Drug and Alcohol Dependence: College on problems of drug dependence meeting, Puerto Rico (June 1996)

Marijuana use and dependence
Alan J. Budneya*, Denise B. Kandelb Don R. Cherekc, Billy R. Martind, Robert S. Stephense Roger Roffmanf

aUniversity of Vermont. Department of Psychiatry, I S. Prospect St., Burlington, VT 05401. USA
bCollege of Physicians and Surgeons of Columbia University, Department of Psychiatry, 722 W. 168th St., Box 20. New York, NY 10032, USA
cUniversity Texas -Houston, Health Science Center, UTMSI, 1300 Moursund St., Houston, TX 77030. USA
dMedical College 'of Virginia - Virginia Commonwealth Universitv, MC V Station, Box 980613, ichmond, VA 23298-0613, USA
eVirginia Polytechnic Institute and State Universitv, Department of Psychology, Blacksburg, VA 24061-0436. USA
fUniversitv of Washington. School of Social Work, JH-30, Seattle. WA 98195, USA
Received 26 December 1996; accepted 4 January 1997

Abstract

Discoveries concerning an endogenous cannabinoid system and observations of dramatic increases in marijuana use among youth in the United States have fueled a recent increase in basic and clinical research to better understand and treat marijuana dependence. At the annual meeting of the College on Problems of Drug Dependence (Puerto Rico, 1996) a symposium 'Marijuana Use: Basic Mechanisms. Epidemiology, and Clinical Issues' reviewed a number of important areas of ongoing research that address marijuana dependence. Overviews and original research were presented regarding the development of dependence (preclinical and clinical research), motivational effects (laboratory models), the epidemiology of dependence and its development, clinical management of marijuana use among patients seeking treatment for other drugs of abuse, and treatment for adult marijuana dependence. This paper summarizes the symposium presentations and provides discussion of recent scientific developments concerning marijuana use and dependence, 1997 Elsevier Science Ireland Ltd.

Keywords: Marijuana use; Cannabinoid; Dependence

1. Introduction

Marijuana has been the most widely used illicit drug over the past 30 years. The Epidemiological Catchment Area and National Comorbidity Studies conducted in the early 1980s and in 1992-1993, respectively, converge on an estimated lifetime prevalence rate of a DSM-diagnosis of marijuana dependence that exceeds 4% among the United States population (Anthony and Helzer, 1991; Anthony et at., 1994). This rate of dependence is the highest among any illicit drug in the general population, probably because the prevalence of marijuana use itself is the highest of any illicit drug, as noted above. However, rates of dependence calculated among users, rather than in the total population, provide more accurate estimates of dependence liability free of differences in baseline rates of use. The National Comorbidity Study found that 9.2 of those who reported any lifetime use of marijuana developed dependence (Anthony et al., 1994). A recent review of findings from Australia concluded that approximately 9% of those who have ever used marijuana will qualify for a lifetime diagnosis of marijuana dependence, and that the risk of developing dependence may be as high among those who have used marijuana more than a few times (Hall et al. 1994). Similarly, as reported in this paper below, for the years 1991-1993 in the United States, 7.4% of adults 18 and older who used marijuana within the last year met criteria for last-year marijuana dependence: twice as many (14.4%) adolescents 12-17 years old did so. While this conditional dependence rate was slightly higher for marijuana than for cocaine among adolescents, it was much lower relative to cocaine among adults (Chen et al., in press).

Despite such high rates of dependence, there had been relatively little scientific attention focused on marijuana's addictive potential or on clinical issues concerning misuse, abuse, or dependence (Budney et al., 1992). Two recent events, however, have fueled a renewed interest in the clinical issues concerning marijuana use. First, recent discoveries concerning the existence of an endogenous, cannabinoid system have uncovered a biological basis for tolerance to and dependence on marijuana. Second, the Monitoring the Future Survey, an annual national survey of high school students, has revealed large increases in the initiation and prevalence of marijuana use among teens, and young adults over the past 4 years (Johnson et al., 1996). Such increased use followed a 10-year period of steady decline in the prevalence of marijuana use among these same groups. This increase in marijuana use has been accompanied by a parallel decrease in the perceived risk of harm associated with the use of marijuana. Both the National Institute on Drug Abuse and the Center for Substance Abuse Treatment have responded to these observations by calling for more research on basic and clinical issues regarding marijuana use and abuse.

The purpose of the symposium, to be reviewed here and which was presented at the College on Problems of Drug Dependence annual meeting in June 1996, was to provide a broad overview of recent research addressing marijuana as a drug of abuse. The title of the symposium was 'Marijuana Use: Basic Mechanisms, Epidemiology, and Clinical Issues'. The participants provided overviews and original research that addressed issues of dependence, motivational effects, epidemiology of dependence, and clinical management of marijuana use or abuse. In particular, the symposium addressed: (a) preclinical research on the endogenous cannabinoid system as it relates to issues of tolerance and dependence: (b) laboratorv research concerning the effects of marijuana use on motivation and work behavior: (c) epidemiological research on the development of marijuana dependence: (d) clinical research on marijuana use among other drug-dependent populations: and (e) treatment outcome research on marijuana dependence.

2. Preclinical research on dependence

Billy Martin began the symposium with a review of preclinical findings addressing the biological basis for the development of tolerance and dependence. In particular, he reviewed evidence that clearly demonstrated the existence of a functional endogenous cannabinoid system in the central nervous system. There is now general consensus that most of the centrally mediated effects of cannabinoids can be attributed to a specific cannabinoid receptor located in the brain. Although cannabinoids produce a unique pharmacological profile and are very potent, evidence for a receptor mechanism emerged slowly. The first indication of a receptor arose from indirect evidence demonstrating enantioselectivity for many of THC's effects (Edery et al., 1972: Little et al., 1989: Martin et al., 1981). Direct evidence for the receptor did not emerge until Devane et al. (1988) demonstrated that a potent synthetic cannabinoid derivative, [3]H-CP 55940 (Fig. 1), bound with extremely high affinity to a single site in brain. This receptor appears to be responsible for most centrally mediated effects of cannabinoids (Compton et al., 1993). Moreover, a similar pattern of distribution is conserved in several species, and the receptor appears to be primarily located in neurons (Herkenham et al., 1991 a.b. 1990). A major breakthrough occurred when the rat cannabinoid receptor was cloned (Matsuda et al., 1990). The brain receptor was referred to as CB, following the identification of a distinct peripheral cannabinoid receptor, designated CB1, in macrophages in the marginal zone of the spleen (Monro et al., 1993). Despite intensive efforts by numerous laboratories, the only receptor subtype found in brain is a splice variant of the CB mRNA (Shire et al., 1995).

Prior to the characterization of the cannabinoid binding site, Hewlett's laboratory demonstrated that cannabinoids inhibited adenylyl cyclase by interaction with a G1 protein (Devane et al., 1988: Hewlett and Fleming, 1984). Childers' group reported that cannabinoid receptor activation resulted in increased binding of the radio labeled non-hydrolyzable GTP analog GTPyS thereby providing a functional measure for the receptor (Selley et al., 1996). Moreover, the distribution of GTPyS binding throughout brain mimicked that of [3H] CP 55940, a potent cannabinoid analog. However, Childers and Deadwyler (1996) pointed out in a recent review that cAMP is not likely to be the sole effector system for cannabinoids.

The discovery of the cannabinoid receptor and the identification of second messenger systems raised the possibility of an endogenous ligand. Efforts in Mechoulam's laboratory resulted in the isolation of anandamide , an ethanolamide derivative of arachiclonic acid (Devane et al, 1992). Despite the apparent dissimilarities between the structures of THC and this eicosanoid derivative, this endogenous substance competed for cannabinoid receptor binding and, like THC, inhibited electrically stimulated contractions in the murine vas deferens. Anandamide produced similar pharmacological effects to THC, such as antinociception, catalepsy, hypomotility, hypothermia (Fride and Mechoulam.,1993: Smith et al., 1994), THC-like properties in rat drug discrimination (Wiley et al., 1995a), and inhibition of adenylyl cyclase (Feeder et al., 1993) and N-type calcium channels (Mackie et al., 1993). Although the exact mechanism of synthesis and metabolism of anandamide has not been resolved, there is ample evidence that biochemical mechanisms exist in brain to carry out these functions (Cadas et al., 1996: Deutsch and Chin, 1993: Devane and Axelrod, 1994, Di Matzo et al., 1994, Kruszka and Gross, 1994).

The recent discovery of a cannabinoid antagonist fulfilled a critical void in marijuana research. Rinaldi-Carmona et al.(1994) discovered a compound which had high affinity for the CB receptor and antagonized cannabinoid-induced inhibition of adenylyl cyclase and smooth muscle contractions. This compound SR 141716A, is now being used extensively by many laboratories. It antagonizes cannabinoid drug discrimination in rats (Wiley et al., 1995b), THC’s ability to depress spontaneous activity, lower body temperature, produce antinociception and catalepsy in mice (Compton et al., 1996) and CP 55940's disruptive effect on the 8-arm radial maze (Lichtman et al. 1995: Lichtman and Martin, 1996).

There has always been considerable interest in the development of tolerance and dependence to cannabinoids. Tolerance readily develops to most pharmacological effects of cannabinoids (Fan et al., 1994). Chronic CP 55940 treatment results in receptor down-regulation similar to that reported by others (Oviedo et al., 1993) and there is a concomitant enhancement of CB1 mRNA levels in the cerebellum (Fan et al., 1996). Presently, it is not known whether similar effects occur throughout the brain or whether there is a cause-effect relationship between these two observations. There is already evidence that development of tolerance attenuates GTPyS binding throughout rat brain (Sim et al., in press). Of course, it is also likely that effector systems other than adenylyl cyclase are involved in cannabinoid pharmacological effects and that they are affected by development of tolerance.

The development of dependence to cannabinoids has been controversial. Although there are a number of patients who seek medical treatment for cannabis dependence each year, the symptoms of cannabis dependence in the general population have not been clearly defined. One of the most definitive demonstrations of dependence to THC was conducted by Jones and Benowitz (1976) who described a mild to moderate physical withdrawal syndrome in subjects following abrupt withdrawal from daily administration of D9THC for more than 2 weeks. Short-term abstinence from heavy marijuana use is associated with subtle effects on attention and information processing (Pope and Yurgelun-Todd, 1996. Solowij et al., 1995), but it is unclear as to whether these effects are the result of withdrawal, residual effects of the drug, or neurotoxic effects of prolonged exposure. There have also been several attempts to develop animal models of dependence. Efforts to chronically treat animals with THC and then observe withdrawal signs upon termination of treatment have resulted in either no observable signs or signs that are not readily reproduced by other laboratories. In one of the earliest reports, Kaymakcalan (1972, 1973) reported that rats and monkeys chronically administered THC produced overt behavioral signs upon termination of treatment. Beardsley et al. (1986) demonstrated that discontinuation of chronic administration of D9THC in rhesus monkeys disrupted conditioned responding that was restored upon readministration of D9-THC. One of the major impediments in the unequivocal characterization of a cannabinoid withdrawal syndrome in laboratory animals has been the lack of a specific antagonist. The recent development of the cannabinold antagonist provided a means for a withdrawal model by challenging rats treated chronically with D9-THC with SR 141716A. A marked withdrawal syndrome ensued (Aceto et al.,1996). Two key features were wet-dog shakes and facial rubbing. Similar results were also reported by another laboratory (Tsou et al.,1995). The availability of a functional experimental model and a selective cannabinoid antagonist provide a means for the systematic study of the effect of chronic exposure to cannabinoids. An important element of these studies is that precipitation of a cannabinoid withdrawal syndrome validates earlier clinical studies in which signs of withdrawal were demonstrated in humans under controlled laboratory conditions. Now that antagonist-precipitated dependence has been established for cannabinoids, the present challenge is to extrapolate these findings to marijuana abuse in humans. It should be borne in mind that dose, frequency of use and duration of exposure are critical determinants regarding the severity of dependence to any drug. The THC treatment regimens used in the cited studies were indeed rigorous and would most closely mimic chronic, heavy use of marijuana.

Based upon the discoveries over the past decade, one can postulate that a cannabinoid neurochemical system does exist. The function of this system and its interaction with other neurochemical systems remain unclear. Future research must answer numerous questions in order to advance our understanding of its physiology and neurochemistry in the brain. Why does such a system exist? What is its physiological role? What would be the physical manifestations of an imbalance in this system? We do know that tolerance and dependence develop following chronic exposure to cannabinoids. These findings provide new opportunities for assessing the consequences of chronic use of marijuana by humans.

 

3. Effects on motivation

Don Cherek's presentation addressed the possible direct effects of marijuana smoking on human motivation. Marijuana use, particularly among adolescents, has been reported to result in apathy, decreased productivity, and a lack of ability to carry out long term goals (McGlothlin, 1968). These behavioral changes following marijuana smoking have been collectively referred to as the 'motivational syndrome'. Despite numerous reports of this syndrome by clinicians, equivocal results have been observed among laboratory and in-field studies that have examined such effects of marijuana smoking.

Mendelson and Mello, in two different studies, found no evidence for motivational effects of marijuana smoking among residential participants performing a simple button pressing response for monetary rewards (Mello and Mendelson, 1985: Mendelson et al., 1976). In contrast, Miles et al., (1974) reported that the availability of marijuana resulted in diminished work activity among male volunteers in a residential setting. Fulton and colleagues reported results from a series of residential laboratory studies. Some of the studies produced results consistent with an motivational interpretation of marijuana's effects, while others found no evidence for such an effect (Fulton and Fishman, 1988: Fulton et al., 1989, 1990 A.B.). Foltin concluded that situational factors determined whether or not one would observe amotivational effects of marijuana.

Dr. Cherek's laboratory research extends this work by examining other conditions under which marijuana may affect motivation. He described an interesting laboratory model developed by his group for the purpose of operationalizing the construct of motivation. The procedures used to measure motivation were based on a behavior analytic model in this protocol, the index of motivation was sensitivity to changes in reinforcer magnitude. Human participants were given the opportunity to earn points exchangeable for money either by pushing a button on a progressive-ratio schedule or by not responding and receiving points on a fixed-time schedule. Thus, participants had the opportunity to work for money on a progressive ratio schedule or to quit working but obtain less money for not working on a time schedule. During each experimental session, participants began in the progressive-ratio schedule. Participants had the option of switching to the fixed-time schedule by emitting ten responses on an appropriate button. Using these schedule contingencies, they examined the effects of smoking placebo or three potencies of marijuana cigarettes on the total number of responses, the response rate in the progressive ratio component, and the number of points earned and time spent in the progressive-ratio and fixed-time components.

Marijuana smoking produced a potency related decrease in the amount of work participants performed and the amount of time they chose to work. These effects could be partially reversed by increases in the magnitude of the monetary reward. That is, a reduction in responding to the progressive-ratio component and earlier escape to the fixed-time response independent point presentation were observed in response to marijuana smoking. These effects were diminished by increasing the point value.

The results from this study are consistent with an interpretation of acute marijuana smoking producing 'motivational' effects in these smokers. Such an effect is consistent with some prior studies, but not others (Fulton et al., 1989, 1990a; Mello and Mendelson, 1985, Mendelson et al., 1976; Miles et al., 1974). The Miles et al. (1974), study, in particular, showed similar results in that the availability and smoking of marijuana produced decreased time spent working and increased time spent in passive entertainment and resting. Some possible reasons for contrasting findings among-laboratory studies were discussed. For example, participant characteristics may influence the effects of marijuana smoking on behavior. Of note, the participants in the present study were less educated and smoked less frequently than those in previous studies. Dr. Cherek highlighted the potential impact of participant characteristics by describing observations of an additional participant who had just completed law school. This participant displayed quite different results

from those included in the study: (1) under baseline conditions this participant worked throughout the entire session, never switching to the nonwork condition and (2) marijuana smoking had no effect on this partic-

ipant’s working. Thus, motivational effects may depend critically upon individual smoking the marijuana. Future research is needed to replicate and determine under what conditions and in which individuals marijuana smoking produces motivational effects.

4. Epidemiology of dependence

In the presentation, Denise Kandel advanced the idea that progress in understanding the phenomenology of substance use and dependence will come from an integration of different research traditions in the epidemiology of drug behavior. In particular, such an integration will involve research on substance dependence, which emphasizes functional impairment to the neglect of patterns of use, and research on substance use in the general population, which usually ignores dependence or abuse criteria. Ongoing work on marijuana use and marijuana dependence that bridges these two research traditions was presented. Five issues were addressed: (1) what are the periods of active marijuana use from adolescence to adulthood; (2) what is the prevalence of last year marijuana dependence; (3) how does the prevalence of marijuana dependence vary by age and gender, (4) what is the relationship between intensity of marijuana use and dependence; and (5) what aspects of marijuana consumption account for general and age specific differences in rates of marijuana dependence.

The research was based on two samples: a longitudinal cohort followed for close to 20 years, the New York State Cohort, and three aggregated waves (1991-1993) of the National Household Survey on Drug Abuse (NHSDA). The longitudinal New York State Cohort provided data on the natural history of marijuana use (Chen and Kandel, 1995; Kandel and Raveis, 1989). The cohort consists of 1160 adults aged 34-35, who have been followed for 19 years since ages 15-16. The cohort is representative of adolescents formerly enrolled in grades 10 and 11 in public secondary schools in New York State in 1971-72. The National Household Survey on Drug Abuse (NHSDA) provided data on substance dependence (Chen et al., in press: Chen et al., unpublished). The NHSDA is a national annual survey of drug use patterns in the general population aged 12 and older in the United States (Substance Abuse and Mental Health Services Administration, 1996). The universe for the NHSDA sample is the civilian non-institutionalized population of the United States, which represents over 98% of the total US population. Persons living in non-institutional group quarters, such as homeless shelters, rooming houses and college dormitories, are included. Youths (12-34 years old) and minorities are oversampled. Analyses were conducted on three aggregated (1991-93) NHSDA surveys (n=87915). Data on self-reported symptoms of dependence, frequency and quantity of use, and drug-related problems experienced within the last 12 months were used to approximate each of the seven DSM-IV criteria underlying substance-use disorders. As per the DSM-IV specifications, an individual was defined as being dependent on marijuana within the last year if he or she met three out of the seven approximate indicators for DSM4V diagnostic criteria for each drug.

Findings showed that marijuana use peaks at ages 19-23 among male and female marijuana uses. Rates of last year dependence are much higher in adolescence than males dependent on marijuana, although this difference is not statistically significant. By contrast, among adults, the rates are significantly higher among male than female users up to age of 50.

Both frequency and quality of use are linearly associated with the probability of being dependent of marijuana. The associations vary significantly by age but not by gender. Adolescents become dependent at a lower threshold than adults: the differences between adolescents and adults increase as intensity of use increases. In multivariate logistic analyses, both frequency and quantity of use retain a unique effect on marijuana dependence, although frequency appears to be more important than quantity in predicting dependence after controlling for other covariates.

Differences in extensiveness of use and in the relationships between extensiveness of use and dependence may explain the different rates of dependence observed among subgroups of marijuana users. Intensity of marijuana use (indexed by frequency and or quantity of use) could be important in several ways. Groups that have higher rates of dependence (1) may be using marijuana more heavily: (2) they may be more sensitive to the effects of marijuana at the same intensity of use: or (3) both processes could be involved. Groups that have similar rates of dependence may be using at different levels of intensity but be differentially responsive to similar doses.

Thus, different groups may experience different liability for dependence at the same levels of use. Dr Kandel's work showed that adolescents are more dependent than adults on marijuana because they experience symptoms of dependence at a lower threshold of use than adults. Although adult males become dependent at a lower threshold than females, adult females experience lower dependence rates than adult males because they use at lower frequency and quantity than males.

These results provide insight into the processes underlying the age and gender differentials observed in the prevalence of marijuana dependence. Once having used marijuana, adolescents appear to experience higher

rates of dependence than adults, not because they use marijuana more frequently than adults. In fact, adolescent males use marijuana less frequently than adult males. Adolescents experience higher rates of dependence than adults because they appear to be more sensitive than adults to the effects of marijuana. At the same levels of frequency (or quantity) of use adolescents experience higher rates of dependence than adults because the threshold at which they first become dependent is lower than for adults. Given increasing intensity of use, the relative rate of increase is the same irrespective of age.

The implications of the findings for the epidemiological study of marijuana use and dependence were discussed. Besides their implications for policy, these results emphasize the mutual relevance of epidemiology and biology for understanding addiction. In particular, this research illustrates how epidemiological studies suggest new hypotheses to be tested in the laboratory. The findings on gender and age differences in the relationships between extent of marijuana use and dependence provide new insights and help frame new questions for research into the biological bases of drug dependence and addiction. At present, epidemiological and biological investigations by and large are carried out independently of each other. Yet, much is to be gained by a closer interchange and collaboration between the two disciplines. The relevance of biology for the epidemiology of substance use disorders is obvious. Biological factors, and not only social and psychological factors, underlie the natural history of drug use and the causes and consequences of using drugs. What is less obvious are the contributions that epidemiology can make in providing novel insights into the biology of addiction and in suggesting new hypotheses to be pursued and tested in the laboratory. As a professional association, the College on Problems of Drug Dependence provides the sort of cross-disciplinary interchanges that can foster the scientific developments that Dr. Kandel is advocating.

5. Marijuana use in other drug-dependent populations

Alan Budney presented data on clinical issues related to marijuana as a secondary drug of abuse. Most cocaine- and opiate-dependent individuals who seek treatment are polydrug abusers. The secondary illicit drug used most frequently in these clinical populations is marijuana. Estimates of the prevalence of marijuana use have ranged from 25% to 80% among cocaine and opiate abusers (Ball et al., 1988: Budney et al., 1996: Miller et al., 1990: Nirenberiz et al., 1996: Saxon et al., 1993). Unfortunately, little research has been conducted on this topic. More scientific information is needed to determine how to most effectively address marijuana use among cocaine- and opioid-dependent patients. Dr Budney presented data from five studies relevant to this issue.

Study 1 examined the relation between marijuana use and sociodemographic, psychosocial, and drug-use variables in treatment-seeking cocaine abusers (Budney et al., 1996). Marijuana involvement was associated with more frequent and earlier initiation of cocaine use, more alcohol, opioid and cigarette use, earning less income, less stable relationship status, more severe legal problems, and more physical and mental health symptoms. Regression analyses that controlled for differences in substance use indicated that the greater psychosocial and health impairments observed among marijuana users were not a function of their greater use of other substances. Although many indicators of problem severity did not differ between marijuana-use groups, the type of impairments associated with marijuana use in this study were consistent with findings from prior general population and clinical studies of marijuana users (Halikas et al., 1983: Kandel, 1984: Stephens et al., 1993). These findings indicate that cocaine abusers who smoke marijuana enter treatment more severely impaired and with more severe and longer histories of substance use than nonusers.

Study 2 examined the relation between marijuana use and sociodemographic, psychosocial, and drug-use variables in treatment-seeking opiate abusers. The results were similar to those observed among cocaine abusers in

Study 1, although fewer and less robust differences between marijuana users and nonusers were observed. Marijuana involvement was associated with less stable relationships, more frequent alcohol use, more financial difficulty, and engagement in more risky behavior including intravenous drug use and needle-sharing. Thus, marijuana use among both cocaine- and opioid-dependent persons is associated with increased psychosocial impairment, health problems, and drug-use severity. Whether such impairment and risk factors have prognostic significance or require additional treatment services remains to be determined.

The third study addressed the notion that polydrug abusing patients perceptions of problem severity and goals for change are likely to differ across the drugs they use. In this ongoing study, cocaine and opioid abusers who also smoked marijuana were administered two University of Rhode Island Change Assessments (URICA: McConnaughy et al.,1983), one modified to assess readiness to change cocaine or opioid use and the other marijuana use. Preliminary results showed differences for primary drug versus marijuana on all four, stages of change scale scores. Precontemplation scores were higher for marijuana than cocaine or opioids; while contemplation, action, and maintenance scores were significantly lower for marijuana than for cocaine or opioids. The majority of clients scored highest on precontemplation for marijuana and highest on action for cocaine or oploids. These findings empirically support the common clinical observation that many cocaine and opioid abusers who use marijuana enter treatment at different levels of readiness for change concerning each of these drugs. They further suggest that optimal treatments for polydrug users should be flexible regarding goals for abstinence across drugs and that different clinical interventions may be necessary to effectively address each drug used by polydrug abusers.

Study 4 examined the effects of marijuana use on outcome among treatment-seeking cocaine-dependent individuals (Budney et al., 1996). Retrospective comparisons between marijuana users and non-users and marijuana users who were and were not dependent were conducted. Participants received a 24-week, outpatient behavioral treatment that consisted of the Community Reinforcement Approach and contingency-management procedures (Higgins et al., 1994). Findings revealed no adverse relations between marijuana use and any of the outcome measures (i.e. cocaine abstinence, Addiction Severity Index composite scores). These results were consistent with a prior study in this group's clinic which demonstrated that regular marijuana use did not interfere with cocaine abstinence during or following treatment in two patients who abused both substances (Budney et al., 1991). Thus, marijuana and cocaine use may be independent of each other at least among some subset of drug abusers (Bickel et al., 1995).

Study 5 examined the effects of marijuana use on treatment outcome among opioid-dependent abusers. Similar to Study 4, retrospective comparisons between marijuana users and non-users were conducted. Participants were involved in one of three clinical trials examining the efficacy of buprenorphine detoxification combined with behavioral therapies. Preliminary findings indicated that marijuana use was not associated with treatment outcome (i.e. opioid, cocaine or benzodiazepine abstinence). Such functional independence between marijuana and opioid use has been previously reported in methadone-maintenance treatment participants (Nirenberg et al., 1996; Saxon et al., 1993). In these previous studies, marijuana users also showed at least equal outcomes regarding opioid and other illicit drug use when compared to those who did not use marijuana. The current study extended these findings to opioid-dependent patients receiving buprenorphine detoxification and behavior therapy. The observations that marijuana use did not adversely affect outcome during outpatient treatment for cocaine or opioid dependence challenges the common assertion that drug-dependent patients must simultaneously cease use of all drugs of abuse to make progress in treatment. Thus, alternative treatment strategies such as a sequential or harm reduction approach to polydrug use warrant continued investigation.

Dr. Budney’s research underscores the need for additional research to further understand the functional relations between different drugs of abuse so that empirically-based treatment guidelines can be developed. In particular, his findings raise important clinical questions regarding how to most effectively approach marijuana use in persons enrolled in outpatient treatment for cocaine or opioid dependence. The present findings indicate that marijuana use is associated with increased problem severity and impairment among cocaine and opioid abusers. Yet, many of these patients may not be interested or willing to change their marijuana use. Moreover, the outcome data suggest that marijuana abstinence is not necessary for achieving abstinence from the primary drug of abuse. Whether or not continued marijuana use affects the patient's ability to maintain abstinence long term remains unanswered. One would expect that finding a method to assist cocaine or opioid abusers abstain from marijuana use would result in a greater likelihood of the abuser making the type of substantial lifestyle changes thought necessary for long-term positive outcome. Clearly, laboratory research and prospective clinical studies are needed to more carefully examine the effects of marijuana use on the treatment of other drug dependence.

6. Treatment of marijuana dependence

Robert Stephens presented assessment and treatment outcome data from two clinical trials conducted in collaboration with Dr. Roger Roffman of the University of Washington. He began by noting the paucity of research focused on treating marijuana dependence or abuse and commented that those two trials appear to be the only controlled research on this topic. This is surprising considering that recent reviews of the literature estimate that 20%-30% of those who have used marijuana more than a few times may develop dependence on the drug (Hall et al., 1994). One reason for the lack of treatment research on marijuana may be the belief that serious marijuana problems always occur in the context of polydrug abuse and that treatment of other drug abuse problems already captures the marijuana abusing population. Evidence counter to this belief was presented. Large numbers of individuals sought treatment when marijuana-specific programs were publicized in the media (n = 984) and only 23% of them were abusing alcohol or other drugs (Stephens et al., 1993, 1994). Most of the participants were white, educated, and in their late 20s and early 30s. Participants averaged over 10 years of near-daily marijuana use and most were using multiple times per day. Most perceived themselves as unable to stop and reported symptoms consistent with a diagnosis of cannabis dependence such as making at least several serious quit attempts and persistent use in the face of multiple forms of impairment.

The purpose of the first study was to test the effectiveness of the relapse prevention (RP) model of treatment with this population (Stephens et al., 1994). Eligible participants (n = 212) were randomly assigned to either an RP group or a Social Support (SS) group. Each treatment consisted of ten 2-h group sessions. The RP intervention emphasized a learning model of recovery, cognitive-behavioral coping skills-training, and anticipating high risk situations for relapse. The SS condition relied on the use of group support for change. Therapists in this condition promoted discussion among group members regarding marijuana cessation.

No significant differences between the RP and SS condition were observed in abstinence rates, days of marijuana use, or problems related to use at any follow-up. A total of 63% of participants in both treatments reported abstinence for at least the last 2 weeks of the treatment period. Continuous abstinence rates at the 1, 3, 6, 9, and 12 month post-treatment follow-ups were 49, 37, 22, 19 and 14%. respectively. Participants averaged 8, 10, 13, 14, and 14 days of use per month at the respective follow-ups reflecting a significant reduction at all time points from the pretreatment mean of 27 days per month. When improvement was defined as a reduction in days of use of at least 50% of the pretreatment level with no concurrent report of problems, 36% of the sample was improved during the final 3 months of the 12-month follow-up period. Data collected from collateral informants and from urinalyses provided strong support for the validity of participants self-reported use.

A 30-month post-treatment follow-up reached 162 (76%) of the participants and again showed no significant differences between the RP and SS treatment conditions. Rates of abstinence (28%) and improvement (19%) for the past 90 days were slightly higher at the 30 month follow-up than at the 12 month follow-up. Although these data might suggest stability of successful outcomes, closer examination revealed substantial fluctuations in outcome status. Outcome status (i.e. improved or not improved) changed in both directions for over one-third of the sample during the 18 months between follow-ups. Interestingly, 34% of participants attended some additional form of psychological, drug abuse, or self-help treatment in the period between the 12 and 30 month follow-ups. This figure is in contrast to the 9% of the sample that reported seeking help for marijuana-related problems prior to participation in the study. Thus, breaking the barrier to treatment engagement may have facilitated additional treatment seeking.

The results of this first study supported the utility of intervening with a chronic marijuana using population but did not support the hypothesis that the RP approach was superior to group discussion. One interpretation of this finding is that many individuals who seek help to quit marijuana use are capable of doing so with only minimal encouragement and support. This interpretation would be consistent with a growing literature on the efficacy of brief interventions with other addictive behaviors (Bien et al., 1993. Chick et al., 1985: Wallace et al., 1988; Schwartz, 1-987). Dr. Stephens and colleagues tested this hypothesis in a second study using a three-group randomized design that compared a group RP treatment with a brief individual intervention and a delayed treatment control group. The aims of this study included identifying differential outcomes as a function of minimal versus extended interventions for marijuana dependence and establishing quit rates in an untreated control group.

The second study involved 291 adult marijuana users. The Relapse Prevention Support Group (RPSG) received 14 group sessions spread over 4 months. This treatment focused on identifying high risk situations for relapse and learning skills to cope with them. Participants were invited to ask a significant other to attend a concurrent, four-session Supporters group designed to help significant others learn how to assist the participant in quitting marijuana use using RP concepts (McCrady, 1989). RPSG groups also were assisted in becoming ongoing, self-help groups after the end of the therapist-led sessions. The RPSG condition, therefore, represented a comprehensive, outpatient treatment approach to marijuana cessation utilizing both cognitive-behavioral and social support processes.

The Individualized Assessment and Intervention (IAI) was based on brief interventions with problem drinkers and used a format modeled after the Drinkers Check-Up (Miller and Sovereign, 1989). Participants attended two individual sessions with a therapist one month apart. During the first session the therapist used a brief feedback report generated from the data collected during the pretreatment questionnaire assessments to stimulate discussion and elicit self-motivational statements. Motivational interviewing principles (Miller and Rollnick, 1991) were used to build motivation and a plan for change, and coping strategies for high risk situations were suggested and discussed with the participant. Participants were invited to bring a significant other to the second session. During this session the therapist reviewed cessation strategies used during the previous month and progress toward abstinence. Modifications to the cessation plans were negotiated as necessary. After this second session, there was no further contact between the participant and the therapist. Participants in the delayed treatment control (DTC) condition waited four months before being reassessed and treated.

Follow-ups were conducted 1, 4, 7, 9, 13 and 16 months after the start of treatment and self-reported drug use was confirmed by collateral informants. RPSG and IAI produced superior outcomes compared with the DTC condition which also showed significant but smaller reductions in marijuana use during the waiting period. Surprisingly, no significant differences between RPSG and IAI were observed at any follow-up period on measures of abstinence rates, days of marijuana use, or problems related to marijuana. Absolute levels of marijuana use and abstinence rates after participation in the RPSG and IAI conditions were similar to those found in the first study.

Taken together, the results of both studies indicate that adults who are dependent solely on marijuana are interested in treatment and respond well to several types of interventions. Brief individual interventions may be more cost-effective than extended group counseling efforts, at least for individuals who are reasonably motivated to make a change. Interestingly, relapse rates were large and comparable to those found with other populations of drug abusers, suggesting that marijuana dependence may be as intractable as other additive behaviors. These data indicate a continued need to develop more effective treatments to promote change and prevent relapse for marijuana abusers.

7. Conclusion

The research presented in this symposium clearly demonstrated the renewed effort of the scientific community to better understand marijuana dependence and its attendant problems. Scientific evidence for a cannabinoid neurochemical system and the biological underpinnings of marijuana dependence has kindled important efforts that will provide much information on acute and chronic effects of marijuana use on human behavior as well as basic information on brain function. Human laboratory studies of marijuana's effects will elucidate the basic behavioral mechanisms and principles by which marijuana influences human behavior, and thus provide needed information regarding for whom and under what conditions marijuana produces its effects and functions as a reinforcer. Epidemiological research has now clearly shown that marijuana dependence is a problem for a substantial number of people. Moreover, the programmatic work described in this symposium highlighted how epidemiology can enhance our understanding of the addictive potential of marijuana and the development of marijuana dependence by comparing rates of dependence across drugs and across different subgroups of the population. The extant treatment research shows that innovative clinical approaches are needed for effectively managing secondary marijuana use among those individuals seeking treatment for other drug dependencies. The few controlled trials addressing primary marijuana dependence suggest that, like most other drug dependencies, clients respond well to several treatments, but large relapse rates are observed. Cross-disciplinary interchanges such as occurred in this symposium at the College on Problems of Drug Dependence annual meeting will continue to foster scientific developments that will improve our understanding of marijuana abuse and dependence and our ability to effectively manage its associated problems.

Acknowledgments

We thank Dr. Charles R. Schuster who served as discussant on the symposium for his thoughtful comments. We also thank the program committee of the College on Problems of Drug Dependence for their support and assistance in organizing this symposium. This research was supported in part by the National Institute on Drug Abuse [DA08655 (AJB), DA05154 (DRC)].

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* Corresponding author.

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