CANNABIS, COGNITION, AND RESIDUAL CONFOUNDING

In this issue of THE JOURNAL, Solowij and colleagues [1] 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 colleagues
[1] 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
study [5] 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 alcohol -- on 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 15000 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 study
[5] 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
(pope@mclean.harvard.edu).

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.

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