PROFILEDenise Kandel is aprofessor of sociomedicalsciences at ColumbiaUniversity’s MailmanSchool of Public Healthin <strong>New</strong> York City. For50 years she hasexplored risk factors fordrug use and addictionSentinel at thegates of addictionThe idea that cigarettes prime the brain for addiction toharder drugs has long been controversial. EpidemiologistDenise Kandel explains how she found hard evidence
OPINION INTERVIEWFor more opinion articles, visit newscientist.com/opinionPhotographed for <strong>New</strong> <strong>Scientist</strong> by Mike McGregorIt’s the 40th anniversary of the gateway drugtheory. What led you to propose it?There had been a large increase in the useof marijuana in the 1970s. I was funded todo a project focused solely on marijuana,but I thought that it might also be interestingto look at other drugs, so I slipped somequestions about drinking and smokinginto the interviews.Once I started looking at the data, I realisedthat there were certain ages at which peopletended to get involved in different classesof drugs. They tended to start on cigarettes,alcohol and marijuana at around ages 12 to 14.By doing cross-sectional and longitudinalstudies of drug use, I found the same patternover and over again.What was that pattern?People started with legal drugs such as wine,beer and cigarettes, and some progressed tomarijuana. Then some moved on to cocaine,and then, perhaps, to heroin. Of course, thisdoesn’t mean that just because you smokecigarettes, you are going to become a heroinaddict. But it was – it is – a very compellingpattern. I proposed that cigarettes and alcoholwere gateways to the use of illegal drugs.This created a lot of controversy.You finally put your theory to the test lastyear in a collaboration with your husband,neuroscientist and <strong>No</strong>bel laureate Eric Kandel.How did that come about?For years, I’d suggested that a rodent modelwas needed to better understand what mightbe driving this pattern. Then, a decade ago,I was invited to go to a meeting in Pragueorganised by the Society for Research onNicotine and Tobacco, so I asked my husbandif he would like to come. He said yes, and whenI told the organisers, they asked if he wouldgive a basic science lecture. He had done somework on cocaine – nothing to do with thegateway theory – and he talked about that.After his lecture, I said, “You know, Eric,I think we should do something in micelooking at the impact of nicotine on theresponse to cocaine.” That was how it started.If we hadn’t gone to the meeting together, if hehadn’t given that lecture, it might never havehappened.You found a strong neurological basis for thegateway effect. Were you surprised?As I said, I didn’t think that the pattern of usewas random. But testing the idea empiricallyin humans was a challenge. You can’t proposea study where you say, “I am going to presentcigarettes and cocaine, in different orders, toa group of kids to see if they are more or lesslikely to want to snort cocaine after havingtried cigarettes.” But you can do somethingalong those lines in mice.When we did that study – and we lookedat the behaviour, the neurobiology andthe molecular biology – we found a stronggateway effect: when you primed a mousewith nicotine and then exposed it to cocaine,the effects of cocaine were enhanced. We sawmore addiction-like behaviours in those mice,and my husband’s laboratory saw changes atthe molecular level.What sort of brain changes emerged?Just one example is that nicotine enhances theexpression of FosB, a gene involved in reward.Such changes make the brain more receptiveto experiencing the rewards of another drug.“ People aren’t talking abouteffects of e-cigarettes onthe brain, but it’s important”What surprised us was that this effect wascompletely unidirectional: when we did thereverse and primed the mice with cocaineand then introduced them to nicotine, therewas no effect on nicotine at all, either inbehaviour or at the molecular level (NEJM,vol 371, p 932).Were there any other surprises?Yes, another unanticipated finding in ourmouse data was that we only saw the gatewayeffect when exposures were overlapping –when mice were primed with nicotine andthen had at least one day where they wereexposed to both nicotine and cocaine. Thissuggested that people have to be activelysmoking when they start using cocaine forthese brain changes to occur.I went back and re-examined theepidemiological data and found that, in theoverwhelming majority of cases, young peoplewere actively smoking when they startedusing cocaine. And the rate of addiction wastwice as high among those who were smokingwhen they started using cocaine as amongthose who were not smoking at the time.It sounds like a fertile marriage of two verydifferent disciplines…The work exemplifies how you can movefrom epidemiology to the biology lab andback again. The two fields have a lot to offerone another – if scientists are open to it.E-cigarettes and vaping are gaining popularity,touted as “safe” alternatives to smoking.What are your thoughts on this?It is a controversial topic. You need to keep inmind that there are two types of e-cigaretteconsumers: people trying to stop smoking,and young people trying something new.If you’re an established smoker, vapingmight be a safer alternative because you aren’texposed to all the carcinogens that cigarettesproduce. But e-cigarettes are unregulatedand may contain all kinds of compoundsand chemicals that we do not know about.Perhaps most importantly, the currentsafety discussions in the medical communityemphasise the effects of these products on thelungs and heart. People aren’t talking abouteffects on the brain. Our work suggests this isimportant. Nicotine is nicotine, whether froma cigarette or an e-cigarette. And when it getsinto the brain, especially the adolescent brain,there are negative consequences.We are learning that the rates of useof e-cigarettes are growing dramatically,especially among young people. What isdriving that? The science is not keepingup with rapidly changing behaviour.Your initial work on the gateway theory alsosuggested that marijuana is a gateway drug.Over the years, people tended to focus onmarijuana being the gateway drug, thesubstance that would ultimately lead you tococaine or heroin. Indeed, that link does notappear to have weakened over time – but thatwasn’t exactly what I was saying. My researchdescribed a link from tobacco or alcohol tomarijuana, and then from marijuana tococaine. The connection between alcoholand cocaine, and between cigarettes andcocaine, is extremely strong.How might your new work translate intopublic health measures to tackle drug useand addiction?Drug addiction stems from a constellation offactors. We know that genes are important,and so is environment. If you are susceptibleto becoming addicted, then it isn’t safe to useany drugs. We have known for a long time thatyou have to start any intervention early for itto be successful. Our work provides a strongrationale for doing so. If you can get youngpeople to not use tobacco or other substances,if you can educate them about the effects onthe brain, you can reduce the risk – and, withluck, make a difference. ■Interview by Kayt Sukel7 March 2015 | <strong>New</strong><strong>Scientist</strong> | 29
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