicotine and results from reduced nitric oxide bioavailability, as well as increased cytokine release and expression of adhesion molecules that promote atherosclerotic plaque development [100]. Nicotine also raises low-density lipoprotein (LDL) cholesterol levels and blood pressure, thereby promoting and accelerating the development of atherosclerosis [101]. Cardiovascular associations with nicotine use in human and animal studies include coronary heart disease, congestive heart failure [102], cardiac dysrhythmias such as atrial fibrillation and ventricular tachycardia/fibrillation [103, 104], and thrombosis [105, 106]. Tobacco smoking produces a cardiovascular response consistent with nicotine’s effects. The nicotine delivery from ENDS products can be comparable to conventional (tobacco) cigarettes, especially when taking into account the number of puffs, puff volume, duration, and velocity [107–109]. Acute physiological effects of ENDS include increases in heart rate, blood pressure, and aortic stiffness [110–112]. Further, exposure to ENDS aerosol has been found to have adverse effects on platelet activation and aggregation in both human and animal studies [113], and daily ENDS use is associated with increased risk of myocardial infarction [114].
Although older studies demonstrated no increase in cardiovascular disease among users of snuff, an orally-administered tobacco product, newer studies have found associations between snuff and endothelial dysfunction, decreases in diastolic heart function and an elevated risk of fatal ischemic heart disease and stroke [115–121].
Cognitive function
The RCP discusses effects of nicotine on cognitive function, but emphasizes the uncertainty in the effects:
[I]t is not clear exactly how long-term nicotine use impacts cognitive function or mental health. Evidence suggests acute and sustained nicotine exposure could have long-term effects on cognitive functioning, which could persist into adulthood as smokers are more likely to experience psychiatric disorders and attention deficits.11 However, the relationship is complex, confounded by other constituents of tobacco smoke, socioeconomic status, parental smoking26 and potentially due to reverse causation whereby people with psychiatric disorders and attention deficits may self-medicate using nicotine,27,28 however, a Cochrane review suggests stopping smoking is associated with improvements in mental health.29 [page 10, emphasis added]
The WHF brief, while focused on effects of nicotine on the cardiovascular system, includes a brief summary of the evidence linking nicotine with adverse effects on cognitive function. The WHF brief, which, while emphasizing the need for further research, identifies a wide range of adverse effects on neurocognitive function:
INTERFERENCE WITH BRAIN DEVELOPMENT
From prenatal life to adolescence is a sensitive period for brain plasticity, as well as an important period in terms of regulation of behaviour and cognition. In particular, it is a critical time for initiation of tobacco and nicotine product use, as evidence shows that most chronic smokers started smoking as teenagers or young adults [51, 127]. Notably, in the past decade, there has been an alarming increase in ENDS use among adolescents [128–131]
The effect of nicotine on brain development has been reported in preclinical and clinical studies, including on maternal smokeless tobacco use, which have demonstrated that the nicotinic cholinergic receptors (nAChRs) in the brain play critical maturational roles during adolescence [132–134]. Preclinical studies also show that there is an increased number of nAChRs in brain regions that are important for reward, as well as an increase in nicotine-induced dopamine release in limbic regions of the adolescent brain [135, 136]. As a result, some behavioural effects of nicotine, such as reward, are more intense in adolescent rats than in adult rats [137, 138]. We also know from animal studies that exposure to nicotine during adolescence can lead to long-term changes in brain and behaviour, including increased rewarding effects of other drugs of abuse, decreased level of attention, and mood disturbances [139, 140]. These preclinical findings suggest that teen nicotine use may result in similar long-term deleterious effects and are consistent with recent observations of linkages between e-cigarette use and substance use, mental health problems and impulsivity, necessitating further longitudinal assessment of health outcomes in teen and young adult e-cigarette users [141].
COGNITIVE AND BEHAVIOURAL IMPAIRMENTS
Chronic nicotine exposure during adolescence has been associated with cognitive impairments, such as reduced attention span, enhanced impulsivity, and depression [142], lower school grades [143], and school- and substance-related risk behaviours [144]. E-cigarette use initiation has also been associated with lower subsequent academic performance [145]. [emphasis added]
Later, in Chapter 9 of the RCP report (“Tobacco industry interests, recent conduct and claims around harm reduction”), it is less equivocal than it was in Chapter 2 (“Nicotine – physiological effects and the characteristics of nicotine-containing products”):
A key concern in this area is evidence from clinical studies and animal models suggesting that nicotine use in adolescence, a developmental period characterised by heightened neuroplasticity, induces changes in critical circuitry including reward-related behaviours that may increase the risk of diverse addictions in the long term. 74 [page 196]
Despite representing a more mainstream scientific view in Chapter 9, it is the equivocal analysis of Chapter 2 that frames the report’s overall support for e-cigarettes for harm reduction.
Other diseases
The RCP report raises the possibility that nicotine may play a role in lung disease, but says the data are inconclusive: “People who smoke are more likely to develop impaired lung function in relation to the number of years of smoke exposure,36 but it is difficult to ascertain the role of nicotine in the development of lung problems. [Page 10]”
The WHF brief, which is focussed on nicotine and cardiovascular disease, notes that, “nicotine exposure has been linked with modified cellular immunity, increased risk of respiratory and gastrointestinal disorders, carcinogenesis and tumour promotion, and negative reproductive and fetal health outcomes such as preterm delivery, stillbirth, and impaired fetal lung development [146]” without going into detail.
The RCP does not address the effects of nicotine on cancer at all, despite the fact that, while not identified as a carcinogen (cancer initiator), nicotine still exerts important effects on cancer once it is established. The 2015 review “Nicotine: Carcinogenicity and Effects on Response to Cancer Treatment – A Review” identifies several potentially important effects beyond carcinogenesis:
- Promotion of cell proliferation and cell survival
- Promotion of metastases once a cancer is established
- Disrupting immunological checkpoints
- Promoting angiogenesis (growth of arteries into tumors)
- Interference with cancer therapy
The RCP recognizes that England is an outlier in its approach to e-cigarettes
In the Introduction to the report, RCP recognized what an outlier England is on the e-cigarette issue:
Nevertheless, in endorsing and promoting vaping as part of a comprehensive national tobacco control programme the UK is an international outlier: few other countries have adopted this approach and none so consistently over the past 15 years. [page xiv]
The report goes so far as to say:
The RCP also understands that that the UK approach of embracing harm reduction as a complement to more conventional policy has been controversial and has attracted criticism, and does not seek to advocate that other countries should necessarily follow the UK in this approach. [Page 5, emphasis added]
Given the incomplete presentation of data on the direct non-addiction health effects of nicotine, people outside (and inside) England would do well not to follow England’s approach.
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