e-cigs: nicotine as gateway drug

Two articles suggesting that nicotine itself is a gateway drug to regular cigarettes in teens; and also may increase the effects/addiction potential of cocaine

1. a very recent article confirms other studies finding that use of e-cigs by teens leads to more cigarette use subsequently. Thanks to Emelia Benjamin for bringing this impressive study to my attention. See ecigs inc youth tobacco jama2019 in dropbox, or doi:10.1001/jamanetworkopen.2018.7794

Details:
-- 6123 youths aged 12 to 15 who had never use cigarettes, e-cigarettes, or other tobacco products at the beginning,were followed in the Population Assessment of Tobacco and Health Study, a longitudinal prospective cohort study representative of the US population, from 2013 to 2016
-- 50% female, 54% non-Hispanic white, mean age 13.4
-- three waves of assessment in this three-year period; all in wave 1 had never used cigarettes
-- youth were divided into risk groups, with low-risk individuals less likely to have sensation-seeking personality traits (e.g. no stating “I like new and exciting experiences, even if I have to break the rules”); less risk-taking behavior (e.g. not using alcohol, marijuana, stimulants or tranquilizers), and lower cigarette susceptibility (e.g. not curious about smoking, not thinking that they will smoke in the future)

Results:
-- by the wave three assessment: 9% reported e- cigarettes as their first tobacco product, 5% reported another non-cigarette product first, 3% used cigarettes first
-- cigarette use at wave three was higher among prior e-cigarette users (21%) versus those with no prior tobacco use (4%)
    -- prior e-cigarette use was associated with more than four times the odds of ever cigarette use, OR 4.09 (2.97-5.63), p<0.001
    -- and three times the odds of current cigarette use, OR 2.75 (1.60-4.73)
-- among low-risk youth, the association of prior e-cigarette use with cigarette initiation was even stronger, OR 8.57 (3.87-18.97), p<0.001 , and this was a pattern not seen with other tobacco product use; ie, in the low-risk group the proportion of those transitioning from e-cigs to combustible cigarettes was  almost twice as high as in the intermediate- or high-risk youth; and the only significant transition to cigarettes in the low-risk group was from e-cigs, and not from other tobacco products
-- conclusion: over the two years between 2013-4 and 2015-16, 22% of new cigarette ever users (178,850 youth) and 15% of current cigarette users (43,446 youth) aged 12 to 15 may be attributable to prior e-cigarette use

Commentary:
-- the results of this analysis are consistent with those of a recent meta-analysis of the initial use of e-cigarette and subsequent cigarette smoking in adolescents and young adults, finding that e-cigarette users had more than three times the odds of subsequent cigarette use. Other studies have also found that use of smokeless tobacco or hookah is associated with subsequent cigarette usage
--the rather staggering numbers of new cigarette users attributable to initial e-cig use is very likely a major understatement of the current numbers, given the skyrocketing numbers of new e-cig users:  a whopping 77.8% in the past year alone (see http://gmodestmedblogs.blogspot.com/2019/02/e-cigs-decrease-adult-smoking-but-in.html )

--and, the number one e-cig seller in youth is Juul, which is marketing a high-tech looking e-cig (appealing to the younger generation), is heavily advertizing to the younger population (targeting younger people who frequent specific websites, apps), and is marketing a remarkably high nicotine product which is more likely to develop addiction ( as noted on CNBC: “Juul makes a product that delivers a lot of nicotine, and it goes down easy. Right now, a single JuulPod is about 5 percent nicotine — which is roughly as much nicotine as is in a pack of cigarettes, according to the company”, see https://www.cnbc.com/2018/07/11/juul-to-introduce-lower-nicotine-pods-for-some-of-its-flavors.html )
--not sure how to explain the increased cigarette use in those considered “low-risk” who then used e-cigs.  “Low-risk” is a classification dependent on how certain questions are answered; and it is not clear why people saying “no” to such questions as “have you ever been curious about smoking a cigarette?” or “do you think you will smoke a cigarette in the next year?” would then start smoking at a higher rate than those saying “yes” to such questions. 
    --??if some “low-risk” kids are different from others similarly categorized in some fundamental and unanticipated ways which predispose them to nicotine addiction?
    --Did some say they were low-risk because they were scared about cigarettes (eg a relative with severe cigarette-related disease, or perhaps an aversion to the smell of cigarettes) yet were open to flavored, smooth e-cigs that did not smell like/remind them of actual cigarettes; and then became inured to their prior cigarette concerns and transitioned  to combustible cigarettes?
    --or was it just the normalization and legitimization of nicotine products ushered in by the e-cig (which, unlike regular cigarettes, are targeting the young) and then the thrill of regular cigarettes once the initial barriers were broken down??
--also, the relationship between e-cigs and regular cigarettes is a bit complex. It does seem that e-cigs are associated with more cigarette use later (an easier transition for some people). But some people start with regular cigarettes and move to e-cigs (??more socially acceptable,  ??better flavors,  ??fewer telltale signs of smoking and less negativity/unacceptability by others around them). And statistics overall are showing a decrease in smoking combustible cigarettes. But will this change in the future with the huge increases in e-cig consumption found currently and likely in the future?? Maybe consumption of real cigarettes will increase again in time???
--and, it is important to remember that e-cigs may have other long-term problems themselves, perhaps related to the additives in them (flavors, solvents, etc, as noted in http://gmodestmedblogs.blogspot.com/2019/02/e-cigs-decrease-adult-smoking-but-in.html which are largely untested as to their potential risk). see article below suggesting that nicotine itself could lead to more use of cocaine, etc

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2. an older article presented a pretty convincing argument that nicotine predisposes people to cocaine addiction (see smoking gateway drug nejm2014 in dropbox, or DOI: 10.1056/NEJMsa1405092)

Details:
--mouse studies:
    --mice given nicotine in their drinking water were no more active than controls
    --mice given cocaine in their drinking water were 58% more active than controls
    --but mice given nicotine for 7 days first and then nicotine plus cocaine for 4 days were 98% more active than controls
    --and mice given 7 days of cocaine first and then 4 days of nicotine plus cocaine did not have increased activity
    --in another experiment, mice given nicotine for 7 days then both nicotine plus cocaine for 4 days had a 78% greater preference to return to the room having that sequence of drinks than mice given only water and then the cocaine
--mechanistically:
    --in very brief: decreasing excitatory input into the nucleus accumbens (which effectively decreases “learning” through long-term potentiation) leads to increasing reward by drugs of abuse (through dopamine); cocaine decreases this excitatory input
        --through a large series of neurophysiologic studies, they have pretty well established the following (see the article for the array of studies and details of the experiments done):
            --nicotine priming for 7 days (but not 1 day) led to dramatic reductions in this long-term potentiation and increased reward properties of cocaine (much more than with nicotine alone, cocaine alone for 7 days, or 7 days of cocaine followed by nicotine)
            --there are several genetic targets changed by nicotine which allow for this increased effective potency of subsequent cocaine over just having cocaine or cocaine followed by nicotine (eg FosB expression, Histones 3 and 4: ie nicotine affecting epigentics)
            --and, priming with nicotine for 7 days but then stopping the nicotine and  waiting 14 days before adding the cocaine did not result in the enhanced effect seen with adding cocaine right away (ie, need to have the nicotine in reasonable temporal proximity to cocaine to get enhanced cocaine effect)
    --the effects of nicotine in enhancing cocaine effects was more impressive in adolescent mice than adult ones
--so, based on an impressive sequence of studies in mice, it is pretty clear both by behavior and biochemistry that pretreatment with continued nicotine stimulation led to enhanced effects of cocaine
--in humans, there are some suggestive supportive data [these were cited in the above article]:
    --a 2012 study of US adults aged 18-34 who had used cocaine found that 88% had smoked cigarettes before using cocaine, 6% began both cigarettes and cocaine at the same time and 3% had never smoked cigarettes
    --a study in students followed from 16 to 37 yo found that 75% of cocaine users were smoking cigarettes during the month prior to starting cocaine. 
    --a large longitudinal study found that the rate of cocaine dependence was highest (20%) among those who started cocaine after smoking cigarettes, vs 6% in those who began cocaine prior to smoking, vs 10% in those who never smoked more than 100 cigarettes, with p<0.001

--another article i found noted that nicotine enhances cue-induced cocaine craving, and that a small number of cocaine-dependent cigarette smokers given a nicotine antagonist had decreased cocaine cravings (see https://www.nature.com/articles/1395259 )
--for some further details on the molecular mechanism and the epigenetic changes, see nicotine epigentics and cocain addiction scitransmed2011 in dropbox, or Levine A. ScienceTranslationalMedicine 2011; 107(3):107ra109.

--One unaddressed concern here is whether nicotine’s priming of the reward system for cocaine is true for other addicting products, such as opiates.  Would be important to know that as well
--it would be interesting to know if stopping smoking/nicotine might decrease the likelihood of cocaine dependence
--and, perhaps giving nicotine replacement therapy (eg patches) might not be the best approach in patients who are cocaine users….

So, these 2 articles highlight 2 aspects of the likely effect of e-cigarettes as “gateway drugs”:
--the repeatedly-shown association in kids that using e-cigarettes to evolves into smoking regular cigarettes
--and, the reasonable assumption, largely based on animal neurobiochemical studies, that nicotine itself (as in e-cigarettes, and perhaps in passive smoking) might predispose people to enhanced dopamine “reward” from cocaine and, ultimately, to higher levels of cocaine addiction/dependence

geoff

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