Making E-Cigarettes Work as a Quitting Aid: Nicotine Type and Nicotine Form

E-cigarettes and Harm Reduction

We’re all still figuring out how best to enjoy e-cigarettes. They’re becoming incredibly popular [1]—and anecdotal feedback shows glowing reviews of how vaping products make users feel: happy, upbeat, satisfied, calm and smokefree. The rapid spread of fourth-generation pod device e-cigarettes like the JUUL have even raised some alarms among some activists, who worry that products designed as quitting aides for smokers might work a little too well, drawing in new non-smokers.[2]

But most experts are optimistic. The principle behind e-cigarettes is the idea of “harm reduction”: traditional “combustible” tobacco is extremely dangerous for all users, while vapor-based nicotine products have far milder effects on our health. So, if we can just get every lover of cigarettes, cigars, and pipes to permanently swap over to e-cigarettes, we could save millions of lives every year. Switching from smoking to vaping is easier than quitting all-together, and is a realistic, achievable goal for many or most smokers.[3]

What this means is that from a public health perspective, e-cigarettes should be embraced as a consumer good similar to nicotine replacement therapies like patches, sprays, gum, and lozenges. Here’s the idea as it appeared in a recent review from the journal Internal and Emergency Medicine:

“Tobacco harm reduction is based on the well-established concept that smokers seek to obtain the effects of nicotine, while the real risks are produced by the toxic components in the smoke. In fact, nicotine is unlikely to contribute significantly to the development of smoking-related diseases.”[4]

And, indeed, the evidence is quite clear. Rates of e-cigarette use are negatively correlated with lung injury, for instance—leaving out unregulated black market THC vaping products, more vaping generally means less smoking, which means healthier lungs.[5] The medical findings behind that pattern are dramatic: when scientists applied e-liquid vapor and cigarette smoke condensate to human lung cells, they found that the vapor was less damaging even at concentrations one hundred time higher than the cigarette smoke.[6]

The findings for toxins and overall cell damage are even more encouraging. While e-cigarettes are not entirely harmless, habitual users have far lower levels of almost every negative biomarker linked to cigarette use,[7] including volatile organic compounds like acrylamide, benzene, and propylene oxide metabolites, which can be up to seven times more prevalent in the bodies of smokers.[8] Compounds linked to respiratory illnesses, such as diacetyl and acetyl propionyl, tend to be ten times less common in e-cigarettes than in combustible tobacco.[9] And the newest vaping products include virtually nonexistent levels of harmful carbonyl emissions, which are linked to cancer risk.[10] UK Public Health continue to stand by their claim that vaping is at least 95% less harmful than smoking combustible tobacco.  

Making the Switch to Vaping

We know that e-cigarettes work as a form of harm reduction, if smokers can make a permanent shift. The trick for e-cigarette manufacturers and public health officials has been getting them to do it.

They have a few advantages. One is the health benefits we were just talking about: e-cigarettes are safer, and people know it. They’re also much cheaper, both for individual users[11] and for government or nonprofit treatment programs.[12]

But health and cost are even stronger motives to quit entirely than they are to switch from smoking to vaping. As any smoker will tell you, vaping is only a credible option if the e-cigarettes feel good to use. For example, flavor makes a big difference. Smokers who switch to flavored e-cigarettes are more likely to stick with it than those who don’t,[13] over both the short and long term.[14] Even among “dual-users,” using flavored products is linked to fewer cigarettes per day.[15] And flavor is far from the end of the story when it comes to e-cigarette preferences…but we’ll get there in a moment. 

At this point we should take a step back, and note that e-cigarettes in general do actually work as quitting aids. The evidence is still coming in, but it’s almost all pointing in the same direction. In one large online survey, more than 80% of former smokers who’d taken up vaping said they’d never gone back,[16] and a recent review reported that 20% of people who’d recently quit cigarettes in Europe had found e-cigarettes helpful.[17] A landmark study by Britain’s National Health Service found that quit attempts using e-cigarettes were almost twice as successful as those that relied on traditional nicotine replacement therapy,[18] and the Cochrane Institute currently estimates that nicotine e-cigarettes are about twice as effective as placebos.[19]  

The question that companies are grappling with is, essentially, how they can raise those numbers by making e-cigarettes more effective as quitting aides. And many of them have realized that the overwhelming popularity[20] of fourth-generation offers a clue: the newer products deliver an experience that’s far closer to smoking combustible tobacco.[21]

Let’s talk about why.

Relieving the Cravings with Nicotine Salts

The goal of harm reduction products is to make it easier to quit cigarettes. They do that by satisfying habitual smokers’ need for nicotine. If enough nicotine isn’t getting into people’s bloodstreams, then the products aren’t going to work very well.

For a long time, that’s created a serious problem for e-cigarettes.

Earlier generations of vapes used freebase nicotine, a form of the nicotine chemical that’s made by treating tobacco products with ammonia, stripping protons off of the naturally occurring nicotine compounds. That has two effects: it makes the “deprotonated” nicotine easier for our cells to absorb (or more “bioavailable”), but it also makes the e-liquid vapor much more alkaline,[22] turning it intensely bitter and making it burn in the users’ throats.[23] Even the most concentrated freebase nicotine available—typically 24 mg/mL—do far less to satisfy cravings and feel less rewarding to use than normal cigarettes do.[24] Medical testing confirms the reason why: not enough nicotine is getting into their blood. In the most detailed study to date, even a 25 mg/mL freebase nicotine vape—a very concentrated product—only produced about one-third the blood nicotine levels of a traditional cigarette.[25]

Nicotine content Vaping Vs Combustible Cigarette

 

This chart shows approximate levels of nicotine in users’ blood following the use of standard cigarettes, high-concentration nicotine salt e-cigarettes, and high-concentration freebase nicotine e-cigarettes. Image based on Pax Labs Patent. 

It turns out that getting an e-cigarette to “feel like a cigarette” requires a delicate combination of factors:

  1. The nicotine has to be in a highly bioavailable form, so it’s absorbed quickly and easily.
  2. The e-liquid has to contain a high concentration of nicotine, so that users aren’t forced to take many long drags in a row.
  3. The vapor can’t burn too badly on the way down—it has to be pleasant enough to use comfortably.  

And with fourth-generation vape products, we seem to have found our answer: nicotine salts.

Nicotine in its natural state is, chemically speaking, a salt: it combines positively and negatively charged chemical components. But because it leans toward the positive side, nicotine molecules naturally attract positively charged protons to neutralize their charge. That makes them much harder for our cells to absorb, however, so natural nicotine salts are not especially effective.

Commercial nicotine salts, like the ones used to make e-liquids for the HAIZ, Alt, RELX and VUSE, treat the nicotine with benzoic or citric acid, both of which our bodies also produce on their own. That simple change allows the nicotine to be absorbed much more quickly, while also letting it vaporize at lower temperatures and getting rid of the burning, alkaline sensation that freebase nicotine produces.[26] Many versions, such as the common nicotine benzoate, offer a similar bioavailability to combustible cigarettes.[27]

The results speak for themselves. A slew of studies back up the main findings we just described, showing that high-concentration nicotine salt e-cigarettes let smokers very quickly, pleasantly, and easily achieve a cigarette-like level of nicotine in their blood.[28] One found that nicotine levels typical of cigarettes would be produced using a mid-intensity 36 mg/mL nicotine salt vape;[29] with consistent use over 60 minutes, another found that vapes could produce blood nicotine levels almost twice as high as those associated with casual cigarette use.[30] And the effects were dramatic, with users of higher-nicotine vapes almost 80% more likely to say that their cigarette cravings were satisfied.

The Link to Quitting

Nicotine salts solve the central problem for using e-cigarettes as quitting aides—they let users get the nicotine kick they need, without all the negative consequences of smoking. But that only tells us that they should work. To confirm that they really do, we can turn to a few other pieces of evidence.

One involves usage patterns. In a study of smokers switching to e-cigarettes, different products turned out to be easier or harder to adjust to. High-concentration pod-style nicotine salts consistently had the best effect: they were easiest for users to adjust to, were used the most consistently, and had the highest user satisfaction. They also significantly reduced cigarette cravings.[31] A similar study asked smokers to switch for an entire month, but let them choose what nicotine concentration they preferred to use. Almost all chose very strong  e-liquids, and the ones who struggled to stick to vaping reported that using a higher-nicotine option often helped.[32] Other studies in laboratory environments have found that only high nicotine concentrations—the kinds only achievable using salts—fully satisfy cigarette cravings for some former smokers.[33] And in murine models, mice given nicotine salts voluntarily consume significantly more than mice given freebase nicotine.[34]

It’s no surprise, then, that preference for stronger, salt-based vape products is so overwhelming, according to a systematic review.[35] Overviews of the field in the last several years have routinely reached the same conclusion: nicotine salts deliver an experience that’s more familiar and more satisfying to smokers, allowing e-cigarettes to do their intended work.[36]

Of course, not all products are created equal. Variability in battery power, e-liquid ingredients, and other details can drastically alter the availability of nicotine from a single puff.[37] E-liquids made primarily from propylene glycol, for instance, tend to yield far more nicotine than those made from vegetable glycerin.[38] In one especially noticeable case, JUUL circumvented European limits on nicotine concentrations by changing several small details—including the material used to make their vaporizer wicks—and achieving a similar nicotine availability they had in their far more concentrated American products.[39]

All this really means, though, is that you need to be careful what you buy. Make sure you’re getting nicotine salts, not freebase nicotine. Make sure you know the concentration of nicotine in your e-liquid, and that you have a flavor you like. Check that the manufacturer is compliant with local regulations, and that they’re a recognizable brand.

Then, when you’re ready to move on from smoking—or just to try something new—it’ll be time to make the switch.

References

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[1] Tackett et al. (2021).

[2] Bhatnagar, Payne, and Robertson (2019); Schmidt (2020).

[3] Prochaska and Benowitz (2019); World Health Organization (2019); Wang, Bhadriraju, and Glantz (2020).

[4] Polosa, Farsalinos, and Prisco (2019, p. 817).

[5] Friedman (2020).

[6] Czekala et al. (2019).

[7] Traboulsi et al. (2020).

[8] St. Helen, Liakoni, et al. (2020).

[9] Farsalinos et al. (2015).

[10] Farsalinos and Gillman (2018).

[11] Liber, Drope, and Stoklosa (2017).

[12] Li et al. (2020).

[13] Friedman and Xu (2020).

[14] Li et al. (2021).

[15] Litt, Duffy, and Oncken (2016).

[16] Farsalinos et al. (2014).

[17] O’Leary, Polosa, and Volti (2021).

[18] Hajek et al. (2019).

[19] Hartmann-Boyce et al. (2020).

[20] Fadus, Smith, and Squeglia (2019).

[21] Barrington-Trimis and Leventhal (2018); Jackler and Ramamurthi (2019).

[22] Stepanov and Fujioka (2015)

[23] Etter (2016); Jackson, Grobman, and Krishnan-Sarin (2020).

[24] St. Helen, Nardone, et al. (2020).

[25] O’Connell et al. (2019).

[26] Caldwell et al. (2012); Gholap et al. (2020); Mallock et al. (2020).

[27] Ebajemito et al. (2020).

[28] Duell, Pankow, and Peyton (2019); Gholap et al. (2020).

[29] Lopez et al. (2016).

[30] Dawkins et al. (2016).

[31] Kimber, Soar, and Dawkins (2021).

[32] Farsalinos et al. (2013).

[33] Ashley et al. (2020); Hiler, Breland, and Spindle (2017).

[34] Henderson and Cooper (2021).

[35] Zare, Nemati, and Zheng (2018).

[36] E.g., Barua, Rigotti, and Benowitz (2018); Bhatnagar, Payne, and Robertson (2019); Rigotti (2018).

[37] Jacobson et al. (2020).

[38] Talih, Salman, and El-Hage (2020).

[39] Mallock et al. (2020).

 

 

 

 

 

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