Cognitive functioning of long-term heavy cannabis users seeking treatment

Journal of the American Medical Association (US) Vol. 287, No. 9 p1123-1131
06/03/02

Nadia Solowij, PhD; Robert S. Stephens, PhD; Roger A. Roffman, DSW; Thomas Babor, PhD, MPH; Ronald Kadden, PhD; Michael Miller, PhD; Kenneth Christiansen, PsyD; Bonnie McRee, MPH; Janice Vendetti, MPH; for the Marijuana Treatment Project Research Group

Context

Cognitive impairments are associated with long-term cannabis use, but the parameters of use that contribute to impairments and the nature and endurance of cognitive dysfunction remain uncertain.

Objective

To examine the effects of duration of cannabis use on specific areas of cognitive functioning among users seeking treatment for cannabis dependence.

Design, Setting, and Participants

Multisite retrospective cross-sectional neuropsychological study conducted in the United States ( Seattle, Wash; Farmington, Conn; and Miami, Fla ) between 1997 and 2000 among 102 near-daily cannabis users ( 51 long-term users: mean, 23.9 years of use; 51 shorter-term users: mean, 10.2 years of use ) compared with 33 nonuser controls.

Main Outcome Measures

Measures from 9 standard neuropsychological tests that assessed attention, memory, and executive functioning, and were administered prior to entry to a treatment program and following a median 17-hour abstinence.

Results

Long-term cannabis users performed significantly less well than shorter-term users and controls on tests of memory and attention. On the Rey Auditory Verbal Learning Test, long-term users recalled significantly fewer words than either shorter-term users ( P = .001 ) or controls ( P = .005 ); there was no difference between shorter-term users and controls. Long-term users showed impaired learning ( P = .007 ), retention ( P = .003 ), and retrieval ( P = .002 ) compared with controls. Both user groups performed poorly on a time estimation task ( P( .001 vs controls ). Performance measures often correlated significantly with the duration of cannabis use, being worse with increasing years of use, but were unrelated to withdrawal symptoms and persisted after controlling for recent cannabis use and other drug use.

Conclusions

These results confirm that long-term heavy cannabis users show impairments in memory and attention that endure beyond the period of intoxication and worsen with increasing years of regular cannabis use.

JAMA. 2002;287:1123-1131

In the current climate of debate about marijuana laws and interest in marijuana as medicine, [1] one issue remains unresolved: Does heavy, frequent, or prolonged use of cannabis lead to a deterioration in cognitive function that persists well beyond any period of acute intoxication? Is the functioning of the brain altered in the long term? With over 7 million people using cannabis weekly or more often in the United States alone [2] and the potential for increased physician recommendations for select patients to use cannabis therapeutically, [1] answers to these questions are of significant public health concern. [3, 4] Scientific evidence from past research clearly showed that gross impairment related to chronic cannabis use did not occur but was inconclusive with regard to the presence of more specific deficits. [5, 6] Recent studies with improved methods have demonstrated changes in cognition and brain function associated with long-term or frequent use of cannabis. Specific impairments of attention, memory, and executive function have been found in cannabis users in the unintoxicated state ( and in children exposed to cannabis in utero [7] ) in controlled studies using brain event-related potential techniques6, [8-10] and neuropsychological assessments [11-15] including complex tasks.

Brain imaging studies of cannabis users have demonstrated altered function, blood flow, and metabolism in prefrontal and cerebellar regions. [16-19] Studies failing to detect cognitive decline associated with cannabis use [20] may reflect insufficient heavy or chronic use of cannabis in the sample or the use of insensitive assessment instruments. Impairments appear to increase with duration and frequency of cannabis use; however, the parameters of use that are associated with short-or long-lasting cognitive and brain dysfunction have not been fully elucidated. The attribution of deficits to lingering acute effects, drug residues, abstinence effects, or lasting changes caused by chronic use continues to be debated. [5, 6] Animal research suggests an important role for the cannabinoid receptor in regulating the neural activity critical for memory processing. [21-24] Long-term use of cannabis may result in altered functioning of the cannabinoid receptor and its associated neuromodulator systems.

This study investigated the nature of cognitive impairments associated with long-term cannabis use employing data collected from a large clinical trial of chronic users seeking treatment for cannabis dependence. The study compared 102 cannabis users assessed prior to treatment on carefully selected neuropsychological tests with 33 nonuser controls. The parameters of cannabis use that contribute to impairment were examined. It was hypothesized that performance would deteriorate as the number of years of regular use increased.

METHODS

Design

A multisite, retrospective, cross-sectional comparison-group design was used to compare ( 1 ) long-term users with a mean of 23.9 years of regular cannabis use; ( 2 ) shorter-term users with a mean of 10.2 years of regular use; and ( 3 ) nonusers of cannabis. Key confounding variables ( age, IQ, other drug use ) were controlled through matching or statistical methods. The sample size required for this study was determined by estimating a 94% chance of detecting a moderate effect size of 0.5 SD units at a 2-tailed of .05.

Recruitment Procedure and Assessment of Drug Use

Sixty-five of the 102 cannabis users were delayed-treatment participants from the Marijuana Treatment Project, a multisite US study ( Seattle, Wash; Farmington, Conn; and Miami, Fla ) conducted between 1997 and 2000 of the effectiveness of brief treatments for cannabis dependence.25 The remainder were recruited through the Marijuana Treatment Project specifically for this study. Participants provided written informed consent as approved by the ethics committees of the participating institutions and were paid $75 for completing the cognitive assessments. Controls ( n = 33 ) were recruited from the general population through media advertisements at only 1 site. The controls were told that the researchers were studying the effects of exposure to drugs and alcohol on cognitive functioning, and that at present only individuals at the lighter end of the spectrum of drug experience were required. The aim was to minimize cannabis use among controls while approximating the other characteristics of the cannabis-using sample. Assessors were not blinded with regard to group assignment. Self-reported drug and alcohol use were assessed by the Addiction Severity Index,26 a separate structured interview, and the Time Line Follow Back procedure. [27, 28] The Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition ( DSM-IV ) Axis I Disorders ( SCID ) [29] assessed cannabis dependence. Duration of regular ( at least twice per month ) cannabis use was an averaged composite measure derived from the Addiction Severity Index, SCID, and the structured interview. Current frequency of cannabis use was calculated from the Time Line Follow Back procedure.

Inclusion/Exclusion Criteria

Cannabis users were included if they had used cannabis regularly for at least 3 years, were currently using at least once a week, were seeking treatment to assist them to cease or reduce their use of cannabis, and were willing to participate in the treatment program offered. Participants were excluded if they had ever had a serious illness or injury that may have affected the brain, any psychotic disorder, met a current DSM-IV diagnosis of dependence on any other drug or alcohol, or had a poor command of the English language.

Sample Characteristics

Table 1 provides demographic information and cannabis use parameters. ( acquisition ( 3 words over 5 trials ) was greater among long-term users ( 13.7% ) than controls ( 0% ) ( P = .007 ) but not shorter-term users ( 5.9% ). The proportion of long-term users recalling fewer than 10 words on trial V ( 27.5% ) was more than among shorter-term users ( 8.5% ) or controls ( 3.0% ) ( P = .002 ). Significantly more long-term users ( 23.5% ) lost 3 or more words over the 20-minute delay between trials VI and VII than shorter-term users ( 4.3% ) or controls ( 3.0% ) ( P = .003 ). Long-term users showed a smaller primacy effect in the serial position curve than either other group ( P = .02 ). Groups did not differ in the recency effect or in words recalled from the middle of the list.

Users overall and long-term users recognized fewer words than controls from list A ( overall, P = .03; long-term, P = .01 ) and list B ( overall, P = .01; long-term, P = .04 ) but long-term users did not differ from shorter-term users. More than half of the long-term users ( 55% ) had a recognition score for list A of 12 or less compared with 28% of shorter-term users and 21% of controls ( P = .002 ). Long-term users misassigned more words ( median, 2 ) than shorter-term users and controls ( each median, 0 ) ( P( .001 ). A greater proportion of long-term users ( 13.7% ) compared with shorter-term users ( 6.4% ) and controls ( 0% ) actually identified fewer words on recognition than they had just prior during recall on trial VII ( P = .02 ). Long-term users' performance was significantly poorer than published norms [47] for the general population on most measures from the RAVLT.

Stroop Test

Cannabis users did not differ significantly from controls after inclusion of covariates in any condition or on interference scores. While there were no performance differences between Color-Word ( CW ) and Color-Read ( CR ) in the control group, performance on CR was, however, poorer than on CW in both long ( P( .001 ) and shorter-term users ( P .03 ). Color-Read was the additional interference condition designed to increase demands on executive function.43 There was an inverse relationship between duration of cannabis use and number of items completed on CR ( partial r, - 0.27; P = .003 ) and CW ( partial r, - 0.27; P = .004 ) after controlling for age and FSIQ. These results suggest that cannabis users are vulnerable to task complexity with increasing demands creating more sources of interference that adversely affect performance.

Wisconsin Card Sorting Test

There were no significant group differences on any Wisconsin Card Sorting Test ( WCST ) measure but a trend on one: long-term users failed to maintain the set more often than shorter-term users ( P = .05 ) or controls ( P = .07 ). Research suggests that this measure best represents attentional dysfunction. [39] There was no evidence of impaired performance with increasing years of cannabis use after controlling for covariates.

Alphabet Task and Omitted Numbers

Groups did not differ in the time taken to complete any trial of the Alphabet Task or in the number of items correct in the Omitted Numbers task. The log time to complete the alternating trial of the Alphabet Task increased as a function of duration of cannabis use ( partial r, 0.26; P = .006 ), as did the square root difference between times taken to complete the alternating and loud trials, an index of interference and lack of flexibility ( partial r, 0.26; P = .006 ).

Time Estimation Tasks

Cannabis users differed from controls ( P( .001 ) in Time Estimation Task A where they estimated the time taken to complete the preceding ( Omitted Numbers ) task. Both long- and shorter-term users underestimated the time by about one third of the actual time taken ( 64.4 seconds ) and differed significantly from controls ( P = .01 and P( .001, respectively ). Groups did not differ in the simple and brief warned passive Time Estimation Task B or Time Production, where they could use strategies such as counting. Time estimation measures did not correlate with duration of cannabis use.

Auditory Consonant Trigrams

Long-term users recalled significantly fewer items than shorter-term users ( P = .007 ), controls ( P = .002 ), and published norms [48] on only the 9-second delay condition. The number of items recalled did not correlate with duration of cannabis use. In the general population, the greater the delay interval the worse the performance. In cannabis users, this general pattern was apparent, though there was greater interference at the shorter-delay interval than would be expected.

Paced Auditory Serial Addition Test

Long-term users had slower processing rates than shorter-term users on trial 1 ( P = .007 ), with trends on trial 2 ( P = .03 ) and the total processing rate across all trials ( P = .02 ). Group differences on all other measures failed to reach significance but the performance of the long-term users was poorer in comparison with one set of norms49 but not another. [50]

Pure Effects Attributable to Cannabis Use and Effects of Recent vs Chronic Use

Excluding all participants with histories of regular other drug or alcohol use, dependence or treatment, and controls with any history of regular cannabis use within the past 20 years reduced the sample to 27 long-term users, 33 shorter-term users, and 26 controls. Despite the reduction in power to detect differences between groups, there remained a significant difference with = .05 between long-term users and controls on RAVLTsum ( P = .03 ), recognition of lists A ( P = .004 ) and B ( P = .01 ), and between users overall and controls on the unwarned Time Estimation task ( P = .02 ). These results support the hypothesis that impaired memory function and time estimation are specific to chronic use of cannabis.

In a separate analysis, exclusion of users whose urinary cannabinoid metabolite levels exceeded those from the night before testing by 50 ng/mg or more ( n = 18 ) still resulted in significant differences between long- and shorter-term users, and long-term users and controls on RAVLT sum ( P = .002 and P = .002, respectively ), on recognition of lists A ( P = .005 and P = .006 ) and B ( P = .01 and P( .001 ), on the 9-second delay of the Auditory Consonant Trigrams test ( P = .02 and P = .03 ), and users still differed from controls on time estimation ( P = .005 ). When the sample was split at the median for time since last use or level of urinary cannabinoid metabolite on the day of testing and analyzed by ANCOVA, there were no differences on any measure between those who had used cannabis within the past 17 hours and those who had used cannabis 17 or more hours ago, or those with high vs low levels of urinary metabolites and no interactions with duration of cannabis use. Including measures of recent use as covariates in ANCOVA did not change the significance of differences between long- and shorter-term users. These results support the hypothesis that impaired performance is not a consequence of recent use prior to testing or the extent of cannabinoid residues present.

To explore further the influences of duration of cannabis use and recency of use, semipartial correlations were calculated using the following predictors: FSIQ, age, duration of cannabis use, and hours since last use of cannabis. As shown in Table 4, the unique contribution of duration of cannabis use to the variance of each test variable was superior or at least equivalent to that of recency of use in all 6 test variables that had significant contributions from at least 1 cannabis use parameter. Recent use contributed only to performance on the memory tests. The fact that a minority of the sample, primarily shorter-term users, reported experiencing mild withdrawal symptoms, yet shorter-term users' performance was not impaired, supports the interpretation of the cognitive impairments observed as a long-term consequence of cannabis use and not a manifestation of overtly experienced withdrawal.

COMMENT

The results of this study have confirmed and extended previous findings of cognitive impairments among chronic heavy cannabis users.

Acknowledgment: We are grateful to Aimee Balmer-Campbell, BA, Kara Brennan Dion, BA, David Duresky, MA, Dave Ghany, BA, Brian Glidden, BA, Cara Gluskoter, MS, Cher Gunby, BA, Jennifer Haley, BA, Heather Haynes, RN, Patricia Holkon, MA, Elise Kabella, PhD, Priscilla Morse, MA, Joe Picciano, MS, Sam Schwartz, MSW, Megan Swan, MA, Debbie Talamini, AS, and Anna Wolfe, BA, for input and assistance with data collection and trial management, Peter Caputi, BA, GradDip, for statistical advice, Brin Grenyer, PhD, for comments on the manuscript, Eva Congreve, DipLib, for library assistance, and to all participants in this research.

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Responses sent to JAMA about the above article

To the Editor: Dr Solowij and colleagues [1] concluded that their findings
"confirm that long-term heavy cannabis users show impairments in memory and
attention that endure beyond the period of intoxication." In his
accompanying Editorial, Dr Pope [2] pointed out that this study could not
establish a causal relationship between use of marijuana and later declines
in cognitive performance. Neither Solowij et al nor Pope, however, referred
to laboratory studies designed to assess causality, such as ours, which
evaluated the effects of acute marijuana administration on complex
cognitive performance in regular marijuana smokers. [3] Unlike the subjects
of Solowij et al, these individuals were not seeking treatment and had
heavier marijuana use, averaging 24 marijuana cigarettes per week.
Participants smoked a single marijuana cigarette during 3 separate
outpatient sessions containing varying amounts of tetrahydrocannabinol,
which had minimal effects on cognitive functioning. Chait [4] reported
similar findings.

Both of these laboratory studies found minimal cognitive deficits after
marijuana administration in experienced users and suggest that recent
marijuana use is a minimal confounder in experienced marijuana users. Data
from well-controlled laboratory studies in combination with data from
retrospective studies can ultimately provide a more comprehensive view of
marijuana-related effects on human cognitive performance.

Erik W. Gunderson, MD; Suzanne K. Vosburg, PhD; Carl L. Hart, PhD;
Department of Psychiatry, Division on Substance Abuse, New York State
Psychiatric Institute and College of Physicians and Surgeons of Columbia
University, New York

1. Solowij N, Stephens RS, Roffman RA, et al, for the Marijuana Treatment
Project Research Group. Cognitive functioning of long-term heavy cannabis
users seeking treatment. JAMA. 2002;287:1123-1131. (
http://www.mapinc.org/drugnews/v02/n395/a10.html )

2. Pope HG Jr. Cannabis, cognition, and residual confounding. JAMA.
2002;287:1172-1174 ( http://www.mapinc.org/drugnews/v02/n396/a01.html )

3. Hart CL, van Gorp W, Haney M, et al. Effects of acute smoked marijuana
on complex cognitive performance. Neuropsychopharmacology. 2001;25:757-765.

4. Chait LD. Subjective and behavioral effects of marijuana the morning
after smoking. Psychopharmacology (Berl). 1990;100:328-333.

To the Editor: While the study of Dr Solowij and colleagues [1]
demonstrates a significant difference in cognitive function between
long-term users and short-term/nonusers of marijuana, I am concerned about
possible selection biases. Because all the marijuana users in this trial
were actively seeking assistance with reduction or cessation, the sample
may be biased toward those individuals who feel they have a substance use
problem so severe it requires treatment.

Michael Watson, MC, USNR, Department of Family Practice, Naval Hospital,
Jacksonville, Fla

1. Solowij N, Stephens RS, Roffman RA, et al, for the Marijuana Treatment
Project Research Group. Cognitive functioning of long-term heavy cannabis
users seeking treatment. JAMA. 2002;287:1123-1131. (
http://www.mapinc.org/drugnews/v02/n395/a10.html )

To the Editor: I would like to point out 2 defects in the study of Dr
Solowij et al. First, it does not control for age-related differences in
cognitive function, which could potentially cause the differences between
the long- and shorter-term user groups. Second, cannabinoids are present
for many days after ingestion. Age-related differences in excretion may
also explain the apparent difference in function between long- and
shorter-term users of marijuana.

Julia R. Nyquist, MD; San Anselmo, Calif

In Reply: Dr Gunderson and colleagues refer to controlled laboratory
studies that found minimal cognitive deficits in experienced users after
acute marijuana administration. These findings support our interpretation
that the observed long-term effects were unlikely to be confounded by
residual effects of recent cannabis use. Our study was designed
specifically to investigate chronic effects, with years of use as our
variable of interest. By requiring several hours abstinence prior to
testing, we induced an unintoxicated cognitive state that long-term users
typically operate in for substantial periods in their daily life. We showed
that impairments were generally unrelated to withdrawal and recent use. We
concluded that a probable causal relationship exists because we controlled
for potential confounding factors.

It should be noted that the experienced cannabis users in these laboratory
studies did not approach the long-term durations reported by participants
in our study, and that the potency of cannabis smoked in the community is
generally greater than that administered in the laboratory. Nevertheless,
we agree that controlled laboratory studies provide a valuable complement
to naturalistic studies like ours. Just as acute effects of cannabis differ
in experienced vs naive subjects, long-term effects vary with the frequency
and duration of cannabis use. This and the mechanisms involved in the
development of tolerance to the acute effects of cannabinoids on cognition
are complex issues that require further research.

Dr Watson expresses concern about selection bias. Although the participants
in this study were seeking treatment, their impairments were related
specifically to the number of years that cannabis had been used,
replicating our previous findings in cannabis users not seeking treatment.
[1] Thus, regardless of treatment seeking, there is good evidence for a
neurobiological explanation underlying cognitive impairments that develop
over many years of exposure to cannabis.

Dr Nyquist claims that there was a lack of control for age differences
between groups. We included age as a covariate in analyses where it
correlated with test performance and we performed semipartial correlations
to examine the unique contributions of age and duration of cannabis use to
the variance in cognitive test performance (reported in Table 4). Because
age and duration of cannabis use are so inextricably linked, isolation of
effects associated with years of cannabis use relies on statistical control
methods; our results showed a greater unique contribution from the years of
cannabis use. We ensured that the control group did not differ in age from
the overall cannabis user sample prior to their division into long- and
shorter-term user groups. Our previous studies1 have shown cognitive
impairments in long-term cannabis users compared with age-matched controls.
We are unaware of any literature showing age-related differences in
excretion of cannabinoid metabolites.

Nadia Solowij, PhD; National Drug and Alcohol Research Centre, University
of New South Wales, Sydney, Australia; Department of Psychology, University
of Wollongong, Wollongong, Australia

Thomas Babor, PhD, MPH; Department of Community Medicine, University of
Connecticut Health Center, Farmington

Robert Stephens, PhD; Department of Psychology, Virginia Polytechnic
Institute and State University, Blacksburg

Roger A. Roffman, DSW; Innovative Programs Research Group, School of Social
Work, University of Washington, Seattle, for the Marijuana Treatment
Project Research Group

1. Solowij N. Cannabis and Cognitive Functioning. Cambridge, United
Kingdom: Cambridge University Press; 1998.

To the Editor: In his Editorial accompanying our paper on cognitive
functioning in long-term heavy cannabis users, [1] Dr Pope [2] makes
inferences that question the validity of our findings. We point out that
the possible confounding factors that Pope alludes to were in fact
controlled in our study. We also wish to clarify other issues that he
brings up.

First, we did not claim that the cognitive impairments associated with
long-term heavy cannabis use in our study were irreversible; we only showed
no performance differences between those abstaining for less than or more
than 17 hours (range, up to 240 hours). A reversible deficit need not
necessarily be due to a residue of cannabinoids or to withdrawal, which our
data did not support. These impairments could be interpreted in terms of a
gradual adaptation of the nervous system to prolonged exposure to exogenous
cannabinoids, possibly resulting in altered functioning of the endogenous
cannabinoid or other neuromodulator systems. After prolonged abstinence,
these systems may well return to healthy function. Future analyses from
this study will investigate recovery of function in the same sample 4
months after cessation or reduction of cannabis use.

Second, Pope suggests that our results may have been influenced by residual
confounding. Our screening of participants was very thorough: there was no
greater incidence among the cannabis users of head injury, concussion,
hospitalization, treatment seeking for psychological or emotional problems,
or use of prescription medications. Data (not reported in the article)
showed no association between performance on the cognitive tests and
psychological distress as measured by the Beck Depression Inventory,
State-Trait Anxiety Inventory, and Brief Symptom Inventory, on which
shorter-term users generally had the highest scores yet did not differ from
controls in cognitive performance.

Similarly, no site differences were found in either sociodemographics or
cognitive test performance. The sex ratio did not differ between any of our
groups but since Pope and Yurgelun-Todd had previously reported sex
differences in cognitive effects of cannabis, [3] we also investigated
these and found none. Contrary to Pope's assertion that the results may be
explained by differences in prior abuse of other substances, we showed that
significant memory impairment was evident in the long-term users after
excluding participants with previous histories of other substance use. We
also reported analyses that countered the hypothesis that these effects
might be due to age or to recent use of cannabis.

The results replicate findings from our earlier studies that used different
cognitive tests and measures of brain electrical activity [4] to show that
cognitive impairments worsen with the number of years of cannabis use. Few
studies have investigated the effects of duration of cannabis use. Of
course, there may be unknown influences affecting associations of this kind
but the evidence from our study supports the most parsimonious conclusion
that it is the years of cannabis use that produces the impairment.

Nadia Solowij, PhD; National Drug and Alcohol Research Centre, University
of New South Wales, Sydney, Australia; Department of Psychology, University
of Wollongong, Wollongong, Australia

Robert Stephens, PhD; Department of Psychology, Virginia Polytechnic
Institute and State University, Blacksburg

Roger A. Roffman, DSW; Innovative Programs Research Group, School of Social
Work, University of Washington, Seattle

Thomas Babor, PhD, MPH; Department of Community Medicine, University of
Connecticut Health Center, Farmington for the Marijuana Treatment Project
Research Group

1. Solowij N, Stephens RS, Roffman RA, et al, for the Marijuana Treatment
Project Research Group. Cognitive functioning of long-term heavy cannabis
users seeking treatment. JAMA. 2002;287:1123-1131.

2. Pope HG Jr. Cannabis, cognition, and residual confounding. JAMA. (
http://www.mapinc.org/drugnews/v02/n396/a01.html )

3. Pope HG Jr, Yurgelun-Todd D. The residual cognitive effects of heavy
marijuana use in college students. JAMA. 1996;275:521-527.

4. Solowij N. Cannabis and Cognitive Functioning. Cambridge, United
Kingdom: Cambridge University Press; 1998.

In Reply: Dr Solowij and colleagues provide reassurance regarding their
extensive efforts to control for possible confounds. Our similar study [1]
of equally long-term cannabis users agrees with theirs in finding cognitive
impairment hours to days after discontinuing cannabis. However, our studies
still disagree on one important point: Solowij et al found increasing
cognitive impairment with increasing duration of cannabis use, whereas we
did not.

I still believe that the most parsimonious explanation for this discrepancy
is residual confounding, either from inadequate adjustment for measured
confounders or (perhaps more likely) from the presence of unmeasured
confounders. This is because both studies depend heavily on the assumption
that, after appropriate statistical adjustments, longer- and
shorter-duration cannabis users are comparable on all factors, other than
the amount of exposure, that would influence the outcome. [2, 3] Such
comparability may be almost impossible to achieve in a retrospective study,
particularly since preexposure cognitive function and latent vulnerability
to neuropsychiatric disorders (either unexpressed or only partially
expressed) may predispose to duration of cannabis use and may influence
outcome.

Even in seemingly well-matched groups, minor confounders can substantially
alter estimated effects. One cannot exclude the possibility that among
cannabis users spontaneously seeking psychiatric treatment for their drug
use, subtle neuropsychiatric factors, not induced by cannabis, may affect
cognitive performance despite the best efforts to control for such factors.
The most that can be concluded is that the effect sizes observed in our 2
studies are simultaneously consistent either with no duration-associated
deficits at all (all observed differences being due to residual
confounding) or with a substantial association of possible clinical
importance. Therefore, I stand by my conclusion that we must live with
uncertainly.

Harrison G. Pope, Jr, MD; Biological Psychiatry Laboratory, McLean
Hospital, Harvard Medical School, Belmont, Mass

1. Pope HG Jr, Gruber AJ, Hudson JI, Huestis MA, Yurgelun-Todd D.
Neuropsychological performance in long-term cannabis users. Arch Gen
Psychiatry. 2001;58:909-915.

2. Greenland S, Robins JM. Identifiability, exchangeability, and
epidemiologic confounding. Int J Epidemiol. 1986;15:412-418.

3. Little RJ, Rubin DB. Causal effects in clinical and epidemiologic
studies via potential outcomes: concepts and analytical approaches. Annu
Rev Public Health. 2000;21:121-145.