Development and Consequences of Cannabis Dependence

Article (PDF Available)inThe Journal of Clinical Pharmacology 42(11 Suppl):28S-33S · November 2002with189 Reads
DOI: 10.1002/j.1552-4604.2002.tb06000.x · Source: PubMed
The past 10 to 15 years of clinical and basic research have produced strong evidence demonstrating that cannabis can and does produce dependence. Clinical and epidemiological studies indicate that cannabis dependence is a relatively common phenomenon associated with significant psychosocial impairment. Basic research has identified a neurobiological system specific to the actions of cannabinoids. Human and nonhuman studies have demonstrated a valid withdrawal syndrome that is relatively common among heavy marijuana users. Last, clinical trials evaluating treatments for cannabis dependence suggest that this disorder, like other substance dependence disorders, is responsive to intervention, yet the majority of patients have difficulty achieving and maintaining abstinence. Of concern, treatment seeking for marijuana dependence has increased almost twofold over the past 10 years. This report briefly reviews selected research literature relevant to our current understanding of cannabis dependence, its associated consequences, and treatment efficacy.
Development and Consequences
of Cannabis Dependence
Alan J. Budney, PhD, and Brent A. Moore, PhD
he question of whether individuals become de-
pendent on marijuana has fueled much contro-
versy. For many years, the scientific community had
been reluctant to acknowledge the dependence poten-
tial of cannabis because certain types of experimental
findings were lacking. Until recently, attempts to dem-
onstrate that nonhuman animals would self-administer
cannabis (THC) in the laboratory were unsuccessful,
which contrasted with that observed with most other
drugs commonly abused by humans.
Second, early
studies of cannabis (THC) withdrawal failed to reveal a
syndrome that included reliable and substantial physi
cal symptoms such as those observed during classic
opioid, sedative, or alcohol withdrawal.
This lack of
evidence for physiological dependence, combined
with a poor understanding of the neurobiology of the
effects of cannabis, cast further uncertainty regarding
its dependence potential. Last, a paucity of clinical
data on cannabis dependence occasioned several com
mon beliefs that minimized its significance. Such be
liefs included the following: the prevalence of cannabis
dependence is very low, it exists only in the context of
polydrug dependence, it is not associated with sub
stantial functional impairment, and treatment is not
necessary because users can quit easily on their own.
In contrast, the past 10 to 15 years of clinical and ba-
sic research have produced strong evidence demon-
strating that cannabis can and does produce depend-
ence. Clinical and epidemiological studies indicate
that cannabis dependence is a relatively common phe-
nomenon associated with significant psychosocial
impairment. Basic research has identified a
neurobiological system specific to the actions of
cannabinoids. Human and nonhuman studies have
demonstrated a valid withdrawal syndrome that is rel
atively common among heavy marijuana users. Last,
clinical trials evaluating treatments for cannabis de
pendence suggest that this disorder , like other substance
dependence disorders, is responsive to intervention,
yet the majority of patients have difficulty achieving
and maintaining abstinence. Below, we briefly review
selected research literature relevant to our current un
derstanding of cannabis dependence and its associated
The fourth edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV) and the ICD-10
Classification of Mental and Behavioural Disorders
consider cannabis dependence a reliable and valid psy
J Clin Pharmacol 2002;42:28S-33S
From the Departments of Psychiatry and Psychology, University of Vermont.
Supported by NIDA grants DA12471, DA12157, and T32-DA07242. Ad
dress for reprints: Alan J. Budney, PhD, Associate Professor of Psychiatry
and Psychology, University of Vermont, Suite 12, 54 West Twin Oaks Ter
race, South Burlington, VT 05403.
DOI: 10.1177/0091270002238791
The past 10 to 15 years of clinical and basic research have
produced strong evidence demonstrating that cannabis can
and does produce dependence. Clinical and epidemiological
studies indicate that cannabis dependence is a relatively
common phenomenon associated with significant
psychosocial impairment. Basic research has identified a
neurobiological system specific to the actions of cannabinoids.
Human and nonhuman studies have demonstrated a valid
withdrawal syndrome that is relatively common among
heavy marijuana users. Last, clinical trials evaluating treat
ments for cannabis dependence suggest that this disorder,
like other substance dependence disorders, is responsive to
intervention, yet the majority of patients have difficulty
achieving and maintaining abstinence. Of concern, treat
ment seeking for marijuana dependence has increased al
most twofold over the past 10 years. This report briefly re
views selected research literature relevant to our current
understanding of cannabis dependence, its associated con
sequences, and treatment efficacy.
Journal of Clinical Pharmacology, 2002;42:28S-33S
chiatric disorder , suggesting that individuals in the
general population experience cannabis dependence
in much the same way as they experience other sub
stance dependence disorders.
By definition, a diag
nosis of substance dependence indicates that an indi
vidual is experiencing a cluster of cognitive, behavioral,
or physiological symptoms associated with substance
use yet continues to use the substance regularly. Epide
miological studies indicate that the lifetime prevalence
of cannabis dependence approximates 4% of the U.S.
population, the highest of any illicit drug.
This high
rate of cannabis dependence is clearly affected by the
greater overall prevalence of marijuana use compared
to the use of other illicit drugs of abuse. Rates of condi
tional dependence—that is, the risk of developing de
pendence among those who have used the drug—pro
vide a better indicator of dependence potential. In this
regard, cannabis has a substantial, albeit lower, rate of
conditional dependence (9%) than substances such as
alcohol (15%), cocaine (17%), heroin (23%), or tobacco
More frequent use results in greater risk of de
pendence. For example, rates of cannabis dependence
are estimated at 20% to 30% among those who have
used at least five times, and even higher estimates
(35%-40%) are reported among those who report near
daily use.
Those who develop cannabis dependence willingly
seek treatment for problems related to their use. For ex-
ample, Stephens and colleagues
reported that more
than 350 adults sought treatment during a 3-month pe-
riod in response to newspaper advertisements offering
assessment and treatment for persons concerned about
their marijuana use. The majority of those patients
were not currently abusing other substances, and most
reported multiple signs of dependence. Such treatment-
seeking patterns and profiles have been replicated in
other U.S. and Australian studies.
National trends
gleaned from the Treatment Episode Data Set
that the number of adults and adolescents who seek
and enroll in treatment for marijuana-related problems
is not small and has been increasing during the past de
cade. Indeed, the demand for treatment for marijuana-
related problems at state-approved substance abuse
programs doubled between 1992 and 1996 across the
United States, such that the percentage of illicit drug
abuse treatment admissions for marijuana (23%) ap
proximated that for cocaine (27%) and heroin (23%).
Similar increases in rates of treatment seeking for can
nabis problems during the 1990s have been reported in
Interestingly, treatment admissions for in
dividuals younger than age 20 comprise about 45% of
all admissions.
Also, approximately 50% of indi
viduals seeking treatment for cannabis-related prob
lems have some involvement with the criminal justice
The severity and specificity of the problems among
adults seeking treatment for marijuana-related prob
lems have been well documented. The great majority of
these patients have been using marijuana for more than
10 years, use marijuana on a daily basis, use multiple
times per day, and clearly meet DSM dependence crite
They exhibit substantial psychosocial impair
ment and psychiatric distress, report multiple adverse
consequences, report repeated unsuccessful attempts
to stop using, and perceive themselves as unable to
quit. The most common consequences mentioned are
procrastination, bad/guilty feelings, low productivity,
low self-confidence, interpersonal/family problems,
memory problems, and financial difficulties. A study
directly comparing marijuana- with cocaine-dependent
outpatients demonstrated that the two groups exhib
ited similar types of problems, but the marijuana abuser s
generally showed a less severe dependence syndrome.
Both groups met multiple DSM-III-R dependence crite-
ria, although the cocaine group reported a significantly
greater number of criteria (7.7 vs. 6.3). The groups did
not differ on the Medical, Legal, Family/Social, or Psy-
chiatric severity scales of the Addiction Severity Index,
but the cocaine group scored higher on the Employ-
ment severity scale. The cocaine group also scored
higher on the Drug and Alcohol severity scales, reflect-
ing greater polydrug abuse in the cocaine treatment
population. Both groups showed clinically significant
elevations on standardized psychiatric symptom
scales, but few between-groups differences were ob-
served. Sociodemographics such as marital status, in
come, and employment status also did not differ.
Although marijuana-dependent outpatients do not
typically experience the acute crises or dramatic conse
quences that many times drive alcohol-, cocaine-, or
heroin-dependent individuals into treatment, they
clearly show psychosocial impairment that warrants
clinical attention. In summary, evidence for a cannabis
dependence disorder is strong and indicative of a dis
order of substantial severity.
Evidence of a withdrawal syndrome has generally been
deemed a classic marker of the dependence potential of
a substance. In the 1970s, nonhuman studies of cessa
tion following chronic THC administration provided
evidence of a withdrawal response, but the effects were
not consistent and were deemed mild compared with
other substances such as opiates and sedatives.
studies with humans in residential laboratories also
found evidence of withdrawal.
Common symptoms
included decreased appetite, irritability, restlessness,
sleep difficulties, and uncooperativeness. These effects
were characterized as mild, transient, and without seri
ous medical complications and thus were considered
clinically insignificant when compared to the dramatic
medical and physiological symptoms associated with
severe opiate, sedative, or alcohol withdrawal. Hence,
investigation of cannabis withdrawal waned during
the 1980s.
The discovery of a cannabinoid receptor
and the
synthesis of a cannabinoid antagonist
renewed scien
tific interest in cannabis withdrawal. These advances
provided a better neurobiological understanding of the
drug’s mechanism of action and a means for conduct
ing antagonist challenge studies to test for cannabinoid
withdrawal. As reviewed elsewhere in this issue, such
studies have demonstrated a marked, precipitated
withdrawal syndrome in rats and dogs.
Recent stud-
ies on withdrawal in humans have also appeared in the
literature. Two placebo-controlled inpatient studies,
using moderate doses of oral THC and smoked mari-
juana, demonstrated withdrawal effects that included
anxiety, decreased contentment and food intake, de-
pressed mood, irritability, restlessness, sleep difficulty,
and stomach pain.
Controlled outpatient studies
have since provided data on the reliability, validity,
timecourse, and clinical significance of cannabis with-
drawal. One study examining 3-day abstinence periods
in heavy daily marijuana smokers validated specific ef-
fects of marijuana abstinence and showed they were re
liable and of clinically significant magnitude.
cifically, decreased appetite, sleep difficulty, strange
dreams, aggression, anger, irritability, restlessness,
craving for marijuana, and weight loss were docu
mented during marijuana abstinence periods. A sec
ond outpatient study documented withdrawal during a
28-day period of abstinence in a similar population of
daily marijuana smokers.
Symptoms similar to those
reported in earlier studies remained elevated for at
least 7 to 14 days, as did Hamilton Depression and
Anxiety scale scores. Last, findings from a recent study
examining a 45-day marijuana abstinence period indi
cate that cannabis abstinence symptoms in heavy mari
juana users are of clinically significant magnitude and
follow a timecourse similar to that of other types of sub
stance withdrawal.
Clinical population studies of cannabis withdrawal
have been consistent with results observed in the labo
ratory, providing further support for a syndrome of
clinical significance. The majority of adolescents in
residential treatment and adults in outpatient treat
ment for cannabis dependence report histories of mari
juana withdrawal with symptom profiles similar to
those observed in the laboratory studies.
For ex
ample, we administered a 4-point (none, mild, moder
ate, and severe), 22-item Marijuana W ithdrawal Symp
tom Checklist to cannabis-dependent outpatients
enrolled in a treatment research clinic and found that
85% reported at least four abstinence symptoms.
most frequently reported symptoms were cravings
(95%), irritability (86%), nervousness (79%), de
pressed mood (74%), restlessness (74%), sleep diffi
culty (71%), and anger (71%). For many, these symp
toms were substantial, as 47% rated four or more
symptoms in the severe category. Thus, most cannabis-
dependent patients seeking treatment perceive and ex
pect that they will experience withdrawal symptoms
when they stop smoking.
Many of the symptoms of the cannabis withdrawal
syndrome overlap with those of other withdrawal syn-
dromes and perhaps most resemble those observed
with nicotine withdrawal.
Studies examining
neurochemical responses in animals following expo-
sure to and withdrawal from cannabinoids have ob-
served reductions in mesolimbic dopamine transmis-
sion and elevations in extracellular-releasing factor
concentrations in the limbic system that closely resem-
ble the responses seen with other major drugs of
The behavioral consequences of these
neurobiological changes are consistent with the type of
negative affective symptoms reported by patients with-
drawing from cannabis and other substances and may
be primary contributing factors to the development and
maintenance of drug dependence. In summary, recent
research on cannabis withdrawal furthers the argu
ment that cannabis dependence is more similar to other
well-recognized types of substance dependence than
was previously believed.
The first randomized controlled trial evaluating treat
ment for adult cannabis dependence did not appear in
the literature until 1994.
Three additional random
ized trials have now been published.
Results across
studies indicate that the same types of psychosocial
treatments found effective for other substance depend
ence disorders are effective for cannabis dependence.
Coping-skills training, relapse prevention, and motiva
tional enhancement therapies have demonstrated effi
cacy compared to delayed treatment controls.
tingency management interventions that provide
positive reinforcement contingent on abstinence from
cannabis, documented by urinalysis testing, can en
J Clin Pharmacol 2002;42:28S-33S
hance treatment outcomes when integrated with other
effective therapies.
Similar types of interventions
have demonstrated efficacy in clinical trials for alco
hol, cocaine, and opiate dependence.
The aforementioned study comparing characteris
tics of marijuana- and cocaine-dependent outpatients
found that the marijuana patients were more ambiva
lent and less confident about stopping their marijuana
use than the cocaine group was about stopping use of
cocaine. These observations suggest that marijuana us
ers might have at least as much difficulty as cocaine pa
tients in initiating abstinence in treatment settings. In
deed, the magnitude of treatment response observed
across the marijuana trials appears similar to that
achieved with treatments for other substance de
pendence disorders. Only the minority (20%-40%)
of cannabis-dependent patients achieve abstinence
during treatment, although more show clinically sig
nificant reductions in marijuana use and associated
In comparison, a recent study of an effec-
tive treatment for cocaine dependence (community re
inforcement therapy plus contingency management)
reported similar abstinence rates.
40% of the cocaine patients who received this inter-
vention, as well as 20% of those receiving community
reinforcement therapy without contingent reinforce-
ment, were abstinent at the end of treatment. Similarly,
in a large multisite study on treatments for alcohol de-
pendence (Project Match), approximately 20% to 25%
of outpatients who received behavioral coping-skills
therapy or motivational enhancement therapy were ab-
stinent at the end of treatment.
Rates of relapse among
cannabis-dependent patients also appear similar to
other substances. A substantial proportion (approxi-
mately 30%) of individuals who achieve 2 or more
weeks of abstinence relapse to pretreatment levels of
use during the 6 months following treatment.
Of course, cross-study comparisons of treatment
outcome pose many methodological problems; none
theless, the cursory comparison provided here suggests
that the treatment response of cannabis-dependent out
patients is similar to that observed with other sub
stances of abuse. Clearly, like other substance depend
encies, cannabis dependence is not easily treated, and
there appears to be ample room for enhancement of
Recent advances indicate that dependence develops
to cannabis in much the same way as with other drugs.
As with other abused substances, many individuals
use cannabis without significant consequence, but oth
ers misuse, abuse, or become dependent and
experience adverse outcomes. Substantial impairment
in psychosocial functioning occurs with cannabis de
pendence, although in general such effects appear less
severe than those associated with alcohol, heroin, or
cocaine dependence. Nonetheless, substantial num
bers of individuals seek treatment for cannabis de
pendence, and the effectiveness of such treatments ap
pears similar in magnitude to that observed with
treatments for other drug dependencies.
Future clinical research efforts might focus on the
development of more potent psychosocial interven
tions, testing of pharmacotherapies, and combined ap
proaches. For example, marijuana abusers may benefit
from treatment approaches that seek to reduce drug use
by systematically applying natural or contrived conse
quences (i.e., contingency management) to enhance
and sustain efforts to quit using.
Such approaches
may be particularly beneficial in this population be-
cause their motivation to change appears to be lower
and more variable than other types of drug abusers, per-
haps because the acute consequences of cannabis de-
pendence are not as severe. Combining effective
psychosocial treatments offers another method that
may enhance treatment effectiveness. Behavior ther-
apy, motivational enhancement therapy, and contin-
gency management can be easily integrated and tested
in controlled trials; indeed, initial evaluations of such
efforts have shown promise.
Although youth younger than age 20 account for al-
most half the treatment admissions for marijuana de-
pendence, no randomized controlled trials specifically
for adolescent marijuana dependence have been pub
lished. A recent multisite study has been completed,
and preliminary findings are consistent with those re
ported with adults.
Behaviorally based treatments ap
pear effective, but the magnitude of treatment response
leaves much room for improvement. Additional con
trolled trials are needed in this area. Moreover , crimi
nal justice system involvement prompts a substantial
proportion of treatment admissions for cannabis de
pendence, particularly in young adults and adoles
cents, yet clinical approaches that systematically inte
grate the judicial system into the treatment process
have yet to be tested.
Pharmacotherapies for cannabis dependence have
not been evaluated. Now that the validity and severity
of cannabis dependence disorder have been estab
lished, a neurobiological cannabinoid system has been
identified, and the treatment response achieved with
effective psychosocial therapies has identified many
nonresponders, the exploration of potential medica
tions for cannabis dependence is warranted. The iden
tification of the cannabinoid receptor (CB1), which has
a central role in mediating the psychoactive effects of
marijuana, creates new opportunities for the develop
ment of agonist or antagonist therapies. The use of
medications to alleviate withdrawal symptoms will
likely prove useful in treatment efforts. Moreover , as
with nicotine and alcohol dependence, the identifica
tion of compounds that affect mood or craving may also
show efficacy for treating cannabis dependence.
Last, many marijuana abusers may avoid seeking
treatment because of ambivalence about the seriousness
of their problem. Efforts directed at this non-treatment-
seeking population could create opportunities to pro
vide services that reduce problematic marijuana use.
One such intervention, the Marijuana Check-Up, is cur
rently under investigation and has shown promise.
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    • "van der Pol). to target the prevention and treatment specifically at frequent users at a high risk of dependence. The distinction between non-dependent and dependent frequent use is important, because dependent users, by definition , experience significant psychosocial impairments related to reduced control over their cannabis use, whereas other frequent users do not develop such drug-related problems (Budney and Moore, 2002; Looby and Earleywine, 2007; Temple et al., 2011). This distinction is especially important since cannabis use per se is regarded to be relatively harmless (Nutt et al., 2010; Van Amsterdam et al., 2010). "
    [Show abstract] [Hide abstract] ABSTRACT: Aims: To examine the course and the predictors of the persistence of cannabis dependence. Methods: Through cannabis outlets and chain referral, a prospective enriched community cohort of 207 young adults (aged 18-30) with DSM-IV cannabis dependence at baseline (T0) was formed and followed-up after 1.5 (T1) and 3 (T2) years. The presence of cannabis dependence, cannabis-related problems, functional impairment and treatment was assessed using the Composite International Diagnostic Interview (CIDI 3.0) and the Sheehan Disability Scale (SDS). Predictors of persistence were lifetime cannabis abuse and dependence symptoms, cannabis use characteristics, distant vulnerability factors (e.g. childhood adversity, family history of psychological/substance use problems, impulsivity, mental disorders), and proximal stress factors (recent life events, social support). Results: Four groups were distinguished: persistent dependent (DDD: 28.0%), stable non-persistent (DNN: 40.6%), late non-persistent (DDN: 17.9%) and recurrent dependent (DND: 13.5%). At T2, persisters (DDD) reported significantly more (heavy) cannabis use and cannabis problems than non-persisters (DNN/DDN/DND). Treatment seeking for cannabis-related problems was rare, even among persisters (15.5%). The number (OR = 1.23 (1.03-1.48)) and type ('role impairment' OR = 2.85 (1.11-7.31), 'use despite problems' OR = 2.34 (1.15-4.76)) of lifetime cannabis abuse/dependence symptoms were the only independent predictors of persistence with a total explained variance of 8.8%. Conclusions: Persistence of cannabis dependence in the community is low, difficult to predict, and associated with a negative outcome. The substantial proportion of stable non-persisters suggests that screening and monitoring or low-threshold brief interventions may suffice for many non-treatment-seeking cannabis-dependent people. However, those with many lifetime abuse/dependence symptoms may benefit from more intensive interventions. © 2015 S. Karger AG, Basel.
    Full-text · Article · May 2015
    • "This link between cannabis use and maladaptive emotional responses with poor coping skills may explain the high number of violent convictions in our cohort of indigenous males who initiated cannabis use at a younger age than reported by others (Copeland et al., 2006; Hall, 2001). The dose–response effect of cannabis use and dependence (high SDS) indicates tolerance and although this has been reported by others (Budney & Moore, 2002; Coffey et al., 2002), our cohort report extremely high rates of use even when compared with other indigenous populations internationally (Adlaf et al., 2005; Fergusson & Boden, 2008; Ministry of Health, 2007; Putt & Delahunty, 2006). Others report greater cannabis dependence identified in youth the younger they were when first in contact with law enforcement, indicating movement towards an established pattern of criminal behaviour (Copeland, 2006; Hall, 2001; Ross, 2007). "
    [Show abstract] [Hide abstract] ABSTRACT: Background: No studies have investigated cannabis withdrawal in indigenous or incarcerated populations, and there is currently no standard treatment for cannabis withdrawal in Australian prisons. Aims: This cross sectional survey examines cannabis use, dependence and involuntary (abrupt cessation) withdrawal in incarcerated indigenous males for the purpose of improving clinical management. Methods: 101 consenting inmates (18–40 years) from an Australian correction centre were interviewed. Demographic characteristics, lifetime cannabis use (LCU), severity of dependence, cannabis withdrawal symptoms, psychological well-being and alcohol use were measured and compared using univariate and multivariate analyses. Results: Cannabis withdrawal symptoms were reported in 57% of current cannabis users compared with 16% of non-users (p < 0.01), indicating detectable cannabis dependence and withdrawal in a unique indigenous inmate population. Multivariate analysis revealed statistically significant associations between LCU and cannabis dependence (OR = 8.1; 95% CI: 2.2–29.1) when controlling for psychological well-being and alcohol consumption. Conclusions: Upon admission to a correction centre, cannabis users should be assessed and monitored for physical and psychological symptoms of withdrawal. Implications: Routine cannabis withdrawal monitoring will maximise staff and inmate safety. This improvement to policy will ensure appropriate risk management of staff and inmates.
    Full-text · Article · Aug 2014
    • "Participants with positive self-reported cannabis, alcohol, caffeine and cigarette, and/or breath alcohol levels > 0.000 were excluded from the MRI session. Immediately prior to their scan, participants completed a Marijuana Craving Questionnaire (MCQ; Heishman et al., 2001) as well as the Marijuana Withdrawal Checklist (MWC; Budney and Moore, 2002; Budney et al., 2003). MRI images were collected using a 3T Siemens Trio whole body scanner equipped with Sonata gradient subsystem (40 mT/m amplitude, 200 s rise time, 100% duty cycle) with a 12-channel coil combined with body coil transmission to achieve greater sensitivity in cortical areas. "
    [Show abstract] [Hide abstract] ABSTRACT: Background Emergent studies show that similar to other substances of abuse, cue-reactivity to cannabis is also associated with neural response in the brain's reward pathway (Filbey et al., 2009). However, the inter-relatedness of brain regions during cue-reactivity in cannabis users remains unknown Methods In this study, we conducted a series of investigations to determine functional connectivity during cue-reactivity in 71 cannabis users. First, we used psychophysiological interaction (PPI) analysis to examine coherent neural response to cannabis cues. Second, we evaluated whether these patterns of network functional connectivity differentiated dependent and non-dependent users. Finally, as an exploratory analysis, we determined the directionality of these connections via Granger connectivity analyses Results PPI analyses showed reward network functional connectivity with the nucleus accumbens (NAc) seed region during cue exposure. Between-group contrasts found differential effects of dependence status. Dependent users (N = 31) had greater functional connectivity with amygdala and anterior cingulate gyrus (ACG) seeds while the non-dependent users (N = 24) had greater functional connectivity with the NAc, orbitofrontal cortex (OFC) and hippocampus seeds. Granger analyses showed that hippocampal and ACG activation preceded neural response in reward areas Conclusions Both PPI and Granger analyses demonstrated strong functional coherence in reward regions during exposure to cannabis cues in current cannabis users. Functional connectivity (but not regional activation) in the reward network differentiated dependent from non-dependent cannabis users. Our findings suggest that repeated cannabis exposure causes observable changes in functional connectivity in the reward network and should be considered in intervention strategies.
    Full-text · Article · Jul 2014
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