Priming Young Adults with Vaping

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The National Institute of Health announced that recent national survey research discovered that almost 1 in 3 (27.8%) 12th graders reported some kind of use of a vaping device in the past year, while the use of hookahs and regular cigarettes is declining. When asked what they thought was in the mist they inhaled, 51.8% said it was just flavoring, 32.8% said the mist contained nicotine, and 11.1% said they were smoking marijuana or hash oil. Nora Volkow, the director of NIDA, said: “We are especially concerned because the survey shows that some of the teens using these devices are first-time nicotine users.” Recent research suggests some of them could move on to regular cigarette smoking … or other drugs. And some additional research suggests many teens don’t actually know what is in the device they are using.

Monitoring the Future (MTF) is a yearly survey of 8th, 10th and 12th graders in school nationwide. The MTF survey is done by the Institute for Social Research at the University of Michigan for NIDA, the National Institute on Drug Abuse. When the survey asked about vaping over the past month, 11% of 12th graders reported vaping nicotine and 4.9% reported vaping marijuana. See the following chart from the NIH news release.

According to the CDC, e-cigarettes are now the most commonly used form of tobacco by youth in the U.S. Dual use, using both regular cigarettes and e-cigarettes, is also common among young adults 18-25. The reasons reported by young people for trying e-cigarettes include curiosity, taste and the belief they are less harmful than other tobacco products. Over 80% of teens and young adults who use e-cigarettes said they use flavored e-cigarettes.

Back in June of 2016 the FDA finalized a rule that extended its regulatory authority to all tobacco products, including e-cigarettes, cigars, hookahs and pipe tobacco. The rule requires health warnings and bans free samples. It also restricts youth access to newly regulated tobacco products by not allowing their sale to those younger than 18 and requiring a photo ID. Manufacturers will have up to two years to continue selling their products while they submit a new tobacco product application (and an additional year while the FDA reviews the application).

The rule will help prevent young people from starting to use these products, help consumers better understand the risks of using these products, prohibit false and misleading product claims, and prevent new tobacco products from being marketed unless a manufacturer demonstrates that the products meet the relevant public health standard.

If the new technology in e-cigarettes helps reduce toxicity compared to conventional cigarettes, encourages current smokers to switch completely and/or are not widely used by youth, they potentially could reduce disease and death. “But if any product prompts young people to become addicted to nicotine, reduces a person’s interest in quitting cigarettes, and/or leads to long-term usage with other tobacco products, the public health impact could be negative.” The FDA encouraged manufacturers to explore product innovations that would maximize potential benefits and minimize risks. The revised rule allows the FDA to further evaluate the impact of these products on the health of both users and non-users.

Psychiatric Times reported e-cigarettes were first developed and commercialized in China in 2003. They entered the US market in 2006. During their first ten years on the market, before the FDA ruling discussed above, advertising and sales of e-cigarettes increased exponentially every year. “While tobacco advertising has been banned from television and radio since 1970, e-cigarettes are promoted widely on these media channels, on the web, and in social media, with many ads reaching youth.” Mislabeling has been a problem with some products labeled as nicotine-free containing nicotine and others having higher concentrations of nicotine than labeled.

The evidence for e-cigarettes as a cessation aid to quit regular cigarette smoking is limited. Dual use of regular cigarettes and e-cigarettes is common. One study reported half of current smokers report regular use of e-cigarettes. A meta-analysis of twenty controlled studies found the odds of quitting cigarettes was 28% lower in individuals who used e-cigarettes. However only 2 randomized controlled trials have been done, and: “The quality of evidence was judged to be low grade, and in both trials, e-cigarettes with nicotine were no different in efficacy for quitting smoking than placebo (nicotine-free) e-cigarettes.”

So at this point in time, the evidence does not support the use of e-cigarettes as an aid to stop smoking regular cigarettes. It should be noted that the American Heart Association’s policy statement of e-cigarettes does not recommend their use. However, if a patient has tried and failed other cessation methods or is unwilling to try them, the AHA does recommend trying e-cigarettes for smoking cessation.

There is evidence that smoking e-cigarettes increases the risk of cardio vascular problems. Swedish researchers, in Antoniewicz et al., demonstrated that in healthy volunteers, ten puffs from an e-cigarette caused an increase in endotheial progenitor cells (EPSs) of the same magnitude as smoking one traditional cigarette. The average e-cigarette user takes 230 puffs per day, raising the prospect that prolonged use could result in serious health consequences. “These findings suggest that a very short exposure to ECV [e-cigarette vapor] caused a rapid EPC mobilization in blood, which may indicate an impact on vascular integrity leading to future atherosclerosis [hardening of the arteries].” A heart specialist for the European Society of Cardiology was quoted in the Daily Mail as saying: “It really surprises me that so little vapour from an e-cigarette is needed to start the heart disease ball rolling. It’s worrying that one e-cigarette can trigger such a response.”

Researchers at the University of Connecticut found evidence that e-cigarettes containing a nicotine-based liquid are potentially as harmful as unfiltered cigarettes in causing DNA damage. The study’s lead author said the results surprised him. “I never expected the DNA damage from e-cigarettes to be equal to tobacco cigarettes.” He was shocked the first time he saw the result, so he diluted the samples and ran the controls again. “But the trend was still there – something in the e-cigarettes was definitely causing damage to the DNA.”

Researchers at the University of North Carolina found that not only do e-cigarettes trigger the same immune responses as regular cigarettes, they also trigger some unique reactions. E-cigarette users uniquely showed significant increases with neutrophil-extracellular-trap (NET)-related proteins in their airways. “Left unchecked neutrophils can contribute to inflammatory lung diseases, such as COPD and cystic fibrosis.” The study also found that e-cigarettes produced negative consequences known to occur in regular cigarettes such as an increase of biomarkers of oxidative stress and activation of defense mechanisms associated with lung disease. They also found an over secretion of mucus secretions that have been associated with diseases like chronic bronchitis, bronchiectasis and asthma.

Another study by Eric and Denise Kandel, “A Molecular Basis for Nicotine as a Gateway Drug” has raised concerns with e-cigarettes as “pure nicotine-delivery devices.” Their study demonstrated that nicotine acted like a gateway drug for cocaine on the brain of mice, “and this effect is likely to occur whether the exposure is from smoking tobacco, passive tobacco smoke, or e-cigarettes.”

These results provide a biologic basis and a molecular mechanism for the sequence of drug use observed in people. One drug affects the circuitry of the brain in a manner that potentiates the effects of a subsequent drug.Although the typical e-cigarette user has been described as a long-term smoker who is unable to stop smoking, the use of e-cigarettes is increasing exponentially among adolescents and young adults. Our society needs to be concerned about the effect of e-cigarettes on the brain, especially in young people, and the potential for creating a new generation of persons addicted to nicotine. The effects we found in adult mice are likely to be even stronger in adolescent animals. Priming with nicotine has been shown to lead to enhanced cocaine-induced locomotor activity and increased initial self-administration of cocaine among adolescent, but not adult, rats. Whether e-cigarettes will prove to be a gateway to the use of combustible cigarettes and illicit drugs is uncertain, but it is clearly a possibility.

Don’t be too quick to dismiss the Kandels’ nicotine-gateway theory. They were doing basic research on the effects of nicotine on specific areas of the brain. Priming with nicotine enhanced the effects of cocaine in the nucleus accumbens. “Priming with nicotine appeared to increase the rewarding properties of cocaine by further disinhibiting dopaminergic neurons in the ventral tegmental area.” They only observed the priming effect of nicotine when mice were given cocaine at the same time as nicotine. For more on Denise Kandel’s gateway hypothesis see: “Rebirth of the Gateway Hypothesis.”


Rebirth of the Gateway Hypothesis

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Writing for the journal Substance Use & Misuse in 2015, John Kleinig thought it was time to “retire” the gateway drug theory. The problem as he saw it was “there are too many gateways and ways of going through them, and we do not have an adequate handle on them.” He thought some versions of the hypothesis used an oversimplification of the dynamics of drug use and “developed [it] into a Medusa’s head of hypotheses about progressive drug use.”  The perceived risk leads to the development of  “social policies that prevent the downward passage through a gate or successive gates.”

The term gateway drug was popularized by Robert DuPont in his 1984 book, Getting Tough on Gateway Drugs: A Guide for the Family. DuPont had been the first director of NIDA (National Institute on Drug Abuse) from 1973-1978 and the second drug czar under Presidents Nixon and Ford from 1973 -1977. DuPont was said to have formed the idea of a gateway drug from two observations. First, some young people he came into clinical contact with reported they first used alcohol and tobacco, which was then followed by marijuana use. Second, because marijuana use was illegal, it was more likely other illegal drugs would be tried afterwards. His thesis was primarily used to demonize marijuana as the gateway drug.

DuPont did not, according to Kleinig, take the point of view that the pharmacological properties of some drugs could transport people through gateways. But others did, as we shall see.

If that had been intended, it would have provided a testable (albeit complex) scientific hypothesis and also provided valuable knowledge. It would have provided the kind of testable hypothesis that we have for some addictions—accounts of how, under certain conditions, particular psychoactive substances affect the chemistry and physiology of the brain, and so forth.

Kleinig seems to have been right in naming DuPont as popularizing the term gateway drug. But historically, the origins of the concept itself it should be attributed to Denise Kandel and her 1975 article for the journal Science, “Stages in Adolescent Involvement in Drug Use.” She initially theorized a four stage sequence to drug involvement: beer or wine or both; followed by cigarettes or hard liquor; marijuana; and other illicit drugs. “The legal drugs are necessary intermediates between nonuse and marihuana.”

Over the intervening years Kandel persevered with her hypothesis while others like Kleinig thought it should be abandoned. And she recently coauthored an article with her Nobel Prize winning husband that suggested pharmacological properties of some drugs could transport rats, if not people, through gateways. But I’m getting ahead of myself. Dr. Kandel edited Stages and Pathways of Drug Involvement: Examining the Gateway Hypothesis in 2002. In her introductory essay, “Examining the Gateway Hypothesis,” she acknowledged that while the “Gateway Hypothesis” originated in the mid-1970s, the idea of progression in drug use dates back to the 1930s as the “Stepping Stone Theory.”

She said there was a crucial difference between the two concepts. The Stepping Stone Theory saw the progression in drug involvement to be inevitable, “the use of marijuana invariably leading to heroin addiction.”  Recall that the 1930s was the time of films like: “Reefer Madness” and “Cocaine Fiends.” See “Remembering Reefer Madness” for more on this topic.

In contrast, the Gateway Hypothesis sees a sequence, where the use of certain drugs precedes the use of other classes, but that progression is not inevitable.  Entry into a particular stage may be common and perhaps even a necessary step, but is not a sufficient prerequisite to enter the next higher stage. Notice the modification below in her drug sequencing stages for the 2002 essay.

According to this notion, there is a progressive and hierarchical sequence of stages of drug use that begins with tobacco or alcohol, two classes of drugs that are legal, and proceeds to marijuana, and from marijuana to other illicit drugs, such as cocaine, metamphetamines, and heroin. The basic premise of the developmental stage hypothesis is that involvement in various classes of drugs is not opportunistic but follows definite pathways; an individual who participates in one drug behavior is at risk of progressing to another. The notion of developmental stages in drug behavior does not imply, however, that these stages are either obligatory or universal, nor that all persons must progress through each in turn.

Dr. Kandel pointed out that numerous investigations have documented regular sequences of progression from legal to illegal drugs among adolescents and young adults of both sexes, regardless of the age of their first use, ethnicity and country. The sequence has been observed in France, Israel, Australia, Japan, Spain and Scotland. She also noted there has been a resurgence of interest in the Gateway Hypothesis “as a framework for understanding adolescent drug involvement.”

An interview Dr. Kandel did with the NPR program, “All Things Considered” in 2015 indicated she had received a grant from NIDA in the early 1970s to study marijuana as a possible gateway drug. On her own initiative, she added questions about tobacco and alcohol use in order to look at other factors besides marijuana. Incidentally, this was during Dr. DuPont’s time as the NIDA director.

When I did the analysis, I found that there was a certain sequence that young people seem to be following when they got involved in drugs. They did not start with marijuana, but they started with drugs that are legal for adults in the society, such as beer and wine and cigarettes, other forms of alcohol.

Nearly forty years after her 1975 paper, she coauthored a paper for the New England Medical Journal with her husband, a Nobel Prize winning neuroscientist, “A Molecular Basis for Nicotine as a Gateway Drug.” “What we found is that when an animal was primed by nicotine and then was exposed to cocaine, the effect of cocaine was amplified many times.” Given how well nicotine primes the brain, she’s concerned about reports showing e-cigarette use is increasing among young people.

Although e-cigarettes eliminate some of the morbidity associated with combustible tobacco, they and related products are pure nicotine-delivery devices. They have the same effects on the brain as those reported here for nicotine … and they pose the same risk of addiction to other drugs and experiences.

The Kandels’ work was done in collaboration with Amir Levine and others; and it drew upon the earlier study by Levine et al., which also found how nicotine acted as a gateway drug on the brain. The effect “is likely also to occur when nicotine exposure is from passive and non-smoked forms.” The authors said this emphasizes the need to develop more effective public health prevention programs for all products containing nicotine, which would include e-cigarettes.

In November 2017 Griffin et al. published a study in Science Advances that showed a similar response with alcohol and cocaine. Alcohol was found to enhance cocaine addiction by suppressing two genes that normally inhibited the effects of cocaine, but not the other way around. In addition, their findings suggested that alcohol and nicotine acted through similar molecular mechanisms to increase vulnerability to cocaine. In other words, the use of one or the other gateway drug changed the brain in such a way that using cocaine was more rewarding.

Our findings indicate that a prior history of alcohol use is required for the enhancement of cocaine addiction–like behavior, and that priming by alcohol is a metaplastic effect, whereby exposure to this gateway drug initiates intracellular events that alter the epigenome, creating a permissive environment for cocaine-induced learning and memory, thereby enhancing the addictive potential of cocaine.

The New York Times published an article on the gateway drug theory, “A Comeback for the Gateway Drug Theory?” But it seemed to confuse Kandel’s Gateway Hypothesis and the Stepping Stone Theory without making the crucial distinction between them, as noted above. The Stepping Stone Theory is not an earlier version of the Gateway Hypothesis. Further misunderstanding was apparent in the criticisms of the Gateway Hypothesis the article cited.

The NYT article seemed to assume a version of the hypothesis that infers causation. It quoted an excerpt from a longer quote by Maia Szalavitz in her 2010 Time article on marijuana as a gateway drug. The excerpt in the NYT article was: “there is no conclusive evidence that the drug effects of marijuana are causally linked to the subsequent abuse of other illicit drugs.” Szalavitz was quoting from a report by the Institute of Medicine of the National Academy of Sciences. Below is the NYT quote from her article in context:

In the sense that marijuana use typically precedes rather than follows initiation of other illicit drug use, it is indeed a “gateway” drug. But because underage smoking and alcohol use typically precede marijuana use, marijuana is not the most common, and is rarely the first, “gateway” to illicit drug use. There is no conclusive evidence that the drug effects of marijuana are causally linked to the subsequent abuse of other illicit drugs.

Kandel’s essay, which is linked above, was careful to note the association, not causation inherent in the Gateway Hypothesis. She said the validity of the Gateway Hypothesis was based on two criteria: the sequencing of drug use between classes and the association of drugs, such that using a drug lower in the sequence increases the risk of using drugs higher in the sequence. “Ultimately, association implies causation if all possibilities for spurious associations have been eliminated. Given the difficulties of establishing true causality in the social sciences, the term association rather than causation is emphasized.”

Some of the other criticisms were not even on point to what Dr. Kandel was saying. A critic of the Gateway Hypothesis quoted in the NYT article was Ethan Nadelmann, the founder and former executive director of the Drug Policy Alliance. He said given that the study was on rats, to make claims about people from it was a stretch. Did this guy even look at the title of the Kandel and Kandel paper, “A Molecular Basis for Nicotine as a Gateway Drug,” let alone read it?

He also noted previous studies showing how one drug enhances the effect of another contradicted “gateway theory.” But again, that wasn’t relevant to Kandel’s Gateway Hypothesis. Nadelmann also alluded to research showing how individuals combining marijuana and prescription opioids were not more likely to abuse alcohol or other drugs.

Given the interest of Dr. Kandel in applying her research conclusions to public health concerns and policy issues, Dr. Nadelmann’s criticisms seem aimed at redirecting the attention of politicians like Jeff Session and Chris Christie and others away from seriously considering her research in the context of social and legislation reform of existing drug policy. The Drug Policy Alliance is a non-profit organization whose stated priorities include the decriminalization of responsible drug use. There seems to be dueling political ideologies at work here that either embrace or reject the Gateway Hypothesis.

Some serious political sparks may begin flying over Kandel and the Gateway Hypothesis soon. Dr. Kandel is wrapping up a similar study to those mentioned here on marijuana and hopes it will be ready for publication sometime in the first half of 2018. Given the careful science of Kandel and Kandel, the political firefights could get ugly if it demonstrates a molecular gateway for marijuana as the above studies have for nicotine and cocaine. But we’ll have to wait and see what they found and then concluded from their data. Pro marijuana legalization activists are probably wishing the Gateway Hypothesis had just remained dead.