In 1984, the prominent researcher Denise Kandel coined the term “gateway drug” to describe the progression from one class of legal drugs (either alcohol or cigarettes) to cannabis during the transitional period into young adult (Kandel and Logan, 1984) (Yamaguchi and Kandel, 1984a). Her group also posited that the prior use of cannabis is necessary for progression to other illicit drugs (Yamaguchi and Kandel, 1984b). 

While her work primarily focused on the gateway effect of alcohol and cigarettes, only the cannabis gateway theory obtained traction in the public eye. Support for the cannabis gateway effect focused on the finding that cannabis users are many times more likely than nonusers to progress to the use of more dangerous drugs. Almost all who have used both cannabis and hard drugs used cannabis first, and the greater the frequency of cannabis use, the greater the likelihood of using hard drugs later. (Again, these relationships were even stronger for cigarettes and alcohol, but received far less attention).

Subsequent work from this lab (Kandel and Kandel, 2014) and others (Levine et al., 2011) demonstrated a molecular basis (in preclinical models) for the progression of nicotine to cocaine. In fact, as adolescent use of tobacco has plummeted over the past several decades, adolescent use of cocaine (as well as other drugs) has fallen as well (Elliott and Adinoff, 2021). Others have described alcohol-induced molecular changes that enhance compulsive cocaine self-administration (Griffin et al., 2017) and cannabinoid exposure in adolescent rats that alters the initial behavioral, molecular, and epigenetic responses to cocaine (Scherma et al., 2020).

Yet demonstrating the gateway theory of cannabis in humans has been problematic – and it’s not for lack of trying. One of the main difficulties with determining cause and effect is that the same set of factors (e.g., genetic, familial, and environmental factors) can increase both the use of cannabis and other substances. The Common Factor model, for instance, posits that the covariation among a set of observed variables reflects the influence of one or more common factors. For substance use, this means that various factors (e.g., a family history of a substance use disorder, childhood trauma, having another mental illness, an anxious, impulsive, and/or non-conscientious temperament, peer pressure, loneliness/social isolation, lack of family involvement, drug availability, and local socioeconomic status) will increase the likelihood of both cannabis use and other drug use. In 2002, RAND's Drug Policy Research Center referred to this effect as Common Propensity and published the first quantitative evidence supporting the strong association between cannabis and hard-drug initiation without the need to posit a gateway effect (Morral et al., 2002a; Morral et al., 2002b).

Perhaps the best study exploring the validity of the gateway theory was by Degenhardt et al. (Degenhardt et al., 2010). These investigators compared patterns and order of initiation of alcohol, tobacco, cannabis, and other illicit drug use across 17 countries with a wide range of drug use prevalence. The study was designed to determine if the initiation of "gateway" substances (i.e. alcohol, tobacco, and cannabis) was differentially associated with the subsequent onset of other illicit drug use, based on background prevalence of so-called gateway substance use. The authors reported that their results suggested that the "gateway" pattern at least partially reflects unmeasured common causes rather than causal effects of specific drugs on subsequent use of others. Thus, even if efforts to prevent the use of specific "gateway" drugs are successful, major reductions in the use of harder drugs may not be observed. In other words, other factors – not the “gateway” drugs themselves – influenced the rates of all observed drug use.

The National Institutes of Drug Abuse has backed away from previously stated concerns about the gateway theory and now conclude that “the majority of people who use cannabis do not go on to use other, ‘harder’ substances. Also, cross-sensitization is not unique to cannabis, as alcohol and nicotine also prime the brain for a heightened response to other drugs and are, like cannabis, also typically used before a person progresses to other, more harmful substances…other factors besides biological mechanisms, such as a person’s social environment, are also critical in a person’s risk for drug use. An alternative to the gateway-drug hypothesis is that people who are more vulnerable to drug-taking are simply more likely to start with readily available substances such as cannabis, tobacco, or alcohol, and their subsequent social interactions with others who use drugs increases their chances of trying other drugs."

Despite 40 years of “gateway theory” scare tactics, there is little evidence to suggest that cannabis use increases the use of other drugs. Regardless, any concern about “gateway drugs” should focus on nicotine and alcohol rather than cannabis. Given that adolescent use of nicotine and alcohol have substantially decreased over the past 40 years through public health efforts in prevention, education, and taxation, efforts to reduce future cannabis harms to adolescents should focus on similar approaches.

‍Doctors for Cannabis Regulation, July 22, 2023

References

1. Degenhardt, L., Dierker, L., Chiu, W. T., Medina-Mora, M. E., Neumark, Y., Sampson, N., Alonso, J., Angermeyer, M., Anthony, J. C., Bruffaerts, R., de Girolamo, G., de Graaf, R., Gureje, O., Karam, A. N., Kostyuchenko, S., Lee, S., Lepine, J. P., Levinson, D., Nakamura, Y., Posada-Villa, J., Stein, D., Wells, J. E., Kessler, R. C., 2010. Evaluating the drug use "gateway" theory using cross-national data: consistency and associations of the order of initiation of drug use among participants in the WHO World Mental Health Surveys. Drug and Alcohol Dependence 108, 84-97.

2. Elliott, M. D., Adinoff, B., 2021. Implications of adult use cannabis legalization for adolescent use, perceptions, health, and consequences. Adolescent Psychiatry 11, 129-146.

3. Griffin, E. A., Jr., Melas, P. A., Zhou, R., Li, Y., Mercado, P., Kempadoo, K. A., Stephenson, S., Colnaghi, L., Taylor, K., Hu, M. C., Kandel, E. R., Kandel, D. B., 2017. Prior alcohol use enhances vulnerability to compulsive cocaine self-administration by promoting degradation of HDAC4 and HDAC5. Sci Adv 3, e1701682.

4. Kandel, D. B., Kandel, E. R., 2014. A molecular basis for nicotine as a gateway drug. N Engl J Med 371, 2038-2039.

5. Kandel, D. B., Logan, J. A., 1984. Patterns of drug use from adolescence to young adulthood: I. Periods of risk for initiation, continued use, and discontinuation. Am J Public Health 74, 660-666.

6. Levine, A., Huang, Y., Drisaldi, B., Griffin, E. A., Jr., Pollak, D. D., Xu, S., Yin, D., Schaffran, C., Kandel, D. B., Kandel, E. R., 2011. Molecular mechanism for a gateway drug: epigenetic changes initiated by nicotine prime gene expression by cocaine. Sci Transl Med 3, 107ra109.

7. Morral, A. R., McCaffrey, D. F., Paddock, S. M., 2002a. Reassessing the marijuana gateway effect. Addiction 97, 1493-1504.

8. Morral, A. R., McCafrey, D. F., Paddock, S. M., 2002b. Evidence does not favor marijuana gateway effects over a common-factor interpretation of drug use initiation: responses to Anthony, Kenkel & Mathios and Lynskey. Addiction 97, 1509-1510.

9. Scherma, M., Qvist, J. S., Asok, A., Huang, S. C., Masia, P., Deidda, M., Wei, Y. B., Soni, R. K., Fratta, W., Fadda, P., Kandel, E. R., Kandel, D. B., Melas, P. A., 2020. Cannabinoid exposure in rat adolescence reprograms the initial behavioral, molecular, and epigenetic response to cocaine. Proc Natl Acad Sci U S A 117, 9991-10002.

10. Yamaguchi, K., Kandel, D. B., 1984a. Patterns of drug use from adolescence to young adulthood: II. Sequences of progression. Am J Public Health 74, 668-672.

11. Yamaguchi, K., Kandel, D. B., 1984b. Patterns of drug use from adolescence to young adulthood: III. Predictors of progression. Am J Public Health 74, 673-681.

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