MAPS: !!! JAMA: Cognitive Functioning of Long-term Heavy Cannabis Users

[Peter Webster <vignes@xxxxxxxxx>]

JAMA
Table of Contents - March 6, 2002
Vol 287, No. 9 pp 1071-1212
http://jama.ama-assn.org/issues/v287n9/toc.html
_____________________________
Cognitive Functioning of Long-term Heavy Cannabis Users Seeking Treatment
     N. Solowij, R. S. Stephens, R. A. Roffman,
     T. Babor, R. Kadden, M. Miller, K. Christiansen,
     B. McRee, J. Vendetti;
     for the Marijuana Treatment Project Research Group
http://jama.ama-assn.org/issues/v287n9/abs/joc11416.html


Editorials

Cannabis, Cognition, and Residual Confounding
     H. G. Pope, Jr
http://jama.ama-assn.org/issues/v287n9/ffull/jed20003.html



Cannabis, Cognition, and Residual Confounding

Harrison G. Pope, Jr, MD

In this issue of THE JOURNAL, Solowij and colleagues1 report a variety of
neuropsychological deficits in long-term cannabis users who were tested a
median of 17 hours after their last reported cannabis intake. Their
findings of impairments in memory and attention are not surprising since
several large and well-controlled studies have found similar deficits on
neuropsychological tests administered to long-term cannabis users after 12
to 72 hours of abstinence.2-5 If these deficits are brief and reversible
(ie, due to a residue of cannabinoids lingering in the brain or to
withdrawal effects from abruptly stopping the drug), they might not be a
serious threat. However, if these deficits are prolonged or irreversible
(ie, due to neurotoxicity from years of cumulative cannabis exposure), they
become a matter of grave concern. The findings of Solowij and colleagues
favor the latter possibility in that longer-term cannabis users in the
study often showed significantly greater deficits than shorter-term users,
and neuropsychological performance measures were often negatively
correlated with lifetime duration of use. Furthermore, these correlations
could not be explained by greater withdrawal symptoms or heavier recent
cannabis consumption among the longer-term users. Solowij and colleagues1
conclude that "our results confirm that cognitive impairments develop as a
result of prolonged cannabis use . . . and [that] they worsen with
increasing years of use."

The findings reported by these leading researchers must be evaluated
carefully. First, Solowij et al report only an association between lifetime
duration of cannabis use and impairment at 17 hours since last cannabis use
and therefore cannot extrapolate from this finding to infer whether
impairment persists for longer periods. Second, the strength of the
evidence for an association, even at the 17-hour mark, must be evaluated in
context with other reports. Previous data from Solowij favor the
possibility of persistent deficits associated with lifetime duration of
cannabis exposure.6 However, the weight of evidence from other studies
seems tilted in the opposite direction. For example, a recent meta-analysis
of neuropsychological studies of long-term marijuana users found no
significant evidence for deficits in 7 of 8 neuropsychological ability
areas and only a small effect size (ie, 0.23 SD units; 99% confidence
interval, 0.03-0.43) for the remaining area of learning.7 Another recent
study5 from our laboratory, published subsequent to this meta-analysis,
found virtually no significant differences between 108 heavy cannabis users
and 72 controls screened to exclude those with current psychiatric
disorders, medication use, or any history of significant use of other drugs
or alcoholon a battery of 10 neuropsychological tests after 28 days of
supervised abstinence from the drug. In addition, no significant
associations were found between the number of episodes of lifetime cannabis
use and any of the test scores at day 28 even though the heavy users had
smoked a median of about 15 000 times over periods ranging from 10 to 33
years.5 Further analysis of these data for associations between lifetime
use and performance at day 0 and day 1 of abstinence revealed trends that
were almost always in the same direction as those reported by Solowij et
al,1 but the effect sizes were much smaller (unpublished data).

We also analyzed the possible reasons for the difference between our study5
and that of Solowij et al in the strength of association between duration
of use and performance after 1 day of abstinence. The participants in the 2
studies reported very similar degrees of cannabis exposure, and the
neuropsychological tests administered were generally similar or even
identical. Both studies had similar sample sizes and thus similar
statistical power. Therefore, the most likely remaining explanation would
seem to be lack of comparability between the exposed and nonexposed groups
within one or both studies with respect to factors associated with the
outcomes of interest (ie, residual confounding).

For example, cannabis users in the study by Solowij et al were seeking
treatment for cannabis dependence, whereas controls were recruited from the
general population by advertisement. Individuals seeking clinical treatment
for cannabis dependence might exhibit higher levels of depression, anxiety,
or attention-deficit/hyperactivity disorder than other cannabis users, and
all of these psychiatric syndromes produce deficits on neuropsychological
testing.8-10 Some cannabis users seek treatment because they have gotten
into trouble with the law and so might have higher levels of antisocial
behavior than other users. Antisocial behavior is also linked to
neuropsychological deficits.11

Although Solowij and colleagues excluded subjects with psychotic disorders
or current drug or alcohol dependence (other than cannabis), subjects with
depression, anxiety disorders, or other psychiatric conditions were not
excluded. Also, subjects receiving prescription psychiatric medications,
such as benzodiazepines or antidepressants, that can impair cognitive
function were also not excluded.12, 13 In our study,5 subjects exhibiting
any current Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition Axis I disorder (other than simple phobia or social phobia) or
taking any psychoactive prescription medication were excluded. Thus,
confounding factors associated with treatment seeking are possible
explanations for the larger effect sizes in the study by Solowij et al.
However, for this to be correct, cannabis users in the study by Solowij et
al would have to have had more psychopathology or medication use than the
controls, and the longer-term users, in turn must have had a higher
prevalence of these features than the shorter-term users.

However, confounding can bias results in both directions. For instance, one
might argue that excluding cannabis users with current psychiatric
disorders or currently using medications would select in favor of unusually
healthy long-term users who performed better on testing than the average of
the overall population from which they were drawn. Moreover, cannabis use
might cause or exacerbate anxiety or depressive disorders and hence be
indirectly to blame for any neuropsychological impairment that these
disorders create. This is a slightly different assertion, however, from the
claim that cannabis impairs cognitive function directly.

Confounders associated with treatment seeking represent only 1 of the many
problems that threaten naturalistic studies of substance abusers. Another
is the problem of adjustment for premorbid differences between groups.
Lacking a historical measure of cognitive function, which is based on
testing subjects before they were first exposed to cannabis, leads to the
question of whether current differences observed between groups are due to
cannabis use or to some difference in premorbid cognitive ability for which
adjustment was not made. By matching groups on measures of intellectual
functioning that are relatively resilient to brain injury, Solowij and
colleagues have done their best to equalize the groups on premorbid
cognitive abilities. But since the 33 controls were recruited at 1 site and
the 102 cannabis users at 3 sites in different geographic settings, the
possibility of residual confounding due to subtle sociodemographic
differences between groups cannot be entirely dismissed.

Two of these sociodemographic differences in the group of longer-term
cannabis users, namely the larger proportion of men and the significantly
greater age of these subjects, are particularly important. Yet comparisons
between the groups were performed without adjustment for sex, and some
comparisons were also performed without adjustment for age, except in
specific cases in which age correlated significantly with a particular
outcome variable. However, it is hazardous to use significance testing
instead of change-in-estimate criteria to exclude a potential confounding
variable from adjustment. Such variables may still change the estimate of
the effect considerably, even if they are not statistically significant,
yielding residual confounding once again.14, 15 This is particularly
worrisome with the age variable, because age differed to a significant
degree between study groups and is also highly associated with cognitive
function. For example, on the Rey Auditory Verbal Learning Test, where
Solowij et al demonstrated the largest cannabis-associated deficits, both
increased age and male sex have been shown to be associated with poorer
performance,16 but the effect sizes shown in Table 3 of the study were not
adjusted for either age or sex.

Solowij and colleagues are aware of these limitations, and show (in Table 4
of their article) that even after adjusting for age (but not for sex),
longer duration of cannabis use is associated with deficits on several key
performance measures, although at a more modest level of significance.
However, 47% of the long-term cannabis users also had a history of regular
use of, dependence on, or treatment for alcohol or other drugs besides
cannabis, introducing another possible confounder.

Given the minefield of possible confounding, should naturalistic studies of
drug users be presumed untrustworthy or be abandoned entirely? As Solowij
and colleagues point out, retrospective designs are the most efficient way
to assess the long-term cognitive effects of cannabis consumption.
Prospective designs would be extremely expensive, time-consuming, and in
some cases unethical. Thus, despite all of their limitations, retrospective
studies remain an important tool for answering these important questions.

In conclusion, currently available scientific evidence shows that almost
certainly, some cognitive deficits persist for hours or days after acute
intoxication with cannabis has subsided. The consensus across studies is
strong enough to discount the likelihood that this finding can be explained
by any combination of confounders. But whether these deficits increase with
increasing years of cannabis exposure remains uncertain. On this question,
the numerous potential confounding variables make it difficult to determine
whether cognitive impairments are attributable to cannabis use or due to
other factors. Even if lifetime duration of cannabis use is associated with
greater impairment after 17 hours of abstinence, the data are insufficient
to know whether greater impairment would be present a week or a month
later. Despite the important contributions of this new study, we must still
live with uncertainty.

Author/Article Information

Author Affiliation: Biological Psychiatry Laboratory, McLean Hospital,
Harvard Medical School, Belmont, Mass.

Corresponding Author and Reprints: Harrison G. Pope, Jr, MD, Biological
Psychiatry Laboratory, McLean Hospital, 115 Mill St, Belmont, MA 02478
(e-mail: pope@xxxxxxxxxxxxxxxxxx).

Editorials represent the opinions of the authors and THE JOURNAL and not
those of the American Medical Association.

Financial Disclosure: This work was supported in part by grant DA10346 from
the National Institute on Drug Abuse.


REFERENCES

1. Solowij N, Stephens RS, Roffman RA, et al. Cognitive functioning of
long-term heavy cannabis users seeking treatment. JAMA. 2002;287:1123-1131.
ABSTRACT  |  FULL TEXT  |  PDF

2. Block RI, Ghoneim MM. Effects of chronic marijuana use on human
cognition. Psychopharmacology. 1993;110:219-228. MEDLINE

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

4. Fletcher JM, Page B, Francis DJ, et al. Cognitive correlates of
long-term cannabis use in Costa Rican men. Arch Gen Psychiatry.
1996;53:1051-1057. MEDLINE

5. 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. ABSTRACT  |  FULL TEXT  |  PDF  |  MEDLINE

6. Solowij N. Cannabis and Cognitive Functioning. Cambridge, England:
Cambridge University Press; 1998.

7. Grant I, Gonzalez R, Carey C, Natarajan L. Long-term neurocognitive
consequences of marijuana: a meta-analytic study. In: National Institute on
Drug Abuse Workshop on Clinical Consequences of Marijuana; August 13, 2001;
Rockville, Md. Available at:
http://www.nida.nih.gov/MeetSum/marijuanaabstracts.html. Accessibility
verified February 5, 2001.

8. Mialet JP, Pope HG Jr, Yurgelun-Todd D. Impaired attention in depressive
states: a non-specific deficit? Psychol Med. 1996;26:1009-1020. MEDLINE

9. Eysenck MW. Anxiety and cognitive functioning. In: Burrows GD, Roth M,
Noyes R, eds. Handbook of Anxiety. Vol 3. Amsterdam, the Netherlands:
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10. Barkley R. Behavioral inhibition, sustained attention, and executive
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12. Lucki I, Rickels K, Geller AM. Chronic use of benzodiazepines and
psychomotor and cognitive test performance. Psychopharmacology.
1986;88:426-433. MEDLINE

13. Amado-Boccara I, Gougoulis N, Poirier Littre MF, Galinowski A, Loo H.
Effects of antidepressants on cognitive functions: a review. Neurosci
Biobehav Rev. 1995;19:479-493. MEDLINE

14. Greenland S. Modeling and variable selection in epidemiologic analysis.
Am J Public Health. 1989;79:340-349. MEDLINE

15. Rothman KJ, ed, Greenland S, ed. Modern Epidemiology, 2nd ed.
Philadelphia, Pa: Lippincott-Raven; 1998:256-257.

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differences in verbal memory. J Clin Psychol. 1988;44:403-411. MEDLINE

~~~~~~~~~~~~~~~~~~~~~

Cognitive Functioning of Long-term Heavy Cannabis Users Seeking Treatment

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

Author/Article Information

Author Affiliations: National Drug and Alcohol Research Centre, University
of New South Wales, Sydney, and Department of Psychology, University of
Wollongong, Wollongong (Dr Solowij), New South Wales, Australia; Department
of Psychology, Virginia Polytechnic Institute and State University,
Blacksburg, Va (Dr Stephens); Innovative Programs Research Group, School of
Social Work, University of Washington, Seattle (Dr Roffman); Department of
Community Medicine (Dr Babor and Mss McRee and Vendetti) and Department of
Psychiatry (Dr Kadden), University of Connecticut Health Center,
Farmington; and The Village South Inc, Miami, Fla (Drs Miller and
Christiansen).

Corresponding Author and Reprints: Nadia Solowij, PhD, National Drug and
Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052,
Australia (e-mail: n.solowij@xxxxxxxxxxx).

Author Contributions: Study concept and design: Solowij, Stephens, Roffman.

Acquisition of data: Stephens, Roffman, Kadden, Miller, Christiansen,
McRee, Vendetti.

Analysis and interpretation of data: Solowij, Stephens.

Drafting of the manuscript: Solowij.

Critical revision of the manuscript for important intellectual content:
Solowij, Stephens, Roffman, Babor, Kadden, Miller, Christiansen, McRee,
Vendetti.

Statistical expertise: Solowij, Stephens.

Obtained funding: Solowij, Stephens, Roffman, Babor, Kadden, Miller.

Administrative, technical, or material support: Solowij, Roffman, McRee,
Vendetti.

Study supervision: Solowij, Stephens, Roffman, Babor, Kadden, Miller,
Christiansen, McRee, Vendetti.

Other Members of the Marijuana Treatment Project Research Group include
Kathleen Carroll, PhD, Karen Steinberg, PhD, (Coordinating Center,
University of Connecticut Health Center, Department of Community Medicine),
Mark Litt, PhD (Farmington Clinical Research Unit, University of
Connecticut Health Center, Department of Psychiatry), Jean Donaldson, MA,
and James Herrell, PhD (Center for Substance Abuse Treatment).

Funding/Support: This study was conducted as part of the Marijuana
Treatment Project, a Cooperative Agreement for a multisite study of the
effectiveness of brief treatment for cannabis dependence. It was funded by
the Substance Abuse and Mental Health Services Administration, Center for
Substance Abuse Treatment (CSAT), US Department of Health and Human
Services (grants UR4 TI11270, UR4 TI11273, UR4 TI11274, UR4TI11310). The
research was conducted in Farmington, Conn, Miami, Fla, and Seattle, Wash,
in cooperation with the following institutions: University of Connecticut
Health Center, The Village South Inc, University of Washington, and
Evergreen Treatment Services.

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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