Kandel, Kandel, and NEJM: flogging the gateway hypothesis to attack e-cigarettes

by Carl V Phillips

I expected to focus today’s post on all the stupid media reports on the publication that I wrote about yesterday via the CASAA press release. But a funny thing happened: almost nothing. Though this was the type of supposedly-authoritative sensationalism that the press usually eats up, there were remarkably few stories in the American press. So I decided to go old-school with the post instead, and focus on the lies and liars.

Now my readers in the UK might not realize that a miracle occurred. The British tabloids (by which I mean: most of the British national newspapers — you guys make our press corps look good) all covered it in the standard churnalistic fashion. My personal favorite:

It seemed to be dutifully reported in India too, as expected. But in the USA, the only major news outlet that reported the sensationalistic junk was Time (no shock there). The New York Daily News reported the headlines, but did at least quote from our press release. That was basically it. Even the inevitable HuffPo piece came out of the UK.

Fingers crossed, of course, because zombies can rise at any time. But perhaps our press release did some good. (Apologies to our friends in the UK — it was just too damn expensive to distribute it outside the USA.) Once a reporter saw it, they faced the choice of ignoring our analysis and running with the sensationalism (always possible), running a story about how misleading the original claims were (a bit too bold for most), or just walking away. There was no way — if they took our critique at all seriously — they could run the standard “the study showed… but some critics argued…” piece. Because, of course, the study clearly did not show what Kandel^2 and the NEJM claimed it did.

As background, all you need to know is that they did a mice torture experiment, and reported that those mice who were dosed with nicotine may have liked cocaine better later. There are obviously more details to it, but that is basically it. If this translates to humans (a big “if”) then the implications are pretty much summed up in this handy lifehack interpretation from Alex Clark:

But the authors and journals did not spin it that way, even though you would think that would be just as good for getting headlines. No, the authors clearly intended to write a paper pushing “gateway effect” claims, which of course refers to one drug causing people to use another drug. Needless to say, liking the other drug better is a far cry from actually seeking it out and using it. Moreover, the authors chose to specifically focus on e-cigarettes, as if that were the only source of nicotine. Funny how nicotine patches did not get mentioned.

I made some random observations about the paper itself to a discussion group of interested researchers (based on the few hours we had to peer review this material before the anticipated media frenzy). So I will just repost what I wrote, for what it is worth, and move on to the blatant lies in the press release.

This paper starts out by acknowledging the problems with what it typically cited as evidence for gateway effects. It is a bad sign that they do this in the context of presenting some of it as if it were informative, but whatever. But then they go on to suggest that epidemiology “cannot” determine what causes “the progression from one drug to the next” (they seem to have already forgotten that they pointed out that we do not actually know that happens) and that only testing on nonhuman animals can.

This is wrong on both counts. Epidemiology can provide useful information about gateways (though it is quite difficult), whereas testing on other species is pretty much useless for understanding phenomena that are all about human volition and social systems. It is possible to use such tests to offer an explanation (largely unprovable, and inevitably one of many candidates) for why something happens (“why do people do this thing we know they do? perhaps it is because of this biochemical phenomenon”). But it obviously cannot show that it really happens.

The next problem is the generic problem with all “brain porn” research (a term used to rightly diminish it by biological scientists and that should be aggressively adopted by social scientists too): Something always changes in the brain when you have an experience. Thus it is possible to find the change. That does not mean what you find is causing a particular outcome. It definitely does not mean that it creates the social science phenomenon in question. The biggest problems with this come from brain scan porn, which are not used here, but what they present about molecules is basically similar.

Consider: If brains do a particular thing in response to nicotine dosing, but people react differently [from one another], that bit of biology does not offer us very good information about behavior. If it turns out that the degree of the biological response is associated with the real-world reaction, then maybe(!) you have found an explanation for behavior. But think about what you need before you can make that conclusion. You would already have to have a good measure of the real-world phenomenon in question, and the biology would just be trying to explain why it happens. It still would not be showing that it does happen.

Notice that when they circle back to people, with reference to a single study, they do not actually have any tie between their mice torture and the people. They basically just repeat the claim that they gave lip-service to denying in the introduction, that correlation is always causation, even when there is obvious massive confounding.

Also, it turns out that mice are not people, so the behavioral observations are not terribly informative. And that is actually an understatement, because lab mice that are forced to live in unnatural captive situations are very much unlike not just people, but mice. It was famously demonstrated that rodent propensity for “addiction” decreased dramatically when they were allowed to live in happy semi-natural colonies.

Another factor to keep in mind is that mouse scientists are every bit as bad about model shopping as bad epidemiologists. We have to wonder how many different versions of this experiment they ran before the mice cooperated to give the results they could publish in NEJM.

Finally, regarding their grossly inappropriate and irresponsible implicit policy conclusions:  Imagine that their results are not cooked, and that they really apply to humans, and that what they observe really translates into real-world preferences. Presumably if you ran the analogous experiment (on humans) enough times with enough different foods/pharmaceuticals/lifestyles/experiences, you would find quite a few of them that increased people’s appreciation of cocaine (caffeine, thrill sports, wild sex, and attending Harvard come to mind — either individually or in conjunction). This would not mean that they cause cocaine use to any measurable degree, and even if they did, it would most certainly not be sufficient to recommend restricting them.

The e-cigarettes emphasis looks like a ploy to turn what was basically boring research (for everyone other than the poor mice and those trying to get better value from their cocaine) into headlines. It was not out-of-the-blue, however. Rodu points out that Denise Kandel has been flogging disreputed Drug War gateway claims for 40 years, and so one could argue that this was a natural extension of her political goals. Still, given that e-cigarettes deliver far less nicotine to people every day than does smokeless tobacco and probably NRT (and obviously cigarettes), it is difficult not to settle on the publicity ploy explanation.

From the paper:

The gateway hypothesis was developed by Denise Kandel, who observed that young people become involved in drugs in stages and sequences.[Reference to her 1975 paper.]

Now some might think that a hypothesis that had been part of the Drug Wars since the 1950s was, at best, labeled in 1975, but whatever. What follows is some of the bait-and-switch that is common among gateway proponents, where they define gateway to mean merely using one drug before the other (which is easy to observe and support), and then quietly drift into claiming the former caused the latter (which is very difficult to try to show, and is seldom supported). It is important to note that after a bit of that game, the authors clearly settle on the normal causal interpretation of the term, and thus their use of the term clearly is a causal claim.

In the Columbia University press release the authors did not even pretend to recognize the difficulties with drawing gateway conclusions, and certainly did not let their emphasis on e-cigarettes get lost amidst any of that pesky sciencey stuff.  The headline was:

E-Cigarettes May Promote Illicit Drug Use and Addiction

When discussing D.Kandel’s claims about the gateway, even the veneer of scientific skepticism in the article, let alone a recognition of the widespread disagreement with her conclusions, was absent. Instead:

Dr. Denise Kandel’s further analysis of 2004 epidemiologic data from a large, longitudinal sample suggested that nicotine also primes human brains to respond to cocaine. She found that the rate of cocaine dependence was highest among users who started using cocaine after having smoked cigarettes. “Our findings provided a biologic basis for the sequence of drug use observed in people,” said Dr. Eric Kandel. “One drug alters the brain’s circuitry in a way that enhances the effects of a subsequent drug.”

What was the basis for saying the data showed a priming of human brains? Basically just the fact that lots of people used cigarettes before cocaine, and not many the other way around. I trust I do not have to explain why this does not show anything interesting, given that cigarettes are much easier to obtain. It is also interesting to contrast this claim (based on epidemiology) with the statement in the paper I refer to above, in which the authors state that epidemiology cannot show such a thing.

The observation that “dependence was highest” (even setting aside the tenuousness of measuring dependence) is easily explained by confounding. People who never smoked but gave cocaine a try are different in many obvious ways from those who acquire the easy smoking habit then add others on top of it. Still, if the tenuous claim really is true, the mouse experiment might indeed provide an explanation for why it happens, as I noted above. That is potentially a real scientific discovery, but one so fraught with uncertainty that even the statement in this paragraph is already going overboard.

So did they leave it at that? What do you think?

in light of the skyrocketing popularity of e-cigarettes, particularly among adolescents and young adults, the researchers say that more effective prevention programs need to be developed for all products that contain nicotine.


“E-cigarettes may be a gateway to both combustible cigarettes and illicit drugs. Therefore, we should do all we can to protect young people from the harmful effects of nicotine and the risks of progressing to illicit drugs.”

Why? The implication is because they are causing people to later use other drugs (recall the headline). But that is not what their research suggested even if you take their interpretation at face value. It merely suggested that you will like cocaine (not “illicit drugs” generally; not cigarettes) better if you use nicotine (not e-cigarettes in particular) first. Does this call for “more effective prevention”? Certainly not if the supposed increased liking for cocaine does not cause anyone to act differently. Do the authors make any attempt to assess whether anyone is acting differently, or even argue that it is happening? Nope.

And even if there were evidence of that, their conclusions would still not follow. Is it necessarily bad that someone likes cocaine more and thus chooses to use it whereas he would not have done so otherwise? That can certainly be argued, but it does not go without saying. Liking something more is normally considered a good thing, and so at least some case must be offered as to why that is not true here. If this leads to more life-ruining cocaine use, there is a case to be made. If it just means that some people enjoy an occasional indulgence that they might have otherwise not found worth the effort, not so much.

Moreover, what if the prevention efforts needed to keep people from using cocaine interfere with THR, or cost millions of dollars per cocaine-user-prevented, or cause most of the population to think that public health people are tyrannical nannying loons and thus ignore useful advice? The real world of public policy making is not nearly as simple as mouse torturers seem to think it is.

Apparently they do not even understand that actions by individual humans are more complicated than mouse biology (“of mice and men” joke omitted — those have already been done to death):

We don’t yet know whether e-cigarettes will prove to be a gateway to the use of conventional cigarettes and illicit drugs, but that’s certainly a possibility.

We don’t yet know if they will destroy the galaxy either, but the mere fact that it is a theoretical possibility is certainly not a basis for policy recommendations. Or a basis for headlines that are clearly intended to be interpreted at “it does that!”

Nicotine clearly acts as a gateway drug on the brain, and this effect is likely to occur whether the exposure comes from smoking cigarettes, passive tobacco smoke, or e-cigarettes.

For something to act “as a gateway drug on the brain”, it needs to cause volition — actual action to use the other drug — not just change preferences. Even if their claims about preferences were supported, they would not tell us that nicotine is acting as a gateway. In fact, the previous sentence in the paragraph (the previous quote) says as much. Notice the bait-and-switch. The previous sentence talks speculatively about the alarming actual gateway effect, while the second conveniently redefines it to a much weaker claim that they then assert to be true.

Oh, and that massive dose of nicotine from “passive tobacco smoke”? Seriously? Do they even understand orders of magnitude? Perhaps not:

the researchers point out that e-cigarette use is increasing exponentially among adolescents and young adults.

This was from the paper and cited to the first CDC scare report, which was based on figures for each of two years (h/t Bill Godshall for noticing that). Two points do not show whether a trend is exponential, linear, geometric, or any other basic shape. You can fit any curve shape to two points. Except we know it is obviously not following the purely exponential shape that would hit those two points, because if it were, the prevalence would exceed 100% by 2016. I tend to think it is a bad idea to trust any claim made by a scientist who does not understand basic math.

And finally,

“The effects we saw in adult mice are probably even stronger in adolescent animals,” said Dr. Eric Kandel.

But are they stronger in people animals or just mice? You don’t really know, do you? I am willing to bet that people of any age are much less inclined than mice to spend their day in a little chamber with cocaine in the water supply. Indeed, if offered the choice, I suspect the mice would have left too.

So who is to blame for this fiasco? The authors, obviously. They were clearly on a mission to trump up support for personal pet theories. Columbia University, no doubt. They are the one who sent out the shark-jumping press release.

What about the New England Journal of Medicine? That one is trickier, since this was not just a research paper, but the presentation (with lots of extra material) of the content of an honorary lecture. In some sense, this magazine was just acting as a typical magazine, merely publishing the thoughts of a couple of authors as-is. But they do have the word “Journal” in their name and normally claim to be a respected peer-reviewed publication. (Unjustly respected, it turns out. They were always my go-to source when I wanted to quickly find a teaching example of bad epidemiology.) There were no caveats accompanying this article to suggest it was not reviewed according to their normal methods and standards. Thus the journal and those who reviewed this paper also bear responsibility for allowing a thinly veiled political statement to be published as if the claims in it were supported by the reported study.

12 responses to “Kandel, Kandel, and NEJM: flogging the gateway hypothesis to attack e-cigarettes

  1. Thank you Carl Phillips, you covered all bases and have proven that this is Junk Science at it’s worst. You also make a sensible comparison to factual basics of studies, of which this junk cannot even begin to compare. An example of what laboratory lab rats must put up with, by the hands of idiots charading as scientists, with no clue about science offensively experimenting on these creatures poor bodies and culpable for the loss of lives that smokers (may) have; there thesis is too unintelligable for most thinking people but is palpable and very agreeable for the evil politicians that will refer to it as often as meets their diabolical schemes, applaud and stamp with approval with great bravado these two clowns in science lab coats, virtueless dribble as reasons for further criminalizing, marginalizing, punitizing and capitalizing on tobacco users and usage. .

  2. But, you forgot about mouse peer pressure. Mice that smoke are more likely to hang around with other mice that smoke. And smoker mice are more likely to have tattoos, wear leather jackets and do cocaine.

    Seriously though, I love logic. Thanks for the analysis.

    Here is what strikes me about the nicotine to cocaine gateway…
    It is logical to assume that in some people using one type of drug will lead to using another type of drug. Obviously tons of people use, say, marijuana, and never go on to use hard drugs like cocaine. But some people use one drug, decide that they really like getting high, and then try to seek out “better” highs from other drugs. (I will not even begin to speculate as to why.) But for that to happen, they have to perceive a relationship between the two. “I liked it that this drug got me high, and I want to get even more high, so I’ll try other drugs.” But for this to apply here someone would have to think, “Oh man, I love the feeling I get from this nicotine! How can I get more of that feeling. I know! Cocaine!”

    I am hoping that this study will help people to see how ridiculous that anti-e cigarette mania is.

    It seems like your average person would read the headline and think, “How does one get from e-cigs to cocaine, isn’t that skipping some steps? Like, a lot of steps?”

    I wonder what percentage of e-cigarette users or experimenters even have the first clue about how to get cocaine.

    • Carl V Phillips

      1. They probably do tattoo the poor mice, though the ink is probably nothing cool. And, ironically, mice that have good peer interactions tend to avoid the drugs. It is the tortured and lonely ones who go for them.
      2. Always happy to provide logic.
      3. Gateway claims always involve some vague hand-waving about why someone would do it. But even the “looking for a better high” cliche tells us nothing about what would have happened had the drug that formed the previous step not existed. If no one used nicotine, then would they just be looking to cocaine for their first high rather than a better one?
      4. I hope so. I really like to think that people’s credulity knows bounds.
      5. Again, I hope so.
      6. Business model!!!

  3. Good point. I guess in the example I provided any intoxicating substance could be a gateway to any other. So it’s really not a gateway any more than playing one board game, deciding you like it and want more, then seeking out other board games would make that first game a gateway. It just happened to be first.

    I guess what I was trying to say is, who associates nicotine and cocaine to the point that they think if they like one they will surely like the other?

    • It is tricky because the gateway proponents play games with the words. I have another paper I’ll release about it this week that is not exactly on that point, but will help clarify. For the claim to mean what they imply it means for policy and practical fears, it needs to mean *cause*. I.e., the cocaine use will occur in the event of nicotine use and will not occur in the absence of nicotine use — so in a world without nicotine that particular cocaine use would never occur. It is obviously possible in theory. In fairness, this particular study actually tried to cobble together a case for that (nicotine makes you like cocaine more), as opposed to most gateway claims in which there is no hint of that at all.

      Nicotine is a fairly unique drug, which makes it really appealing. Stimulation but also focus (calming it is often called). It makes you both more productive and smarter (to focus on the advantages for the likes of us — obviously it serves a different purpose for others). Cocaine does not do that; it makes you really productive, but what you produce is generally utter crap. You could make a better case that caffeine -> cocaine is a more obvious progression, since caffeine is more like that.

  4. Where might Adderall fall on that scale?

    • It is supposed to function like nicotine, at least those for whom it is indicated, though I am not sure it has the cognitive enhancement properties. Indeed, it has often been speculated that the reduction in smoking among kids is a lot of the reason there is so much demand for it now — smoking was self-medication for basically the same difficulties that Adderall was designed to treat (much more profitably for the medical-industrial complex, of course).

  5. late breaking news, I have examined several years of data and found that drunk driving leads to an increased risk of motor vehicle accidents. Clearly driving is a gateway to alcoholism. I have as much support for this as the authors of the NEJM article do for their conclusions. By their logic all forms of medicals approved NRT( nicotine replacement therapy) should be banned to prevent a wave of illicit drug use. Sadly the tag line “ecig cause cocaine addiction” sells newspapers and even academia is not above sensationalism.

    • One might even go so far as to say the corner of academia that is crusading against THR is *all about* sensationalism.

      • The sensationalism is necessary to garner the media coverage. And the media coverage is necessary in order to garner top dollar in future grant money. Thus the sensationalism, AND the poorly designed and presented research that makes the sensationalism possible, are a direct result of money-grubbing by researchers putting the mortgages on their million-dollar mansions ahead of scientific pursuit.

        Any researcher who flagrantly engages in such behavior should receive a strict reprimand from some sort of neutral “board” similar to that which might decide on disbarring lawyers or yanking doctor’s medical licenses (if there’s any way of ensuring such neutrality in this atmosphere!) for a first offense.

        A second offense within five years should merit a personal fine levied upon all researchers whose names are on the research in question, from their own personal pockets, for five times the amount of whatever grant supported that research and went into their pockets.

        A third offense should result in their semi-permanent “disbarment” and the prohibition of any further grants from any official government or organized nonprofit organization. (Semi-permanent could allow a cracked gateway, years down the line, for repentant and rehabilitated researchers who have clearly worked hard to undo the public harms caused by their original deliberately flawed research. Such researchers could be given a provisional pass of some sort to re-enter the research field … on probation.)

        A system like that might do a lot to fix the problems we’ve seen in antismoking research over the past 30 years or so.

        – MJM

  6. Carl, you mention caffeine, and that brings an interesting question to mind. K&K chose a comparison between a legal drug, nicotine, and an illegal drug, cocaine. Wouldn’t it have been an OBVIOUS “control condition” to anyone beyond a high-school science-project level, to include consideration of caffeine in the analysis? Did K&K include it AT ALL? And, if they did not, can you honestly think of any justification for such exclusion OTHER than the deliberate stab at sensationalism/grants that might have been watered down by such inclusion and comparison?

  7. Pingback: Researchers Suggest that E-Cigs May Promote Illicit Drug Use and Addiction

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