Illicit drug use and abuse/dependence: Modeling of two-stage variables using the CCC approach
Drug use and abuse/dependence are stages of a complex drug habit. Most genetically informative models that are fit to twin data examine drug use and abuse/dependence independent of each other. This poses an interesting question: for a multistage process, how can we partition the factors influencing each stage specifically from the factors that are common to both stages? We used a causal-common-contingent (CCC) model to partition the common and specific influences on drug use and abuse/dependence. Data on use and abuse/dependence of cannabis, cocaine, sedatives, stimulants and any illicit drug was obtained from male and female twin pairs. CCC models were tested individually for each sex and in a sex-equal model. Our results suggest that there is evidence for additive genetic, shared environmental and unique environmental influences that are common to illicit drug use and abuse/dependence. Furthermore, we found substantial evidence for factors that were specific to abuse/dependence. Finally, sexes could be equated for all illicit drugs. The findings of this study emphasize the need for models that can partition the sources of individual differences into common and stage-specific influences.
Illicit drug use and abuse/dependence:
modeling of two-stage variables using the CCC approach
, M.C. Neale
, K.C. Jacobson
, K.S. Kendler
Department of Human Genetics, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia
Commonwealth University, Box# 980003 Suite 1-154, Richmond, VA 23298-0003, United States
Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University,
Department of Psychiatry, United States
Drug use and abuse/dependence are stages of a complex drug habit. Most genetically
informative models that are fit to twin data examine drug use and abuse/dependence independent
of each other. This poses an interesting question: for a mul tistage process, how can we partition the
factors influencing each stage specifically from the factors that are common to both stages? We
used a causal-common-contingent (CCC) model to partition the common and specific influences on
drug use and abuse/dependence. Data on use and abuse/dependence of cannabis, cocaine, sedatives,
stimulants and any illicit drug was obtained from male and female twin pairs. CCC models were
tested individually for each sex and in a sex-equal model. Our results suggest that there is evidence
for additive geneti c, shared environmental and unique environmental influences that are common to
illicit drug use and abuse/dependence. Furthermore, we found substantial evidence for factors that
were specific to abuse/dependence. Finally, sexes could be equated for all illicit drugs. The
findings of this study emphasize the need for models that can partition the sources of individual
differences into common and stage-specific influences.
D 2004 Elsevier Ltd. All rights reserved.
Keywords: Illicit drugs; Use; Abuse; Dependence; Twin
0306-4603/$ - see front matter D 2004 Elsevier Ltd. All rights reserved.
* Corresponding author. Tel.: +1 804 828 8157; fax: +1 804 828 1471.
E-mail address: arpana
email@example.com (A. Agrawal).
Addictive Behaviors 30 (2005) 1043 –1048
Illicit drug use is moderately heritable (26–40% due to genetic factors or A) with
evidence for the role of shared environmental (environment shared by members of a
twin pair or C) and individual-specific environmental factors (E). Abuse/dependence of
illicit drugs is highly heritable (28–79% due to A) with the remainder of the variance
due to individual-specific environmental influences (Kendler, Karkowski, Neale, &
Prescott, 2000; Kendler, Karkowski, Corey, Prescott, & Neale, 1999; Tsuang, Bar,
Harley, & Lyons, 2001; van den Bree, Johnson, Neale, & Pickens et al., 1998).
However, drug involvement is a two-stage process where drug use (the so-called
bupstreamQ variable), in certain cases, is followed by the clinically diagnosed stage of
abuse/dependence (the bdownstreamQ variable). This contingent nature (use must precede
abuse/dependence) was not considered in previous univariate models. The causal-
common-contingent (CCC) model is an improvement over the standard independent
assessments of drug use and abuse/dependence (Kendler, Neale, & Sullivan et al., 1999).
The model allows for partitioning of genetic and environmental factors common to drug
use and abuse/dependence from the factors that are unique to abuse/dependence. Using
the CCC model, in the present study we sought to examine the role of common and
specific additive genetic (A), shared environmental (C) and unique environmental (E)
factors on the two stages (use and abuse/dependence) of cannabis, cocaine, sedatives,
stimulants and any illicit drug involvement and test for the presence of quantitative
This study utilized drug use and abuse/dependence information from 1191 (702 MZ
and 489 DZ pairs) male and 934 (556 MZ and 378 DZ pairs) female same-sex
monozygotic (MZ) and dizygotic (DZ) Caucasian twin pairs from the Virginia Adult
Twin Study of Psychiatric and Substance Use Disorders (VATSPSUD), a longitudinal
study based on participants from the Virginia Twin Registry (now a part of the Mid-
Atlantic Twin Registry). The most recent and complete waves of interview were used for
these analyses. Detailed descriptions for data collection are available elsewhere (Kendler,
Karkowski, & Corey et al., 1999; Kendler et al., 2000).
Use, abuse and dependence were assessed using an adaptation of the Structured
Clinical Interview for DSM-IIIR-Patient Version (American Psychiatric Association, 1994;
Spitzer, Williams, & Gibbon, 1987). Use and abuse/dependence were coded as binary
A. Agrawal et al. / Addictive Behaviors 30 (2005) 1043–10481044
2.3. Twin modeling
All model fitting was performed using the structural equation modeling software Mx
(Neale, 1990). The common-causal-contingent (CCC) model was fit, individually, for
cannabis, cocaine, sedatives, stimulants and any illicit drug. Thresholds were adjusted by age
of the participant at the time of the interview. Quantitative sex differences were tested by
equating all parameters, except thresholds, across sexes. The relative fit of the sex difference
model was tested using the Akaike’s Information Criterion (AIC), which is an index of fit and
parsimony (Akaike, 1987; Williams, 1994).
Mean age of the female twins was 35.8 years (range 21–62 years) at the fourth wave of
interviews with a mean education level of 14.3 years. The male twin pairs had a mean age of
35.5 years (range 20–58 years) and a mean education level of 13.6 years at the second wave
of interviews. Standardized parameter estimates for each illicit drug are presented in Table 1,
separately for males and females. For all the illicit drugs, except sedatives, a
0.48 and 0.73, c
ranges between 0.13 and 0.28 and e
ranges between 0.11and 0.17. This
estimate of unique environment includes measurement error that is partitioned during
) and ranges from 0.03 to 0.11. However, for cocaine and sedatives, the results in
the females only are similar to those for the other illicit drugs. Estimates could be equated
Drug use and abuse/dependence should be modeled as a two-stage process. Previous
studies have typically modeled use and abuse/dependence, individually, without considering
the contingent relationship between them. Two previous studies used data from the same data
set to assess use and abuse/dependence with the CCC approach. In this study, we sought to
obtain the best estimates of additive genetic, shared environmental and unique environmental
factors on illicit drug use and abuse/dependence using the CCC model in both sexes. Our
results suggest that a moderate proportion of the genetic, shared and unique environmental
factors that influence abuse/dependence are common to the first stage of drug use. The
estimate of the common-causal-contingent pathway b bQ was su bstantial (0.59–0.86).
However, we also found evidence for genetic and unique environmental factors that were
specific to abuse/dependence.
The limitations of this study include shortcomings of an exclusively Caucasian sample
and the biases associated with retrospective reporting of information. We were also
restricted by low prevalence of other illicit drugs, such as hallucinogens and opiates and
could not test these within the CCC framework. Notwithstanding these limitations, the
findings of the current study have four significant implications. First, we observe a
A. Agrawal et al. / Addictive Behaviors 30 (2005) 1043–1048 1045
Standardized variance component estimates for each sex and the sex-equal model for the CCC model
Drug Sex a
Any illicit drug
Male 0.54 0.25 0.21 0.67 0.46 0.00 0.54 0.11
Female 0.61 0.24 0.15 0.93 0.34 0.00 0.66 0.33
Sex Equal 0.61
Male 0.56 0.26 0.18 0.91 0.31 0.00 0.69 0.29
Female 0.56 0.28 0.16 0.78 0.36 0.00 0.64 0.23
Sex Equal 0.55
Male 0.88 0.00 0.12 0.67 0.00 0.28 0.72 0.26
Female 0.52 0.35 0.12 0.81 0.35 0.00 0.65 0.28
Sex Equal 0.73
0.13 [0.02–0.48] 0.14
Male 0.70 0.00 0.30 0.68 0.08 0.00 0.92 0.15
Female 0.59 0.00 0.41 0.39 0.38 0.00 0.62 0.00
Sex Equal 0.85
Male 0.54 0.19 0.27 0.50 0.53 0.00 0.47 0.05
Female 0.38 0.20 0.42 1.00 0.00 0.99 0.01 0.07
Sex Equal 0.48
The percentages noted in the first column refer to prevalence of use and abuse/dependence (AD) in our sample, where use and AD was more prevalent in
male twins, in all cases. a
refer to the influence of genetic, shared and unique environmental factors on the upstream use variable, respectively. a
refer to the influence of genetic, shared and unique environmental factors on the downstream abuse/dependence variable, respectively. The path
bbQ transmits the influence of A
on the downstream abuse/dependence variable. bkQ refers the unsquared estimate of measurement error that does
not influence the downstream variables. A diagrammatic representation of the CCC model along with a detailed discussion are available in other publications
(Kendler, Karkowski, & Corey et al., 1999; Kendler, Karkowski, & Neale et al., 1999).
A. Agrawal et al. / Addictive Behaviors 30 (2005) 1043–10481046
significant overlap of latent risk factors that influence illicit drug use and abuse/dependence
suggesting that a proportion of the total variance in the downstream (abuse/dependence)
variable is due to genetic and environmental factors that are common to both stages of drug
involvement. Second, we find support for genetic and environmental factors that are
specific to abuse/dependence. These may include genes that influence neurotransmitter
systems that are modified due to drug abuse. Furthermore, drug toxicity may lead to
changes to the functioning of binding proteins, metabolism and other cellular activity
(Kauer, 2003; Tanda, Pontieri, & Di Chara, 1997). Third, the present analyses indicate a
consistency of outcomes across several categories of drugs suggesting that pharmacolog-
ically and behaviorally different illicit drugs are influenced to the same extent by genetic
and environmental risk factors. Finally, we were able to equate the magnitude of genetic,
shared and environmental influences on illicit drug use and abuse/dependence across males
and females. Therefore, we cannot reject the equality of estimates of genetic, shared and
unique environmental factors that were common and specific to illicit drug use and abuse/
dependence across sexes.
This work was supported by NIH grants MH-40828, MH/AA/DA-49492, AA-09095 and
DA-11287. We acknowledge the contribution of the Virginia Twin Registry, now part of the
Mid-Atlantic Twin Registry (MATR), for ascertainment of subjects for this study. The MATR,
directed by Dr. J Silberg, L Corey and L. Eaves, has received support from the National
Institutes of Health, the Carman Trust and the WM Keck, John Templeton and Robert Wood
Akaike, H. (1987). Factor analysis and AIC. Psychometrika, 52, 317 –322.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders. Washington,
DC7 American Psychiatric Association.
Kauer, J. A. (2003). Addictive drugs and stress trigger a common change at VTA synapses. Neuron, 37,
Kendler, K. S., Karkowski, L. M., Corey, L. A., Prescott, C. A., & Neale, M. C. (1999). Genetic and
environmental risk factors in the aetiology of illicit drug initiation and subsequent misuse in women. British
Journal of Psychiatry, 175, 351–356.
Kendler, K. S., Karkowski, L. M., Neale, M. C., & Prescott, C. A. (2000). Illicit psychoactive substance use,
heavy use, abuse, and dependence in a US population-based sample of male twins. Archives of General
Psychiatry, 57, 261 –269.
Kendler, K. S., Neale, M. C., Sullivan, P., Corey, L. A., Gardner, C. O., & Prescott, C. A. (1999). A population-
based twin study in women of smoking initiation and nicotine dependence. Psychologie in der Medizin, 29,
Neale, M. C. (1990). Statistical Modeling with Mx. Dept.of Psychiatry, Box # 980710, Richmond VA 23298.
Spitzer, R. L., Williams, J. B., & Gibbon, J. (1987). Structured clinical interview for DSM-III-R: Patient version
(SCID-P). New York7 New York State Psychiatric Institute.
A. Agrawal et al. / Addictive Behaviors 30 (2005) 1043–1048 1047
Tanda, G., Pontieri, F. E., & Di Chiara, G. (1997). Cannabinoid and heroin activation of mesolimbic dopamine
transmission by a common mu1 opioid receptor mechanism. Science, 276, 2048 –2050.
Tsuang, M. T., Bar, J. L., Harley, R. M., & Lyons, M. J. (2001). The Harvard twin study of substance abuse: What
we have learned. Harvard Review of Psychiatry, 9(6), 267– 279.
van den Bree, M. B., Johnson, E. O., Neale, M. C., & Pickens, R. W. (1998). Genetic and environmental
influences on drug use and abuse/dependence in male and female twins. Drug and Alcohol Dependence, 52,
Williams, L. J. H. P. J. (1994). Parsimony-based fit indices for multiple-indicator models: Do they work?
Structural Equation Modeling, 1, 161 –189.
A. Agrawal et al. / Addictive Behaviors 30 (2005) 1043–10481048