Neuropsychological Residual FX THC (1) 2002

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Pharmacology
The Journal of Clinical
2002; 42; 48 J. Clin. Pharmacol.
R Gonzalez, C Carey and I Grant
review
Nonacute (residual) neuropsychological effects of cannabis use: a qualitative analysis and systematic
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GONZALEZ ET AL NEUROPSYCHOLOGICAL EFFECTS OF CANNABIS USE NOVEMBER SUPPLEMENT
Nonacute (Residual) Neuropsychological
Effects of Cannabis Use: A Qualitative
Analysis and Systematic Review
Raul Gonzalez, MS, Catherine Carey, BA, and Igor Grant, MD
T
he general climate toward medicinal and recre-
ational use of cannabis, both in Europe and the
United States, has changed in recent years. According
to several national and statewide surveys conducted in
the United States, approximately 60% to 70% of re-
spondents are in favor of allowing patient access to
cannabis for medicinal purposes.
1,2
Paralleling public
opinion, changes in legislation have emerged to facili-
tate patient access to cannabis when deemed appropri-
ate. Even though U.S. federal law continues to view
cannabis as a Schedule I drug, eight U.S. states have en-
actedmedical marijuana laws. InEurope, several coun-
tries have taken an approach toward drug policies that
focus on harm reduction rather than prohibition.
Switzerland has recently begun regulation of mari-
juana sales, and several other countries (e.g., Germany,
Spain, Portugal, Belgium, and the Netherlands) have
made permissive changes to their policies regarding
cannabis consumption.
Anecdotal and limited scientific observations sug-
gest that constituents of cannabis may improve appe-
tite and facilitate weight gain,
3-5
as well as alleviate
muscular spasticity, tremor, and neuropathic pain.
6
Thus, cannabis may be helpful in managing the symp-
toms of several debilitating diseases, including AIDS,
cancer, diabetic neuropathy, and multiple sclerosis.
7-9
These claims have been raised and reviewed in some
detail by recent expert panels, including the NIH Ex-
pert Panel Report,
10
andby the Institute of Medicine,
2,11
both of which concluded that cannabis and its constit-
uents may have some clinical utility. Furthermore, the
potential therapeutic value of synthetic and endoge-
nous cannabinoids, as well as those naturally found in
cannabis, appears to show promise in the treatment of
poststroke patients.
12
Several animal studies have doc-
umented the ability of some cannabis constituents and
their analogs to function as potent antioxidants,
13
re-
duce glutamate-mediated excitatoxic injury to the
brain,
13,14
and reduce experimentally induced infarct
volume both in vitro
15
and in vivo.
16
It is evident that if social, political, and scientific
trends regarding medical uses for cannabis continue in
the current direction, the possibility exists that deci-
sions will need to be made whether to treat patients
with cannabis or synthetic cannabis-like substances.
Because of this possibility, it is imperative that the po-
tential dangers of cannabis be assessed as carefully as
48S J Clin Pharmacol 2002;42:48S-57S
Fromthe Department of Psychiatry and the Center for Medicinal Cannabis
Research, University of California, San Diego (Dr. Grant); the Veterans Af-
fairs Healthcare System, San Diego (Dr. Grant); and the SDSU/UCSDJoint
Doctoral Program in Clinical Psychology, San Diego (Mr. Gonzalez, Ms.
Carey). Address for reprints: Igor Grant, MD, University of California, Cen-
ter for Medicinal Cannabis Research, 150 West Washington Street, Sec-
ond Floor, San Diego, CA 92103.
DOI: 10.1177/0091270002238794
Because there is a possibility that cannabis or cannabis-like
molecules might be used as treatments for certain conditions
in the future, it becomes important to consider the possible
adverse effects of these compounds. Inthis paper, the authors
review the evidence for persisting effects of nonacute can-
nabis use on the central nervous system, as reflected by al-
teration in neuropsychological performance. From the 40
articles that met criteria for inclusion in this review, the au-
thors could not detect consistent evidence for persisting
neuropsychological deficits incannabis users; however, 22 of
the 40studies reportedat least some subtle impairments. The
inability to reacha firmconclusionresults largely frommeth-
odological limitations inherent in most studies. These are
considered in detail to inform future studies on (nonacute)
consequences of cannabis consumption on cognitive
abilities.
Journal of Clinical Pharmacology, 2002;42:48S-57S
its benefits. Of particular concern are the effects of
cannabis on brain functions, as reflected by
neuropsychological abilities, such as attention, mem-
ory, and executive functions. Ample literature and an-
ecdotal information document the detrimental effects
that acute intoxicationwithcannabis canhave onsome
of these abilities. However, investigations examining
the presence, nature, and duration of longer term
nonacute effects of cannabis on neuropsychological
performance present equivocal findings.
The goal of this paper is to present a systematic as-
sessment of the existing literature on the nonacute per-
sisting effects of cannabis use on neuropsychological
performance. In a review conducted by Pope and col-
leagues,
17
the question of nonacute effects was divided
into two subcategories: residual and CNS alter-
ations. Residual meant slowly reversible alterations,
consistent with gradual elimination of cannabis, or
withdrawal phenomenon. CNS alterations connoted
permanent brain changes. The current review will en-
compass studies that have investigated the presence of
either residual effects or CNS alterations due to canna-
bis consumption. However, rather than focusing pri-
marily on the outcome of such studies, our review ex-
amines the quality of their methodology and research
designinanattempt todocument researchstandards in
the field and to explore how they may affect study re-
sults. In a separate manuscript, we will report on the
use of a meta-analytic approachinaneffort to quantita-
tively assess outcome through the estimation of effect
sizes of the persisting nonacute effects of cannabis con-
sumption on neuropsychological performance.
METHOD
Twoinvestigators (CC&RG) conductedpreliminarylit-
erature searches to establish a set of keywords that
would produce the maximum number of studies per-
taining to the questionof nonacute neuropsychological
effects of cannabis in adult humans. After deciding on
the optimal keywords, both investigators independ-
ently searched the literature using 11 separate online
databases. Keywords andBooleanoperators were mod-
ified as necessary to comply with specific database re-
quirements. Results fromeachdatabase were compiled
by each investigator, and duplicate entries were de-
leted. The combined search results yielded 1014
unique citations, the titles and abstracts of which were
examined to identify empirical studies relevant to this
review. When abstracts were not available or the infor-
mationprovidedwas insufficient todetermine the rele-
vance of an article, the decision to include the article
was postponed until the full manuscript was obtained.
If a study empirically investigated the nonacute
neuropsychological effects of cannabis in adult hu-
mans, it was deemed eligible for inclusion in this re-
view. Inaddition, due to the language limitations of the
investigators, only studies written in English were ex-
amined in detail. A second consensus meeting was
heldbetweenbothinvestigators to agree onthe final set
of studies for review. After resolving the status of 7 arti-
cles on which authors classifications disagreed, a total
of 38 articles were ultimately identified. Two more arti-
cles,
18,19
published after the literature searches were
completed, were added to this review, bringing the to-
tal number of articles reviewed in this article to 40.
Due tothe limitedscope of this review, manyarticles
that examined the general issue of nonacute effects of
cannabis on the brain were not included. The largest
proportion of these studies included nonhuman sam-
ples anddidnot assess neuropsychological functioning.
Investigations examining psychiatric/psychological is-
sues (including prevention) constituted the second
largest proportion of studies that were not included in
our final analysis. The thirdlargest subset of studies fo-
cused on nonadult human subjects (e.g., children, ado-
lescents, or infants). The remainder of excludedstudies
focusedprimarily onmedical factors, neuroimaging re-
sults, effects of acute intoxication, or polydrug abuse.
In investigating the nonacute effects of cannabis on
neuropsychological performance, it is imperative that
certain critical issues be addressed by investigators.
The neuropsychological performance of a cannabis-
using groupcoulddiffer fromthat of a control groupfor
many reasons aside from the groups history of canna-
bis consumption. Therefore, necessary steps must be
taken so that between-group differences can be more
confidently attributed to differences in history of can-
nabis use. Prior to conducting the literature search, a
set of criteria was established, representing the mini-
mum requirements a study must fulfill to adequately
address confounds and establish a cannabis effect. Ta-
ble I presents these minimal criteria.
RESULTS
Increasing Number
of Studies Published
The literature on the effects of cannabis on the brain
has grown dramatically over the past decade. Using all
of the citations retrieved in our literature search that
provided a year of publication, we tabulated the num-
ber of unique studies published during several epochs
from 1968 through 2001. With the exception of the
early1980s, the number of citations retrievedincreased
NOVEMBER SUPPLEMENT 49S
NEUROPSYCHOLOGICAL EFFECTS OF CANNABIS USE
steadily across epochs, showing 56% growth from the
late 1980s to the early 1990s and an additional 59%
growth from the late 1990s to 2001. More new studies
were publishedinthe past 6 years thaninthe entire pe-
riod from 1969 to 1985. A similar trend was observed
for articles that focusedspecifically onthe nonacute ef-
fects of cannabis on neuropsychological abilities. Of
the 40 articles reviewed in this article, 13 were pub-
lished prior to 1980. Only 5 of the 40 articles were pub-
lished during the period between 1980 and 1989. Not
surprisingly, the vast majority of articles pertaining to
this specific question appeared after 1990 (n = 22).
Tables II through IVprovide summaries of reviewed
studies, including sample characteristics, cognitive do-
mains assessed, and authors conclusions. Studies
were grouped into one of three tables, depending on
the number of minimal criteria not met. The most
widely assessed cognitive domain across all studies
was attention/working memory (n = 31), followed by
learning (n = 28), perceptual motor (n = 25), forgetting
(n = 23), abstraction/executive (n = 22), verbal (n = 15),
simple reaction time (n = 11), and motor (n = 8).
Neuropsychological Findings
Fifty-five percent of studies reported at least some sub-
tle impairment in a given cognitive ability as a result of
nonacute cannabis use. Poorer performance by canna-
bis users was most frequently reported for the atten-
tion/working memory domain (45%). Thirty-eight per-
cent of studies that investigated performance in the
motor domainand35%of the studies that lookedat the
forgetting domain reported significantly poorer perfor-
mance for the cannabis groups relative to controls. Less
than one-third of studies concluded a detrimental effect
of cannabis when assessing the perceptual/motor
(28%), abstraction/executive (27%), simple reaction
time (27%), learning (7%), and verbal (7%) domains. It
is important to note that these tabulations are based on
the conclusions provided by the studies authors and
are therefore subject to some bias (see Discussion).
Quality of Studies Based
on Minimal Criteria
Detailed investigation of the study designs revealed
that any overall conclusion based on the results of
these 40 studies should be interpreted with caution.
Only a fewstudies adequately met all of the a priori cri-
teria that we established (i.e., the minimum require-
ments for controlling confounds andconfidently estab-
lishing the presence of an effect from cannabis
consumption) (see Table I). It is important to note that
we were lenient in establishing whether a study vio-
lated our criteria. For example, the control group and
cannabis-using group did not have to be matched on
the prevalence of psychiatric or neurological problems,
nor didthe investigators have to control statistically for
such factors. Rather, a study was deemed to comply
with criterion 7 if the presence of neurological or psy-
chiatric disorders in the cannabis-using group was ad-
dressed by investigators or if study participants were
screened for such factors. Even though we were per-
missive when determining if the criteria were ade-
quatelyaddressed, onlyone-third(n=13) of the studies
were infull accordwiththese standards, andmore than
half violated at least two criteria.
To examine if the overall quality of publications in
this area has improved in recent years, we examined if
studies published more than two decades ago (those
prior to 1989) differed from studies published in or af-
ter 1990 on the number of criteria violations. On aver-
age, studies prior to 1990 had 1.9 criteria violations,
whereas those published in or after 1990 violated an
average of 1.4 criteria. A Wilcoxon rank sum test did
not reveal statistically significant differences in the
number of criteria violations between these two groups
(z = 1.45, p = 0.14). Although some might consider this
result to suggest a trendtowardsignificantly less criteria
violations in studies published in the past decade, the
magnitude of this difference is very small (1.4 vs. 1.9).
GONZALEZ ET AL
Table I Minimal Criteria for Establishing Nonacute Cannabis Effect
1. Includes a group with history of primarily marijuana use
2. Includes an appropriate control group (i.e., non-drug-using or extremely limited marijuana use)
3. Outcome measures include valid neuropsychological tests
4. Marijuana-using group is drug free on day of neuropsychological testing
5. Study reports length of abstinence from marijuana before testing
6. Study addresses other potential substance use in marijuana group
7. Study addresses potential history of neurological or psychiatric problems
(text continues on p. 54S)
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53S
We further examinedthe studies todetermine which
criteria were most commonly violated. Because the cri-
teria established to rate study quality are not equally
important, Table I ranks themfrommost essential (i.e.,
includes a group with history of cannabis use) to those
considered less critical (i.e., study addresses potential
neurologic and/or psychiatric confounds). Although
consideredless critical, the latter criteria are still essen-
tial to confidently establish a cannabis effect. Because
the focus of this review was limited to studies that in-
vestigated the nonacute effects of cannabis on
neuropsychological functioning, all studies met the
first criterion (i.e., included a group with history of
cannabis use). Our third criterion (i.e., use of valid
neuropsychological tests) was violated by only one
study. The high compliance to this criterion was also
influencedby our searchstrategy, as a study was imme-
diately discarded from review if it was clear upon first
examination that it did not use neuropsychological
outcome measures. Examination of compliance for the
remaining criteria across studies reveals important in-
formation on some of the specific limitations encoun-
tered in many of the studies reviewed.
Of the remaining five criteria, the one least likely to
be violated was the inclusion of an appropriate control
group. Onlyseven(18%) of the studies failedtocomply
with this standard. It is important to underscore the le-
nient approach used to determine if a study violated
any criterion. For example, a control group was de-
termined to be appropriate if it consisted of non-
drug-using individuals or individuals with minimal
histories of drug use (including marijuana). Therefore,
it was often the case that a study would meet this re-
quirement without actuallymatching groups onimpor-
tant factors, suchas other drug use, educational history,
and pertinent demographic factors (i.e., age, sex, eth-
nicity), all of which could have ultimately affected a
studys conclusion.
Most studies attempted to quantify or address other
drug use, as well as the presence of neurologic or psy-
chiatric disorders in the cannabis group. Thus, criteria
6and7were violatedbyonly25%(n=10) and28%(n=
11) of studies, respectively. We determinedthat a study
successfully complied with these criteria if there was
mention in the manuscript of any instrument, ques-
tionnaire, or interview used for establishing the pres-
ence of psychiatric and/or neurologic disorders or
other substance use. Because of the leniency of these
criteria, there were some studies that employed
suboptimal means for assessing these potential con-
founds. Furthermore, when differences between
groups on these confounds were discovered, the in-
vestigators either opted to statistically covary for these
differences or did nothing at all. In cases where a
study did not comply with either of these criteria or
did not control for their potential effects on
neuropsychological functioning, concluding that
group differences were based solely on history of can-
nabis use cannot be justified.
The aforementioned criteria can be applied to any
study using neuropsychological outcome measures.
They include using appropriate control and experi-
mental groups, using valid outcome measures, and
controlling for important confounds. The remaining
criteria we examined are specific to studies on the
performance. Criteria 4 and 5 are imperative in deter-
mining if there is a residual effect or CNS alteration as-
sociated with cannabis consumption rather than an
acute effect. Criterion 4 requires that participants are
determined to be drug free (i.e., not intoxicated) on the
day they complete their neuropsychological evalua-
tion. Inkeeping withour lenient determinationof crite-
rion compliance, investigators (at a minimum) needed
to mention that participants did not appear intoxicated
at the time of testing. Criterion 5 requires that an at-
tempt be made by investigators to assess the recency of
last cannabis use to determine how long a participant
has been abstinent fromcannabis. Forty-three percent
(n = 17) of studies violated criterion 4, and an even
larger proportion (45%, n = 18) failed to be in accor-
dance with criterion 5. Although both criteria are
clearly essential in establishing a persistent, nonacute
effect of cannabis on neuropsychological performance,
almost half of the studies examined in this review did
not explicitly address this issue in their research
design.
DISCUSSION
Overall, the most important and consistent finding re-
vealed by our review of the literature examining the
function was that most studies to date do not meet de-
sired research standards. Few studies met all of our
a priori criteria, which were developed to indicate the
minimum requirements necessary to confidently es-
tablish an effect of cannabis on neuropsychological
functioning. This observationwas particularly trouble-
some, given the propensity for conclusions from indi-
vidual studies to be quickly disseminated in popular
(and scientific) culture. Complex and equivocal find-
ings are generally distilled and summarized in a di-
chotomous manner, which fail to accurately represent
the actual results. As an illustration, consider a study
that finds poorer performance on a measure of atten-
GONZALEZ ET AL
tion for a group of individuals with a history of heavy
cannabis use relative to a control group. This same
study may have used several measures of attention but
discovered statistically significant differences on only
one of these measures. Nevertheless, the study may
conclude that a history of heavy cannabis use is associ-
ated with deficits in attention and ultimately summa-
rize its findings to suggest that a history of cannabis use
is detrimental to cognitive functioning, when in reality
the studys findings could be easily explained by other
factors, including Type I error. Because of this, the sum-
mary of study results presented in this review, or any
review that summarizes investigators conclusions, is
severely limited. Regardless, our review found that
only 55%of studies concluded that nonacute cannabis
use is associated with poorer neuropsychological per-
formance. When examining all studies that assessed a
given cognitive domain, we found that most failed to
find between-group differences. A better way to ad-
dress this question and more accurately quantify the
presence, if any, of a nonacute cannabis effect is by us-
ing meta-analytic procedures. Between-group differ-
ences on individual neuropsychological tests can be
computed, averaged within ability areas, and then
combined across studies to determine the overall can-
nabis effect for each ability area. This approach bene-
fits fromits ability to generate a quantitative estimate of
an effect and its confidence limits, which more closely
approximates a real effect than a dichotomous con-
clusion. We recently conducted a meta-analysis of the
studies in this review that violated only a few of our
minimal criteria.
Following a thorough examination of the studies in-
cluded in this review, additional methodological con-
cerns surfaced that were not directly addressed by our
a priori minimal criteria. Of particular concern was
the possibility that the control and cannabis groups in
several studies differed on influential factors not di-
rectly related to cannabis consumption. For example,
demographic factors such as age, sex, ethnicity, and
years of education are known to affect neuropsycho-
logical performance.
20,21
Therefore, if groups differed
on any of these factors, observed between-group differ-
ences on neuropsychological performance could not
have been confidently attributed solely to cannabis
use. The effects of these factors canbe reducedbyusing
demographically corrected normative data for neuro-
psychological outcome measures or by using demo-
graphic factors as covariates in statistical analyses;
however, few studies took advantage of these ap-
proaches. Nevertheless, both of these methods have
limitations. Specifically, comprehensive normative
data that adjust for all pertinent demographic factors
are not available for most neuropsychological instru-
ments. Covariates may reduce the effects of
demographic differences between groups, but their use
does not equate groups on these factors, nor does it
completely eliminate their influence and is subject to
other limitations.
22
Another relatedissue affecting most studies was that
the premorbid neuropsychological abilities of these
subjects were largely unknown because subjects
neuropsychological performance prior to the onset of
regular marijuana use was not documented. Some
studies attempted to estimate premorbid intelligence
through consideration of performance on tests that are
not likely to be affected by subtle brain injury (e.g.,
scores on the Vocabulary subtest of the Wechsler Adult
Intelligence Scale [WAIS] series). Although the use of
these methods is better than doing nothing at all, they
do not effectively equate groups on all important influ-
ential factors and cannot ensure that subjects come
fromthe same population. As a result, theyare oftenin-
adequate. It is important that the groups examined are
sampled from the same population and resemble each
other onas manyfactors as possible, withthe exception
of cannabis use. Some of the most elegant and sophisti-
cated studies reviewed in this article suffered from
some of these methodological problems despite meet-
ing our minimal criteria. Furthermore, given the
characteristics of their sample (i.e., only cannabis-
dependent individuals, patients from recovery homes,
etc.), some studies obtained results that are not
generalizable to the entire population of individuals
with histories of cannabis use.
We acknowledge the difficulties inherent in study-
ing this topic, given the vast array of potential con-
founds that could affect results. It is because of these
difficulties that we strongly believe it is inaccurate to
conclude the presence of a cannabis effect when em-
ploying suboptimal designs. Stronger research designs
can be implemented to more accurately determine the
presence of a cannabis effect. For example, studying
children and young adolescents prior to entering a pe-
riod for risk to cannabis exposure can reduce the influ-
ence of several confounds. An alternative strategy
wouldbe to examine monozygotic twins discordant for
marijuana and other substance use. In such studies,
one canbe more confident of controlling for native en-
dowment. In the absence of such designs, which can
be costly to implement, the approach developed by
Pope and colleagues
19
represents the next best alterna-
tive. By examining regular active users who were in-
structed to abstain and then were repeatedly tested
during a lengthy supervised abstinence period, studies
such as those designed by Pope et al bring us closer to
understanding the persisting effects of marijuana
use while simultaneously minimizing important
confounds.
The results fromthis article should present a clearer
picture of the researchmethodologycommonlyusedin
studies investigating the nonacute effects of cannabis
on neuropsychological performance. Some of the most
important methodological shortcomings and con-
founds in these studies were highlighted, and tech-
niques to eliminate or minimize their influence were
discussed. Future studies that attempt to establish a
nonacute effect of cannabis on neuropsychological
functioning should take special care to ensure that
these issues are addressed. In this way, misinterpreta-
tion of study results can be minimized, thus revealing
the true impact of cannabis use on cognitive abilities.
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