ESCALATION OF DRUG USE IN EARLY-ONSET CANNABIS USERS VS CO-TWIN CONTROLS

Context: Previous studies have reported that early initiation of cannabis
(marijuana) use is a significant risk factor for other drug use and
drug-related problems.

Objective: To examine whether the association between early cannabis use
and subsequent progression to use of other drugs and drug abuse/dependence
persists after controlling for genetic and shared environmental influences.

Design: Cross-sectional survey conducted in 1996-2000 among an Australian
national volunteer sample of 311 young adult (median age, 30 years)
monozygotic and dizygotic same-sex twin pairs discordant for early cannabis
use (before age 17 years).

Main Outcome Measures: Self-reported subsequent nonmedical use of
prescription sedatives, hallucinogens, cocaine/other stimulants, and
opioids; abuse or dependence on these drugs (including cannabis
abuse/dependence); and alcohol dependence.

Results: Individuals who used cannabis by age 17 years had odds of other
drug use, alcohol dependence, and drug abuse/dependence that were 2.1 to
5.2 times higher than those of their co-twin, who did not use cannabis
before age 17 years. Controlling for known risk factors (early-onset
alcohol or tobacco use, parental conflict/separation, childhood sexual
abuse, conduct disorder, major depression, and social anxiety) had only
negligible effects on these results. These associations did not differ
significantly between monozygotic and dizygotic twins.

Conclusions: Associations between early cannabis use and later drug use and
abuse/dependence cannot solely be explained by common predisposing genetic
or shared environmental factors. The association may arise from the effects
of the peer and social context within which cannabis is used and obtained.
In particular, early access to and use of cannabis may reduce perceived
barriers against the use of other illegal drugs and provide access to these
drugs.

Over the past decade there has been a steady increase both in the
prevalence of cannabis (marijuana) use among young people [1, 2] and
in the number of people entering treatment for cannabis-related
problems.[3] In 1999 there were 220,000 cannabis-related admissions to
publicly funded substance abuse treatment programs in the United
States.[3] This represented 14% of all such treatment admissions, with
admissions occurring primarily among youth: approximately a third of
all cannabis-related admissions were among people 12 to 17 years of
age and a further third were among those 18 to 25 years of age. These
increases in treatment seeking have been paralleled by heightened
concerns about the long-term consequences of chronic cannabis use[4,
5] and a recognition of the need for treatment and other interventions
to ameliorate the effects of drug dependence, which is best
characterized as a chronic, recurring condition.[6]

The majority of cannabis-related admissions among youth result from
referrals either from the justice or educational systems,[7] and it is
probable that at least some of these referrals were motivated more by
concern over the future consequences of early initiation to cannabis
use than by apparent negative effects of current cannabis use. A major
focus of concern is the extent to which early cannabis use may
increase the risks for escalation to other drug use and drug
dependence. Stage theory posits that there is an invariant sequence in
initiation and use of drugs, with use of cannabis preceding the use of
"hard" drugs such as cocaine and heroin.[8-10] This theory has been
highly influential in drug policy debates and has provided a major
rationale for sustaining prohibition against cannabis,[11] as it is
assumed that delaying or preventing early cannabis use may reduce
risks of other illicit drug use.

While this broad theory has found some empirical support,[8-10, 12-14]
such data on temporal sequencing do not establish that the use of one
drug causes the use of drugs higher up the sequence.[11, 14] Rather,
the observed pattern of initiation and use may reflect other factors
such as availability and access.[11] Nonetheless, several studies
using event history analysis[15] and regression analyses[16-19] have
reported that early initiation to cannabis use remains a significant
risk factor for both the use of other drugs and experiencing
drug-related problems.

We are unaware of any studies that have controlled for genetic
influences on the association between earlier initiation of cannabis
use and other drug use and drug-related problems. Nonetheless, one
viable hypothesis to explain this apparent association is that it
arises from the joint influence of genetic and/or shared environmental
factors on both risks of early initiation to cannabis use and,
independently of this, on increased risks of subsequent drug use and
dependence. This hypothesis is supported by evidence that cannabis and
other drug use and drug abuse/dependence are moderately to highly
heritable.[20-22]

The examination of other drug use and drug abuse/dependence in twin
pairs discordant for early cannabis use provides a powerful test of
the hypothesis that the association between early cannabis use and
later outcomes can be explained by common predisposing genetic and/or
shared environmental risk factors. Since these predisposing factors
are shared by twin pairs raised together, if the association between
early cannabis use and later drug use can be explained by shared
environmental factors, then in twin pairs discordant for early
cannabis use, individuals who do not initiate early cannabis use
should be at equal risk of developing drug-related problems as their
co-twin who initiates cannabis use early. If correlated genetic
effects explain these associations, then monozygotic pairs discordant
for early use should still have equal risks. In contrast, if the
association is causal or explained by environmental factors for which
twin pairs are discordant, we would expect to find higher rates of
other drug use and abuse/dependence in the early cannabis user than in
his or her co-twin. In this article, this issue is explored using data
from a large community sample of young adult Australian monozygotic
and dizygotic twins.

METHODS

Interviewees were members of the young adult cohort of the Australian
Twin Register, a volunteer twin panel born between 1964-1971.[20, 23,
24] The data presented in this report are derived from responses to a
single telephone interview during the period 1996-2000 when the median
age of the sample was 30 years (range, 24-36 years). Informed consent
was obtained from participants prior to administering the interviews,
as approved by the institutional review boards of Washington
University School of Medicine and the Queensland Institute of Medical
Research.

An overview of the study design is shown in Figure 1. Of 4010 pairs
that could be traced, interviews were completed with both members of
2765 pairs (69% pair-wise response rate) and 1 member of another 735
pairs (78% individual response rate). A total of 861 members of the
sample (13.7%) reported initiating cannabis use before age 17 years;
311 of these (36.1%) were from same-sex twin pairs in which their
co-twin had not used cannabis by age 17 years. The analyses in this
article are based on this subset of 622 same-sex twins from pairs
discordant for early cannabis use. There were 74 female and 62 male
monozygotic twin pairs and 84 female and 91 male same-sex dizygotic
twin pairs. Zygosity was determined on the basis of responses to
standard questions about physical similarity and confusion of the
twins by parents, teachers, and strangers, methods that have been
found to give better than 95% agreement with results of
genotyping.[25-28]

Assessments

A structured diagnostic interview designed for genetic studies on
alcoholism, the Semi-Structured Assessment for the Genetics of
Alcoholism,[29] was adapted for telephone use with an Australian
sample and updated for Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition (DSM-IV) diagnostic criteria.[30] The
interview also included assessments of sociodemographic factors,
childhood family environment, and experiencing childhood sexual
abuse.[23] These measures are described below.

Measures of Subsequent Drug Involvement

Lifetime Drug Use

Respondents were asked whether they had ever engaged in nonmedical use
of other drugs. In the analysis sample of 622 individuals from
same-sex pairs discordant for early cannabis use, the following
results were found: (1) sedative use (ie, benzodiazepines,
barbiturates) was reported by 12.7% of women and 14.8% of men; (2)
hallucinogen use was reported by 18.7% of women and 35.2% of men; (3)
cocaine or other stimulant use was reported by 32.4% of women and
42.4% of men; and (4) opioid use was reported by 6.7% of women and
13.5% of men.

Lifetime Drug Abuse/Dependence

Individuals reporting using cannabis, sedatives, cocaine/other
stimulants, or opioids on at least a monthly basis were asked
additional questions concerning the extent to which they may have
experienced symptoms of drug abuse (use in physically hazardous
situations; use interfering with major role obligations) or dependence
(using more frequently or for longer periods than intended; needing
larger amounts to achieve an effect [tolerance]; continued use despite
use causing emotional problems; recurrent desire to cut down on use).
Abuse was operationalized by endorsement of either abuse symptom;
dependence was operationalized by endorsement of 2 or more dependence
symptoms. While the dependence measure did not provide formal DSM-IV
criteria, previous analyses exploring the validity of these modified
criteria for cannabis dependence indicated that they had both
excellent sensitivity (96.7%) and specificity (94.6%) when compared
with DSM-IV criteria.20

Given the relatively low prevalence of drug abuse and dependence,
measures of abuse and dependence for each drug class were combined. We
assessed abuse/dependence for the following drug classes: (1)
cannabis; (2) sedatives (ie, benzodiazepines, barbiturates); (3)
cocaine/other stimulants; and (4) opioids. Additionally, these drug
classes were combined to form a measure of any drug abuse or
dependence. The prevalence of these outcomes is summarized separately
by sex in Table 1.

Lifetime Alcohol Dependence

Lifetime alcohol dependence was assessed using full DSM-IV30 criteria:
27.9% of women and 44.8% of men met criteria for alcohol dependence.

Family, Social, and Individual Factors

A number of family, social, and individual factors were included in
the analysis as control variables. These were selected on the basis of
a previous analysis with this sample that identified risk factors
associated with cannabis dependence.[20]

Psychiatric Disorders

Criteria for conduct disorder and major depression from the DSM-IV 30
were assessed using the modified Semi-Structured Assessment for the
Genetics of Alcoholism, and diagnoses were assigned by computer
algorithm. A nondiagnostic measure of social anxiety was also
defined.[23]

Early Tobacco Use

A measure of early tobacco use was constructed by classifying subjects
who reported smoking at least 1 day a week for a period of 3 weeks or
more before age 17 years as early tobacco users (36.6% of twins from
pairs discordant for early cannabis use reported such use).

Early Regular Alcohol Use

A measure of early alcohol use was constructed by classifying subjects
who reported that they started drinking alcohol at least once a month
for a period of 6 months or more before age 17 years as early regular
alcohol drinkers (11.6% of twins from pairs discordant for early
cannabis use reported such use).

Statistical Analyses

All statistical analyses were conducted using SAS31 and STATA.32 As an
initial test of heritability of onset of cannabis use, rates of
concordance for early (before age 17 years) cannabis use were compared
between monozygotic and dizygotic twin pairs. Differences in
concordance rates were tested using the Breslow-Day test of
heterogeneity of odds ratios (ORs), and separate tests were conducted
for males and females. Conditional logistic regression models were
then fitted to test for excess risk to early-onset cannabis users from
same-sex discordant pairs, compared with their co-twin controls. The
significance of the interactions between early cannabis use and both
twin pair zygosity and sex were tested and, as these were
nonsignificant (P).10 in all cases), data were pooled across zygosity
and sex. Analyses were repeated including the family and individual
control variables described above. Stepwise regression with backward
selection was conducted with the measure of early cannabis use forced
into the model. These analyses were used to estimate conditional ORs
for drug use and drug abuse/dependence in twins discordant for early
cannabis use with control for other significant predictors.

Power was estimated using computer simulation. For example, for
cocaine/stimulant abuse or dependence, we first obtained estimates of
the prevalence (pE = 12.5%, exposed twin; pU = 4.5%, unexposed
co-twin) and of the twin-pair tetrachoric correlation (r = 0.47). We
then estimated the minimum OR = pE(1 - pE)/pU(1 - pU), such that a
difference between the prevalence in the exposed twin and the
unexposed co-twin would be detected with 80% power given a sample of
311 twin pairs at the .01 significance level, with pU and r fixed at
their observed values. Our results indicate that power would be 80% or
better for an OR greater than 1.7 for 5 measures: hallucinogen use,
cocaine/stimulant use, cannabis abuse/dependence, any abuse or
dependence, and alcohol dependence. Power was over 80% for an OR
greater than 2.5 for the measures sedative use, opioid use, and
cocaine/stimulant abuse or dependence. Power was low under the
reasonable range of OR for the measures sedative abuse/dependence and
opioid abuse/dependence.

RESULTS

Rates of concordance for early cannabis use (before age 17 years)
among the full interview sample (2765 pairs; see Figure 1) were
significantly higher in monozygotic than dizygotic twin pairs for both
men (65 concordant and 88 discordant monozygotic pairs vs 59
concordant and 110 discordant dizygotic pairs, [chi] 21 = 7.92, P =
.005) and women (61 concordant and 98 discordant monozygotic pairs vs
44 concordant and 111 discordant dizygotic pairs, [chi] 21 = 7.80, P =
.005), indicating heritable influences on age of initiation of
cannabis use. The first 2 columns of Table 2 show estimates of the
lifetime prevalence of drug use and drug abuse/dependence for those
initiating cannabis use before age 17 years and for their co-twins
(who either reported no lifetime cannabis use or who reported
initiating cannabis use at age 17 years or older). The majority of
subjects reporting both cannabis and other illicit drug use reported
initiating cannabis use before initiating the use of other drugs.
Three individuals reported initiating sedative use before cannabis
use, 6 individuals initiated hallucinogen use, 5 initiated stimulant
use, and 3 initiated opioid use before the use of cannabis. These
individuals were excluded from the analyses. Table 2 also shows the
conditional ORs, both unadjusted and adjusted for major risk factors,
for the drug use outcomes. The results in Table 2 can be summarized as
follows:

1. Relative to their co-twins who had not used cannabis by age 17
years, those who had used cannabis by this age had elevated lifetime
rates of other drug use, illicit drug abuse/dependence, and alcohol
dependence.

2. The unadjusted conditional ORs indicated that in individuals who
initiated cannabis use before age 17 years, the odds of other drug
use, alcohol dependence, and other drug abuse/dependence were 2.1 to
5.2 times higher than in their co-twins who did not report early
cannabis use. In all but 1 comparison (sedative abuse/dependence),
these associations were statistically significant.

3. Controlling for known risk factors for later drug use and drug
abuse/dependence had only negligible effects. Specifically, after such
adjustment, relative to their discordant co-twins, those who had used
cannabis before age 17 years had significantly elevated rates of 9 of
the 10 outcomes. The nonsignificant association between early cannabis
use and sedative abuse/dependence is likely to be a reflection of
reduced statistical power due to the low base rate of this outcome.

The final column of Table 2 shows the significant or marginally
significant (P(.10) predictors of each outcome. While covariates
differed between equations, early regular use of tobacco and alcohol
emerged as the 2 factors most consistently associated with later
illicit drug use and abuse/ dependence. While early regular alcohol
use did not emerge as a significant independent predictor of alcohol
dependence, this finding should be treated with considerable caution,
as our study did not provide an optimal strategy for assessing the
effects of early alcohol use.

Analyses Restricted to Those Reporting Lifetime Cannabis
Use

Our analysis found that 24.8% of twins in pairs discordant for early
cannabis use in fact reported no lifetime cannabis use. To examine the
extent to which the associations in Table 2 may have been related to
risks associated with any cannabis use rather than early cannabis use,
these analyses were replicated with the sample restricted to those who
reported lifetime cannabis use (54 monozygotic female pairs, 53
monozygotic male pairs, 56 dizygotic female pairs, 71 dizygotic male
pairs). The results of these analyses, shown in Table 3, were broadly
consistent with the previous results. In particular, before adjustment
for covariates, early use remained a significant predictor of all but
1 of the outcomes (sedative abuse/dependence) among twin pairs
concordant for lifetime cannabis use but where 1 twin reported
initiation of cannabis use before age 17 years and the other did not.
After statistical control for measured risk factors, early use was not
a significant predictor of sedative abuse/dependence, and there was
only a marginally significant association (P = .06) between early
initiation of cannabis use and subsequent abuse/dependence on cannabis.

Subsidiary Analyses

Separate analyses of monozygotic- and dizygotic-discordant pairs were
conducted in which early cannabis use was defined as use before age 15
years, before age 16 years, and before age 18 years. The results of
these analyses confirmed the previous conclusions. For all definitions
of early cannabis use, individuals who initiated cannabis use at an
early age had elevated odds of later drug use and abuse/dependence
relative to their discordant co-twin.

COMMENT

The results of our co-twin control analyses indicated that early
initiation of cannabis use was associated with significantly increased
risks for other drug use and abuse/dependence and were consistent with
early cannabis use having a causal role as a risk factor for other
drug use and for any drug abuse or dependence. Individuals who used
cannabis before age 17 years had a 2.3- to 3.9-fold increase in odds
of other drug use and a 1.6- to 6.0-fold increase in odds of alcohol
dependence and other drug abuse/dependence, relative to their co-twin
who had not used cannabis by age 17 years, regardless of whether or
not the pair were monozygotic. Alternatively, there may be unmeasured
environmental influences not shared by members of a twin pair that
increase risks both of early cannabis use and of other drug use or
abuse/dependence. We consider this less plausible, since twin pairs,
having been reared in the same household, would be expected to be
highly concordant for environmental experiences. Unmeasured family
background risk factors or heritable risk factors cannot explain the
observed association, since twin pairs will share the same family
background, and monozygotic pairs the same genetic risk factors.

Potential limitations of this study include the reliance on
self-report and retrospective data, and the lack of data about ages at
progression to more frequent use or onset of problems. Age of first
use was obtained earlier in our interview than the assessment of drug
use problems to minimize recall biases; and the associations with
early cannabis use that we observed in this twin pair sample have
previously been reported in prospective studies.[16-19] An association
due to underreporting of drug use by 1 twin seems implausible, since
cannabis use, even by self-report, was highly prevalent and some use
at least would be considered normative for this birth cohort in
Australia, and since significant associations remained when analyses
were limited to pairs concordant for lifetime cannabis use. It is also
unlikely that we are observing only delayed onset of other drug use or
drug abuse/dependence, rather than lower lifetime rates in the
co-twins, since the median age of the sample (30 years) is
considerably higher than typical ages of onset of drug use and drug
abuse/dependence.[33] For example, more than 95% of cannabis users in
our total sample reported onset of marijuana use by age 24 years, the
youngest age represented in the sample. Our estimates of the lifetime
use of cannabis and other drugs are high but are consistent with those
reported by other large-scale epidemiological surveys of drug use in
Australia.[34] Further, a recent study of cannabis use in a US
national twin sample concluded that twin studies of substance use are
unlikely to be biased and that findings from such studies can be
generalized to other (nontwin) family relationships.[35] The relative
crudeness of our measure of exposure (any use before age 17 years as
opposed to frequent, heavy, or problem use) makes the findings of an
association even more remarkable.

If the association with early cannabis use is indeed causal, the
mechanisms by which this association arises remain unclear.
Pharmacological mechanisms might be hypothesized in which it is
assumed that exposure to cannabis induces subtle biochemical changes
that encourage drug-taking behavior.[36] This hypothesis is supported
to some extent by recent findings that [Delta] 9-tetrahydrocannabinol
and heroin have similar effects on dopamine transmission through a
common u1opioid receptor mechanism[37] and that chronic treatment with
[Delta] 9-tetrahydrocannabinol induces cross-tolerance to
amphetamine[38] and opioids[38, 39] in rats. However, an argument
against such biological hypotheses is that the levels of cannabis use
at the beginning of drug-using careers are substantially lower than
the equivalents used in laboratory-based research and perhaps too low
to induce long-term biochemical changes.

Other mechanisms that might mediate a causal association between early
cannabis use and subsequent drug use and drug abuse/dependence include
the following:

1. Initial experiences with cannabis, which are frequently rated as
pleasurable,[40] may encourage continued use of cannabis and also
broader experimentation.

2. Seemingly safe early experiences with cannabis may reduce the
perceived risk of, and therefore barriers to, the use of other drugs.
For example, as the vast majority of those who use cannabis do not
experience any legal consequences of their use, such use may act to
diminish the strength of legal sanctions against the use of all drugs.

3. Alternatively, experience with and subsequent access to cannabis
use may provide individuals with access to other drugs as they come
into contact with drug dealers.[41] This argument provided a strong
impetus for the Netherlands to effectively decriminalize cannabis use
in an attempt to separate cannabis from the hard drug market.12 This
strategy may have been partially successful as rates of cocaine use
among those who have used cannabis are lower in the Netherlands than
in the United States.[42]

While the findings of this study indicate that early cannabis use is
associated with increased risks of progression to other illicit drug
use and drug abuse/dependence, it is not possible to draw strong
causal conclusions solely on the basis of the associations shown in
this study. Further research in other cultures and using a range of
innovative research designs (including evaluation of prevention
efforts aimed at delaying the onset of cannabis use) is needed to
explore whether there is a causal link between early cannabis use and
progression to other drug use and, if so, to elucidate the mechanisms
that may underlie any such causal association.

Regardless of the mechanisms underlying these associations, it is
apparent that young people who initiate cannabis use at an early age
are at heightened risk for progressing to other drug use and drug
abuse/dependence. In addition to cannabis dependence, the health risks
associated with chronic cannabis use may include chronic bronchitis,
impaired lung function, and increased risks of cancers of the
aerodigestive tract.[4] Given historical increases in the use of
cannabis and other drugs,[1, 2] it is probable that more individuals
will experience these adverse consequences and there will be an
increasing need to develop strategies both to prevent and to
ameliorate the adverse consequences of chronic drug use. Given that
early initiation of use may be associated with increased risks both
for progressing to the use of other drugs and for developing drug
abuse/dependence, there is a need for greater physician awareness of
those risks associated with early use. There is also a need to develop
focused interventions to prevent escalation to use of other drugs
among young people identified as being at risk due to their early
initiation of cannabis use.

Author/Article Information

Author Affiliations: Queensland Institute of Medical Research, Brisbane,
Queensland, Australia (Drs Lynskey and Martin and Ms Statham); Missouri
Alcoholism Research Center and Department of Psychiatry, Washington
University School of Medicine, St Louis (Drs Lynskey, Heath, Bucholz,
Madden, and Nelson); and Missouri Alcoholism Research Center and Department
of Psychology, University of Missouri, Columbia (Dr Slutske).

Corresponding Author and Reprints: Michael T. Lynskey, PhD, Missouri
Alcoholism Research Center, Department of Psychiatry, Washington University
School of Medicine, 40 N Kingshighway, Suite One, St Louis, MO 63108
(e-mail: mlynskey@matlock.wustl.edu).

Author Contributions: Study concept and design: Heath, Martin.

Acquisition of data: Heath, Bucholz, Slutske, Madden, Statham,
Martin.

Analysis and interpretation of data: Lynskey, Heath, Nelson,
Slutske.

Drafting of the manuscript: Lynskey, Heath.

Critical revision of the manuscript for important intellectual
content: Bucholz, Slutske, Madden, Nelson, Statham, Martin.

Statistical expertise: Lynskey, Heath, Martin.

Obtained funding: Heath, Martin.

Administrative, technical, or material support: Heath, Slutske,
Statham, Martin.

Study supervision: Heath, Madden.

Funding/Support: This work was supported by National Institutes of Health
grants AA07728, AA09022, AA10249, AA11998 (Dr Heath), AA 12640, DA 14363,
DA 14632 (Dr Bucholz), DA00272, DA12854 (Dr Madden), and AA00277 (Dr
Nelson), as well as grants 951023 and 981351 from the National Health and
Medical Research Council (Dr Martin).

Acknowledgment: We thank the Australian Twin Registry and the twins
themselves for participating in this research.

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