Investigating causal associations between use of nicotine,
alcohol, caffeine and cannabis: a two-sample bidirectional
Mendelian randomization study
Karin J. H. Verweij* , Jorien L. Treur* & Jacqueline M. Vink
Behavioural Science Institute, Radboud University, Nijmegen, the Netherlands
Background and Aims
Epidemiological studies consistently show co-occurrence of use of different addictive substances.
Whether these associations are causal or due to overlapping underlying inﬂuences remains an important question in
addiction research. Methodological advances have made it possible to use published genetic associations to infer causal
relationships between phenotypes. In this exploratory study, we used Mendelian randomization (MR) to examine the
causality of well-established associations between nicotine, alcohol, caffeine and cannabis use.
MR was employed to estimate bidirectional causal effects between four addictive substances: nicotine (smoking initiation
and cigarettes smoked per day), caffeine (cups of coffee per day), alcohol (units per week) and cannabis (initiation). Based
on existing genome-wide association results we selected genetic variants associated with the exposure measure as an
instrument to estimate causal effects. Where possible we applied sensitivity analyses (MR-Egger and weighted median)
more robust to horizontal pleiotropy.
Most MR tests did not reveal causal associations. There was some weak
evidence for a causal positive effect of genetically instrumented alcohol use on smoking initiation and of cigarettes per
day on caffeine use, but these were not supported by the sensitivity analyses. There was also some suggestive evidence
for a positive effect of alcohol use on caffeine use (only with MR-Egger) and smoking initiation on cannabis initiation (only
with weighted median). None of the suggestive causal associations survived corrections for multiple testing.
Two-sample Mendelian randomization analyses found little evidence for causal relationships between nic-
otine, alcohol, caffeine and cannabis use.
Keywords Alcohol, caffeine, cannabis, causality, gateway, genes, Mendelian randomization, nicotine, pleiotropy.
Correspondence to: Karin J. H. Verweij, Behavioural Science Institute, Radboud University, Montessorilaan 3, 6525 HR Nijmegen, the Netherlands.
Submitted 24 July 2017; initial review completed 14 September 2017; ﬁnal version accepted 2 January 2018
*Joint ﬁrst authors
Epidemiological studies consistently show correlations
between use of nicotine, alcohol, caffeine and cannabis,
such that individuals who use one substance are more
likely to also use another (e.g. ). Two main mechanisms
may explain this co-occurrence: (1) a causal relationship
and (2) common liability. A causal relationship entails that
use of one drug increases the probability of use of others. A
prominent theory in line with a causal explanation is the
gateway hypothesis, posing that substance use progresses
in a stage-like sequence, in which use of legal substances
such as alcohol and tobacco is followed typically by use of
cannabis, which precedes the use of other (more
dangerous) illicit drugs [2–4]. However, the sequential
order of use is less clear in other cases; e.g. for the co-
occurrence of smoking and alcohol use or caffeine
consumption. Also, several studies have found evidence
supporting a reverse-gateway hypothesis (i.e. reverse cau-
sation) in which, for example, the use of cannabis or illicit
substances increases the use of nicotine or alcohol use
[5,6]. Hence, the gateway hypothesis cannot explain all ob-
served associations. Different mechanisms could underlie
causal relationships. They can be due to biological effects,
such as cross-sensitization and activation of the reward
system, or because the use of one substance inﬂuences
the metabolism or enhances the effect of another sub-
stance [7–12]. Also, social/environmental effects could
© 2018 Society for the Study of Addiction Addiction, 113,1333–1338