In a single-blind crossover randomized clinical trial, researchers found that salt-based nicotine in e-cigarettes led to higher nicotine intake, more positive subjective effects, and more intense puffing behaviors compared with freebase nicotine among young adult e-cigarette users.

The study, published in JAMA Network Open, also found that menthol flavoring and higher nicotine concentrations increased the addiction potential of e-cigarettes.

The study included 72 participants who were current daily e-cigarette users aged 21 to 25 years (mean [standard deviation, SD] age, 22.4 [1.4] years); 42 (58.3%) of whom were female. Three participants (4.2%) were Black, 6 (8.3%) were Hispanic, 55 (76.4%) were White, and 8 (11.1%) were other race/ethnicity or multiracial. Participants reported a mean of 27.0 days (SD = 6.2) of e-cigarette use in the past 30 days, with minimal use of other tobacco products. They completed up to nine vaping sessions, starting with their own e-cigarette brand followed by eight sessions using study e-liquids that varied by nicotine form (salt-based vs freebase), concentration (5% vs 1%), and flavor (menthol vs tobacco). Each session included a 5-minute standardized vaping period, followed by 30 minutes of ad libitum use.

Compared with freebase nicotine, salt-based nicotine resulted in 94% (95% confidence interval [CI] = 74%–115%) higher plasma nicotine levels after 5 minutes of standardized vaping and 63% (95% CI = 48%–80%) higher levels after 30 minutes of ad libitum use. The highest nicotine levels were achieved by 5% salt-based nicotine, averaging 11.2 ng/mL (95% CI = 9.3–13.2 ng/mL) at 5 minutes, 8.5 ng/mL (95% CI = 7.3–9.6 ng/mL) at 10 minutes, and 17.2 ng/mL (95% CI = 14.3–20.1 ng/mL) at 35 minutes, meeting or exceeding the nicotine delivery of a combustible cigarette.

Salt-based nicotine also yielded higher ratings on positive subjective effects compared with freebase nicotine:

• Wanting: 38.8 (95% CI = 35.6–41.9) vs 29.5 (95% CI = 26.5–32.5)
• Liking: 42.8 (95% CI = 39.4–46.1) vs 32.0 (95% CI = 28.6–35.3)
• Enjoyment: 43.3 (95% CI = 40.0–46.6) vs 32.3 (95% CI = 29.0–35.7)
• Pleasure: 45.2 (95% CI = 41.9–48.4) vs 32.8 (95% CI = 29.5–36.0)
• Satisfaction: 45.6 (95% CI = 42.4–48.8) vs 35.4 (95% CI = 32.3–38.5).

Menthol flavor increased positive ratings across all measures compared with tobacco flavor:

• Wanting: 38.9 (95% CI = 35.7–42.1) vs 29.4 (95% CI = 26.4–32.3)
• Liking: 43.2 (95% CI = 39.7–46.7) vs 31.5 (95% CI = 28.4–34.7)
• Enjoyment: 43.2 (95% CI = 39.8–46.7) vs 32.4 (95% CI = 29.2–35.6)
• Pleasure: 44.3 (95% CI = 40.9–47.7) vs 33.6 (95% CI = 30.5–36.7)
• Satisfaction: 44.9 (95% CI = 41.6–48.1) vs 36.1 (95% CI = 33.0–39.2).

Lower nicotine concentration (1% vs 5%) was associated with more positive subjective ratings—but also led to compensatory puffing behaviors.

During the ad libitum vaping sessions, salt-based nicotine resulted in 25% (95% CI = 12%–40%) more puffs, 5% (95% CI = 2%–8%) longer puff duration, 11% (95% CI = 6%–16%) lower interpuff interval, 11% (95% CI = 6%–16%) larger puff volume, and 9% (95% CI = 0%–20%) higher total puff volume compared with freebase nicotine. Lower nicotine concentration (1% vs 5%) was associated with even more intense puffing: 47% (95% CI = 31%–65%) more puffs, 20% (95% CI = 17%–24%) longer puff duration, 15% (95% CI = 7%–22%) lower interpuff interval, 25% (95% CI = 20%–31%) larger puff volume, and 54% (95% CI = 41%–68%) higher total puff volume. Menthol flavor resulted in 4% (95% CI = 1%–7%) longer puff duration compared with tobacco flavor.

All study e-liquids effectively reduced cravings, with significantly lower ratings for urge and craving measures (QSU-Desire, QSU-Relief, MNWS-Total, MNWS-Craving) at 5, 10, and 35 minutes compared with baseline. However, 1% nicotine concentration was less effective in reducing cravings at 35 minutes compared with 5% nicotine, resulting in 8% (95% CI = 3%–14%) higher QSU-Desire scores (mean [SE], 16.7 [0.5] vs 15.4 [0.5]) and 4% (95% CI = 1%–8%) higher QSU-Relief scores (mean [SE], 9.5 [0.3] vs 8.9 [0.3]).

One investigator reported receiving grants from the National Institutes of Health and the U.S. Food and Drug Administration during the conduct of the study; no other disclosures were reported.