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It’s the 40th anniversary of the gateway drug theory. What led you to propose it?
There had been a large increase in the use of marijuana in the 1970s. I was funded to do a project focused solely on marijuana, but I thought that it might also be interesting to look at other drugs, so I slipped some questions about drinking and smoking into the interviews.

Once I started looking at the data, I realised that there were certain ages at which people tended to get involved in different classes of drugs. They tended to start on cigarettes, alcohol and marijuana at around ages 12 to 14. By doing cross-sectional and longitudinal studies of drug use, I found the same pattern over and over again.

What was that pattern?
People started with legal drugs such as wine, beer and cigarettes, and some progressed to marijuana. Then some moved on to cocaine, and then, perhaps, to heroin. Of course, this doesn’t mean that just because you smoke cigarettes, you are going to become a heroin addict. But it was – it is – a very compelling pattern. I proposed that cigarettes and alcohol were gateways to the use of illegal drugs. This created a lot of controversy.

You finally put your theory to the test last year in a collaboration with your husband, neuroscientist and . How did that come about?
For years, I’d suggested that a rodent model was needed to better understand what might be driving this pattern. Then, a decade ago, I was invited to go to a meeting in Prague organised by the Society for Research on Nicotine and Tobacco, so I asked my husband if he would like to come. He said yes, and when I told the organisers, they asked if he would give a basic science lecture. He had done some work on cocaine – nothing to do with the gateway theory – and he talked about that.

After his lecture, I said, “You know, Eric, I think we should do something in mice looking at the impact of nicotine on the response to cocaine.” That was how it started. If we hadn’t gone to the meeting together, if he hadn’t given that lecture, it might never have happened.

You found a strong neurological basis for the gateway effect. Were you surprised?
As I said, I didn’t think that the pattern of use was random. But testing the idea empirically in humans was a challenge. You can’t propose a study where you say, “I am going to present cigarettes and cocaine, in different orders, to a group of kids to see if they are more or less likely to want to snort cocaine after having tried cigarettes.” But you can do something along those lines in mice.

When we did that study – and we looked at the behaviour, the neurobiology and the molecular biology – we found a strong gateway effect: when you primed a mouse with nicotine and then exposed it to cocaine, the effects of cocaine were enhanced. We saw more addiction-like behaviours in those mice, and my husband’s laboratory saw changes at the molecular level.

What sort of brain changes emerged?
Just one example is that nicotine enhances the expression of FosB, a gene involved in reward. Such changes make the brain more receptive to experiencing the rewards of another drug. What surprised us was that this effect was completely unidirectional: when we did the reverse and primed the mice with cocaine and then introduced them to nicotine, there was no effect on nicotine at all, either in behaviour or at the molecular level ().

Were there any other surprises?
Yes, another unanticipated finding in our mouse data was that we only saw the gateway effect when exposures were overlapping – when mice were primed with nicotine and then had at least one day where they were exposed to both nicotine and cocaine. This suggested that people have to be actively smoking when they start using cocaine for these brain changes to occur.

I went back and re-examined the epidemiological data and found that, in the overwhelming majority of cases, young people were actively smoking when they started using cocaine. And the rate of addiction was twice as high among those who were smoking when they started using cocaine as among those who were not smoking at the time.

It sounds like a fertile marriage of two very different disciplines…
The work exemplifies how you can move from epidemiology to the biology lab and back again. The two fields have a lot to offer one 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 in mind that there are two types of e-cigarette consumers: people trying to stop smoking, and young people trying something new.

If you’re an established smoker, vaping might be a safer alternative because you aren’t exposed to all the carcinogens that cigarettes produce. But e-cigarettes are unregulated and may contain all kinds of compounds and chemicals that we do not know about.

Perhaps most importantly, the current safety discussions in the medical community emphasise the effects of these products on the lungs and heart. People aren’t talking about effects on the brain. Our work suggests this is important. Nicotine is nicotine, whether from a cigarette or an e-cigarette. And when it gets into the brain, especially the adolescent brain, there are negative consequences.

“People aren’t talking about effects of e-cigarettes on the brain, but it’s important”

We are learning that the rates of use of e-cigarettes are growing dramatically, especially among young people. What is driving that? The science is not keeping up with rapidly changing behaviour.

Your initial work on the gateway theory also suggested that marijuana is a gateway drug.
Over the years, people tended to focus on marijuana being the gateway drug, the substance that would ultimately lead you to cocaine or heroin. Indeed, that link does not appear to have weakened over time – but that wasn’t exactly what I was saying. My research described a link from tobacco or alcohol to marijuana, and then from marijuana to cocaine. The connection between alcohol and cocaine, and between cigarettes and cocaine, is extremely strong.

How might your new work translate into public health measures to tackle drug use and addiction?
Drug addiction stems from a constellation of factors. We know that genes are important, and so is environment. If you are susceptible to becoming addicted, then it isn’t safe to use any drugs. We have known for a long time that you have to start any intervention early for it to be successful. Our work provides a strong rationale for doing so. If you can get young people to not use tobacco or other substances, if you can educate them about the effects on the brain, you can reduce the risk – and, with luck, make a difference.

This article appeared in print under the headline “Sentinel at the gates of addiction”