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CME Dose-related neurocognitive
effects of marijuana use
K.I. Bolla, PhD; K. Brown, MPH; D. Eldreth, BA; K. Tate, BA; and J.L. Cadet, MD
Abstract—Background: Although about 7 million people in the US population use marijuana at least weekly, there is a
paucity of scientific data on persistent neurocognitive effects of marijuana use. Objective: To determine if neurocognitive
deficits persist in 28-day abstinent heavy marijuana users and if these deficits are dose-related to the number of
marijuana joints smoked per week. Methods: A battery of neurocognitive tests was given to 28-day abstinent heavy
marijuana abusers. Results: As joints smoked per week increased, performance decreased on tests measuring memory,
executive functioning, psychomotor speed, and manual dexterity. When dividing the group into light, middle, and heavy
user groups, the heavy group performed significantly below the light group on 5 of 35 measures and the size of the effect
ranged from 3.00 to 4.20 SD units. Duration of use had little effect on neurocognitive performance. Conclusions: Very
heavy use of marijuana is associated with persistent decrements in neurocognitive performance even after 28 days of
abstinence. It is unclear if these decrements will resolve with continued abstinence or become progressively worse with
continued heavy marijuana use.
NEUROLOGY 2002;59:1337–1343
Marijuana is the most widely used illicit drug in the
United States and the western hemisphere. In 2000,
an estimated 76% of America’s 14.8 million illicit
drug users used marijuana alone (59%) or in con-
junction with other illicit drugs (17%).
1
About 7 mil-
lion people in the US population use marijuana at
least weekly.
1
Because of debate about medicinal
uses and legalization of marijuana, knowing whether
marijuana has persistent effects on the brain is of
interest.
Studies of residual cognitive effects of marijuana
following a brief period of abstinence show that
heavy marijuana use is associated with deficits in
executive cognitive functioning, sustained attention,
and memory.
2-5
These studies have some method-
ologic limitations. First, marijuana users were only
monitored for abstinence for 17 to 72 hours before
testing. Because marijuana has an apparent half-life
of 4.1 ⫾1.1 days,
6
it is difficult to determine if the
these observations
2-5
were due to drug residues in
the body or to withdrawal symptoms such as anxiety
or irritability.
7
Second, the quantification of heavy
versus light users may be problematic. Marijuana
users have been grouped by frequency of use
2
and
duration of use.
3,4
When marijuana users are sepa-
rated by duration of use, it is troublesome to sepa-
rate the effects of marijuana from differences in age
and education (a cohort effect). Third, no structured
psychiatric interview was used to exclude disorders
like depression,
3
which is associated with poor cogni-
tive performance.
8
Until 2001, there were no published reports of the
residual effects of marijuana use on cognitive func-
tioning after a period of abstinence longer than 12 to
72 hours. In a carefully designed study, marijuana
users were grouped by frequency of use and neuro-
cognitive testing was repeated over 28 days of absti-
nence (0, 1, 7, and 28 days).
9
Decrements in memory
for word lists were found at 7 days of abstinence but
not after 28 days of abstinence. The authors thus
concluded that cognitive deficits are reversible after
7 days of abstinence and are related to recent, not
cumulative, cannabis use. Knowledge about the cog-
nitive effects of marijuana could also provide a basis
for determining the relative contribution of marijuana
when used in combination with other drugs such as
methylenedioxymethamphetamine (MDMA).
10,11
The current study was conducted to determine
whether neurocognitive deficits persist in 28-day ab-
stinent heavy marijuana users and if these deficits
are dose-related (joints smoked/week). Based on our
previous work in cocaine and MDMA users,
12,13
we
hypothesized that deficits in cognitive performance
would be observed only in the heaviest users of
marijuana.
Methods. Participants. This protocol was approved by
the National Institute on Drug Abuse–Intramural Re-
Additional material related to this article can be found on the Neurology
Web site. Go to www.neurology.org and scroll down the Table of Con-
tents for the November 12 issue to find the title link for this article.
From the Department of Neurology (Dr. Bolla and D. Eldreth), Johns Hopkins University School of Medicine, Hopkins Bayview Research Campus; and
Molecular Neuropsychiatry Section (K. Brown, K. Tate, and Dr. Cadet), NIH/NIDA-IRP, Baltimore, MD.
Supported by the Intramural Research Program of NIDA.
Received May 6, 2002. Accepted in final form July 11, 2002.
Address correspondence and reprint requests to Dr. Karen I. Bolla, Johns Hopkins Bayview Medical Center, Department of Neurology, 4940 Eastern Ave.,
Baltimore, MD 21224; e-mail: kbolla@jhmi.edu
Copyright © 2002 by AAN Enterprises, Inc. 1337
search Program (NIDA-IRP), the Joint Committee on Clin-
ical Investigation, and the Johns Hopkins Bayview
Medical Institutional Review Boards. All participants gave
written informed consent and were compensated for their
time. Marijuana abusers were recruited using newspaper
advertisements. Participant selection was based on drug
use history obtained using structured interviews including
the Drug Use Survey Questionnaire (DUSQ),
14
the Addic-
tion Severity Index (ASI,)
15
and the Diagnostic Interview
Schedule (DIS).
16
Marijuana group. The marijuana group consisted of
nontreatment-seeking individuals claiming marijuana as
their drug of choice who used marijuana for at least 2
years, smoked marijuana at least three times per week,
reported alcohol consumption of less than 14 alcoholic
drinks per week, and had a urine toxicology screen that
was positive for cannabis metabolites at the time of admis-
sion to the study. This ensured that all participants were
abstinent for a uniform period of time. Participants were
still eligible for inclusion if dependent on caffeine or to-
bacco. Participants were excluded if they met the Diagnos-
tic and Statistical Manual of Mental Disorders–IV (DSM-
IV) criteria gleaned from the DIS for current or past
dependence on any other psychoactive substance other
than marijuana, including alcohol, or if their urine toxicol-
ogy screen was positive for substances other than mari-
juana and its metabolites. The ASI and DUSQ were used
to estimate the number of joints smoked per week and the
duration of marijuana use.
Exclusion criteria for all participants. Volunteers were
excluded for past or current psychiatric disorder by
DSM-IV criteria using the DIS (i.e., anxiety disorder, post-
traumatic stress disorder, and major depressive disorder).
Volunteers were also excluded for a past or current history
of neurologic illness (e.g., head trauma resulting in loss of
consciousness, seizure disorder, stroke), an abnormal neu-
rologic examination, or pregnancy.
Data collection. At the initial visit to the Clinical Inpa-
tient Research Unit (CIRU) at NIDA-IRP, all participants
had a medical evaluation, a neurologic examination, urine
toxicology screen, and pregnancy test for women. Partici-
pants were then admitted to the CIRU for approximately
30 days. This allowed us to examine persistent effects of
marijuana on the brain, rather than acute effects. Random
drug screens were performed during the inpatient stay to
ensure abstinence. No treatment or medications were
given over the 30-day stay.
Neuropsychological measures. The neurocognitive test
battery was administered by a trained psychometrician
under the supervision of a neuropsychologist (K.I.B.). The
neurocognitive battery consisted of tests that assess a va-
riety of cognitive domains. General intelligence was esti-
mated using the Shipley Institute of Living Scale.
17
The
Shipley estimated IQ correlates with the Wechsler Adult
Intelligence Scale–Revised (WAIS-R) full-scale IQ (r⫽
0.79). Measures of IQ are believed to be good estimates of
native intellectual abilities (premorbid intelligence) and
are resistant to the effects of brain injury. Language skills
were assessed using Controlled Oral Verbal Fluency.
18
Verbal memory was assessed by the Logical Memory from
the Wechsler Memory Scales–Revised (WMS-R)
19
and the
Rey Auditory Verbal Learning Test (RAVLT),
20
whereas
visual memory was assessed using the Rey Osterreith
Complex Figure
21
and the Symbol Digit Paired Associate
Learning Test.
22
Attention and concentration were as-
sessed using the Verbal and Non-Verbal Cancellation
Test
23
for both randomly placed letters and symbols. Exec-
utive functioning was measured with the Digit Symbol
Substitution from the WAIS-R,
24
Trails A, Trails B,
25
Stroop,
26
and the Wisconsin Card Sorting Test (WCST).
27
The
Rey Complex Figure (copy), Block Design (WAIS-R),
24
and
Judgment of Line Orientation
28
assessed visuoperception/
visuoconstruction. The California Computerized Assessment
Package (CALCAP)
29
was used to assess both simple and
Table 1 Demographic characteristics of marijuana users by amount used
Characteristic All, n ⫽22 Light group, n ⫽7 Middle group, n ⫽8 Heavy group, n ⫽7
Age, y 22.4 ⫾4.9 (18–37) 24.6 ⫾6.1 (18–37) 21.9 ⫾5.3 (18–34) 20.7 ⫾2.4 (18–25)
Education, y 11.4 ⫾1.5 (8–14) 12.7 ⫾0.7* (12–14) 10.9 ⫾1.5 (8–12) 10.7 ⫾1.5 (8–12)
Shipley IQ 95.9 ⫾10.9 (78–115) 101.9 ⫾9.9 (86–115) 95.0 ⫾11.2 (80–114) 91 ⫾10 (78–101)
Sex, M/F 19/3 5/2 7/1 7/0
Ethnicity, W/AA/other 1/18/3 1/5/1 0/6/2 0/7/0
Handedness, R/L 19/3 7/0 6/2 6/1
Marijuana use
Joints/wk 48.5 ⫾36.9 (2–117) 10.5 ⫾4(2–14) 42.1 ⫾18.2 (18–70) 93.9 ⫾15.4 (78–117)
Days/wk 5.8 ⫾1.7 4.4 ⫾1.0 5.9 ⫾1.9 7.0 ⫾0.2
Duration, y 4.8 ⫾3.1 (2–15) 3.4 ⫾1.6 (2–6) 5.4 ⫾4.2 (2–15) 5.3 ⫾2.4 (3–10)
Alcohol use
Days/wk 1.1 ⫾1.3 (0–5) 1.0 ⫾1.4 (0–3) 0.6 ⫾0.7 (0–2) 1.5 ⫾1.7 (0–5)
Drinks/wk 3.2 ⫾4.2 (0–13) 2.4 ⫾4.1 (0–11) 3.1 ⫾4.6 (0–13) 4.1 ⫾4.3 (0–13)
Duration, y 3.8 ⫾6.1 (0–26) 2.3 ⫾3.9 (0–10) 2.0 ⫾2.1 (0–5) 3.0 ⫾2.7 (0–7)
Values are mean ⫾SD (range).
*p⬍0.05; Mean difference is between the light and middle and light and heavy groups.
Light group ⫽2–14 joints/wk; middle group ⫽18 –70 joints/wk; heavy group ⫽78 –117 joints/wk. W ⫽white; AA ⫽African American.
1338 NEUROLOGY 59 November (1 of 2) 2002
choice reaction times (psychomotor speed). Manual dexterity
was assessed using Finger Tapping
25
and Grooved Peg-
board.
30
Participants were tested on the 27th or 28th day
after admission to the inpatient research unit. This elimi-
nated any acute drug effects and possible confounding effects
on neurocognitive performance from the physical or psycho-
logical symptoms associated with drug or alcohol withdrawal.
All testing was performed in the morning to reduce diurnal
fluctuations in performance. The examiner was blind to the
intensity and duration of drug use.
Data analyses. Multiple linear regression models were
used for data analyses. Neurocognitive variables were log
transformed if not normally distributed. Exploratory anal-
yses examined the possible effects of age, education, Ship-
ley IQ, depression score (Center for Epidemiologic Studies–
Depression), and sex on the neurocognitive performance
measures. An independent variable was retained in the
model if associated (p⬍0.05) with the neurocognitive out-
come variable. A separate multiple regression analysis was
performed for each of the neurocognitive tests. As with our
previous studies that found dose-related effects of cocaine
13
and MDMA
12
on neurocognitive performance predomi-
nately at higher doses, it was desirable to establish a dose-
related relationship between quantity and duration of
marijuana use and possible neurocognitive decrements.
Therefore, models included either joints per week, dura-
tion of use, or a cross-product of joints per week ⫻dura-
tion. A joints per week squared term was also included in
the models to test for nonlinear effects that would indicate
a threshold effect. We did not examine the association
between frequency of use and neurocognitive performance
because 82% of our sample smoked marijuana 20 or more
days a month. Interaction terms (i.e., Shipley IQ ⫻joints/
week) were also examined. All analyses were performed
with SPSS statistical software program (Chicago, IL).
Results. Table 1 shows the demographic and drug use
characteristics of the marijuana users. When taken as a
whole, the entire group consisted of predominantly heavy
marijuana users (median joints per week ⫽35; range 2 to
117). The group was also divided into light, middle, and
heavy users by dividing the group using terciles of joints
per week smoked (see table 1). Except for years of educa-
tion, there were no significant differences for any of the
subject characteristics listed in table 1 (see also below).
Table 2 summarizes significant dose-related effects on
key outcome variables for the regression analyses. The R
2
total reflects the overall proportion of the variance ac-
counted for by the model after the last significant variable
was entered in the equation. The results show both linear
and nonlinear dose-response effects (i.e., as joints per week
increase, neurocognitive performance declines; p⬍0.05).
This was found for tests of verbal memory (RAVLT, delayed
recall, F[1,21] ⫽7.30), visual learning and memory (Symbol-
Digit Paired Associate Learning, F[1,21] ⫽6.57), executive
functioning (WCST categories completed, F[1,20] ⫽7.09),
psychomotor speed (simple reaction time [CALCAP], F[1,21]
⫽8.32; complex reaction time–number correct, F[1,21] ⫽
11.96), and manual dexterity (Grooved pegboard–nondomi-
nant hand, F[1,21] ⫽6.55). A significant dose-related effect
in the opposite direction (i.e., as joints per week increased,
performance increased) was found for the CALCAP–numbers
in sequence, false positive responses (F[1,21] ⫽4.87). More-
over, the models accounted for a moderate to a large amount
of variance (19 to 57%) in neurocognitive performance. Dura-
tion of use was associated only with a decrease in perfor-
Table 2 Linear regression analyses of outcome variables, demonstrating a significant dose-related effect with marijuana use
Dependent variable Independent variable* Exposure variable pValue Total R
2
RAVLT—delayed recall Joints/wk 0.01 0.27
Symbol–digit paired associate learning Joints/wk
2
⫻Shipley IQ Joints/wk
2
0.02 0.45
(p⫽0.01)
Stroop Joints/wk ⫻Shipley IQ Joints/wk 0.01 0.45
(p⫽0.01)
WCST—categories completed Joints/wk 0.02 0.28
Rey complex figure—copy Duration 0.05 0.19
RT—simple Joints/wk
2
0.01 0.52
RT—repetition of numbers, number correct Joints/wk
2
⫻Shipley IQ Joints/wk
2
0.01 0.57
(p⫽0.03)
RT—numbers in sequence, false positives†Shipley IQ Joints/wk 0.04 0.32
(p⫽0.01)
Grooved Pegboard—nondominant hand Joints/wk
2
⫻Shipley IQ Joints/wk
2
0.02 0.44
(p⫽0.01)
* To control for possible confounding effects, these variables were retained in the model if a significant association (p⬍0.05) was found
with performance.
†For this variable, as marijuana use increases, performance improves; for all the other variables, as marijuana use increases, perfor-
mance declines.
RAVLT ⫽Rey Auditory Verbal Learning Test; WCST ⫽Wisconsin Card Sorting Test; RT ⫽reaction time from the California Comput-
erized Assessment Package.
November (1 of 2) 2002 NEUROLOGY 59 1339
mance on one test, a test of visuoperception/visuoconstruction
(Rey Osterreith Complex Figure–copy, F[1,21] ⫽4.38). Fi-
nally, the combination of amount and duration was not re-
lated to performance on any of the tests.
To illustrate differences in neurocognitive performance
between the lightest and heaviest marijuana users, the
group was divided into three groups based on the amount
of marijuana smoked as noted above (see table 1). The
light group smoked a mean of 11 ⫾4 joints/week (range 2
to 14), the middle group reported smoking a mean of 42 ⫾
18 joints/week (range 18 to 70), and the heavy marijuana
group reported smoking a mean of 94 ⫾15 joints/week
(range 78 to 117) (see table 1). The groups did not differ
significantly on age, Shipley IQ score, number of women
and men, duration of marijuana use, and alcohol use (see
table 1). However, because the mean Shipley IQ score was
different for the light (102), middle (95), and heavy (91)
users, we elected to take a conservative approach and ana-
lyze the group differences using an analysis of covariance
(ANCOVA) with Shipley IQ score as a covariate. The mean
performance scores, adjusted for differences in Shipley IQ,
are presented in the online supplementary table (available
at www.neurology.org). Differences among the three
groups were examined with post-hoc t-tests. Comparison of
group means shows the heavy users performing worse
than the light users on 24/35 (69%) of the neurocognitive
performance measurements; this difference was significant
on five of the neurocognitive measures. Significant group
differences were also found between the light and middle
users on four of the tests, and between the middle and
heavy users on two of the tests. When the scores of the
heavy users were compared to published age-appropriate
normative values for each of the tests, scores considered to
be clinically relevant (below the ninth percentile for the
general population) were found for the WCST–categories
completed, Rey Complex Figure (copy and delayed recall),
and Finger Tapping (dominant hand).
Interaction effects. There were four significant interac-
tions involving joints/week and Shipley IQ. A Shipley IQ ⫻
joints per week interaction was found for the Stroop
(F[1,21] ⫽10.31). A Shipley IQ ⫻joints per week
2
interac-
tion was found for Symbol-Digit Paired Associate Learning
(F[1,21] ⫽8.67), reaction time repetition of numbers-
correct (F[1,21] ⫽5.89), and Grooved Pegboard–nondomi-
nant hand (F[1,21] ⫽8.25) (see table 2). In general,
individuals with lower Shipley IQ scores (less than 96)
showed decreasing cognitive performance with increasing
number of joints smoked/week whereas individuals with
higher Shipley IQ scores had fewer decrements and better
performance with increasing marijuana use. To visualize
the joints smoked ⫻Shipley IQ interaction, joints smoked/
week was divided into terciles and the mean for each ter-
cile was used for the joints/week ⫻Shipley IQ adjusted
plots (figure, A and B). Shipley IQ groups were formed by
splitting the group by the median Shipley IQ score of 96.
Discussion. In very heavy marijuana users, per-
sistent, negative dose-related effects are found on
tests measuring verbal and visual memory, executive
functioning, visuoperception, psychomotor speed,
and manual dexterity. This effect was nonlinear for
some tests, suggesting a threshold effect. Although
we find a dose-related association between joints per
week smoked of marijuana and cognitive decline, du-
ration of use is only associated with performance on
one test and a combination of joints/week ⫻duration
is not associated with performance on any test. In
contrast to previous findings,
4
duration is not
strongly related to performance. This is probably be-
cause our marijuana group has shorter duration of
use (4.8 ⫾3.1 years, range 2 to 15 years) compared
to other samples of marijuana users (7.1 ⫾7.9 years,
range 2.7 to 31.7 years).
4
Additionally, our findings
do not confirm previous reports showing resolution of
cognitive effects after 24 days of marijuana absti-
nence.
9
This discrepancy may be due to our approach
to estimating marijuana use (i.e., joints per week) in
contrast to those of other investigators (i.e., duration
and frequency).
2-5,9
Indeed, joints smoked per week
may be a better estimate of total marijuana intake
than frequency or duration of use because a mari-
juana user smoking 10 joints/day for 10 years would
probably show greater neurocognitive effects than a
marijuana user smoking one joint/day for 10 years.
Heavy marijuana use was associated with lower
performance on tests of memory, executive function-
ing, and manual dexterity. These findings are simi-
lar to the findings of others.
2,4
The RAVLT delayed
memory test shows a significant association with the
amount of marijuana smoked and there is a trend
showing that heavy users performed below the light
users on all measures of verbal learning and mem-
ory. In fact, the magnitude of the difference in mean
performance between the heavy and light users is
substantial (1.0 to 3.3 SD units). However, because
the heavy marijuana group can recognize previously
Figure. (A) Relation between amount
of marijuana smoked
2
and Repetition of
Numbers Task, number correct for the
high Shipley IQ group (squares) and
the low Shipley IQ group (circles). (B)
Relation between amount of marijuana
smoked
2
and performance on the Stroop
task for the high Shipley IQ group
(squares) and the low Shipley IQ group
(circles). The lower the IQ score the
worse the performance. Both A and B
reveal a significant joints per week ⫻
Shipley IQ interaction.
1340 NEUROLOGY 59 November (1 of 2) 2002
learned material (RAVLT–Recognition), this pattern
suggests difficulty with information recall, not prob-
lems with acquisition or retention of information.
This pattern of memory performance is characteris-
tic of subcortical, prefrontal lobe involvement, and
normal aging. Visual learning and memory (Symbol-
Digit Paired Associate Learning) are also affected by
heavy marijuana use.
There was also an association between increasing
marijuana use and decreasing executive cognitive
functioning. This is apparent on the WCST and the
effect sizes are large (4.1 to 4.2 SD units). Poor perfor-
mance on the WCST indicates difficulty incorporating
feedback to guide and change incorrect response selec-
tion. The Stroop test requires suppression of a more
habitual response in favor of an atypical one (response
inhibition) and involves performance monitoring. Per-
formance on the Stroop is affected by marijuana use
but only in individuals with lower cognitive reserves,
as illustrated by the significant joints per week ⫻Ship-
ley IQ interaction (see the figure, B). This is consistent
with the suggestion that individuals with higher intel-
lectual functions, or cognitive reserve, demonstrate a
higher threshold for developing neurocognitive deficits
after insults to the brain.
31
This argument is supported
by observations that individuals exposed to solvents,
32
aluminum,
33
and MDMA (Ecstasy)
12
show similar in-
teractions. Difficulties with executive functions indi-
cate a prefrontal lobe dysfunction. The prefrontal lobe
is suspected to play an important role in substance
abuse/addiction and dysfunction of this region may be
associated with perpetuation of self-destructive drug
using behavior and resistance to treatment.
34
The heavy marijuana users also showed slower reac-
tion times on a simple reaction time test (CALCAP).
However, when presented with more complex reac-
tion time tests, the difference between the heavy and
light marijuana users became less pronounced. The
reason for this is unclear. In addition, heavier use of
marijuana is not associated with less accurate per-
formance except for the Repetition of Numbers task
but only for those with lower Shipley IQ (see the
figure, A). No dose-related association is found for
false positive responses, a measure of impulsivity.
Thus, heavy marijuana use appears to be unrelated
to decrements in response time, accuracy, or impul-
sive performance on complex psychomotor speed/
reaction time tests. Heavy marijuana use is also
associated with lower performance on both manual
dexterity measures (Finger Tapping and Grooved
Pegboard).
This study has a number of limitations. Despite
making multiple comparisons, we used a pvalue of
0.05 in order to detect small adverse effects of mari-
juana on neurocognitive functioning. More adverse
associations were found than could be accounted for
by chance alone. In addition, although our ability to
detect more effects might have been limited by the
relatively small sample size, significant effects were
found on several measures. Moreover, in the regres-
sion analyses, the sizes of the effects were moderate
to large (R
2
⫽0.22 to 0.57). Likewise, the heavy
users performed two standard deviations or more
below the light users on 8/35 (23%) of the measures;
this is not a trivial effect. Furthermore, heavy users
showed clinically abnormal scores on four of our test
measures. Although we use a different estimate of
marijuana use (i.e., joints per week) in general, our
findings show decrements on similar tests of neuro-
psychological functioning.
4
Those decrements are not
secondary to concomitant use of other drugs because
participants were excluded for a current or past his-
tory of significant use of other substances including
alcohol. Although the presence of a dose-related re-
sponse strengthens the ability to make causal infer-
ences, no definitive statements about causality can
be made. This can only be determined with a pro-
spective study of controlled marijuana administra-
tion, an approach that would be ethically untenable.
Finally, because our primary interest is the determi-
nation of a dose-related effect of marijuana on neuro-
cognitive function, we did not include a group of
nonusers. We agree with others that a comparison
between light users and heavy users is less influ-
enced by confounding variables (i.e., background dif-
ferences) than a comparison between marijuana
users and nonusers.
2
It may be difficult to generalize these findings to
all users of marijuana because of our strict selection
criteria. For example, comorbid psychiatric disorders
(i.e., anxiety disorders, major depression) and heavy
alcohol use are common in substance abusers. How-
ever, we excluded individuals with these disorders to
avoid any possible confounding effects on neurocog-
nitive functioning. Finally, it could be argued that
the self-reports of marijuana use are inaccurate. The
finding of a biologically plausible dose-response sug-
gests that the estimates of drug use were accurate,
although this cannot be proven definitively.
The neurocognitive functions most negatively af-
fected were memory, executive function, and manual
dexterity. The hippocampus, prefrontal cortex, and
cerebellum play a major role in these functions. All
of these regions are dense with cannibinoid recep-
tors,
35
and these results are biologically plausible be-
cause tetrahydrocannabinol (THC) has been shown
to cause deleterious effects on these brain regions.
Our observations in humans are consistent with
studies in laboratory animals that find learning and
memory impairments after administration of ⌬
9
-
THC.
36
In rats, morphologic changes are found in the
CA1 region of the hippocampus with acute adminis-
tration of a synthetic THC analogue.
37
Damage to the
CA1 is also seen after ischemia,
38
toxin exposure,
39
or
traumatic brain injury.
40
Therefore, cannabinoids
may exert changes in the hippocampus that are sim-
ilar to those found with other types of brain injury.
Changes in CB1 receptors in the hippocampus are
also observed in rats after THC administration and
are associated with selective deficits in working
memory.
41
These animal studies provide strong evi-
November (1 of 2) 2002 NEUROLOGY 59 1341
dence that hippocampal changes might indeed un-
derlie the memory deficits in the current report.
Following marijuana administration, brain im-
ages show lower rCBF in the human motor cortex
and superior temporal gyrus and higher rCBF in
paralimbic brain regions during a dichotic listening
task.
42
The authors suggest that the increases in
rCBF may modulate the intoxicating and mood-
related effects of marijuana whereas reductions in
task-related rCBF in the temporal lobe regions may
account for impaired cognition associated with mari-
juana intoxication. In 26-hour abstinent marijuana
abusers, lower rCBF was found during a resting con-
dition in the ventral prefrontal cortex, bilaterally.
43
Thus, when taken together with the evidence of
THC-induced hippocampal damage in animals and
with the THC-associated neurophysiologic alter-
ations in humans, our current data suggest that
THC may exert a significant negative impact on the
human brain.
Finally, whereas heavy use of marijuana is associ-
ated with decrements in neurocognitive performance,
except for a few tests, performance was not clinically
abnormal. However, the average age of our group
was only 22 years. Given the large extent of the
effects, very heavy continuous use of marijuana
could produce progressive declines in performance
that might reach clinical significance. In fact, be-
cause the pattern of performance on the learning and
memory tests is consistent with normal age-related
declines in the elderly, continued heavy marijuana
abuse might result in premature cognitive decline.
Acknowledgment
The authors thank all the nurses and staff at NIDA-IRP who
contributed to this project. They especially thank Regina Hess,
BA, for editorial assistance with the final manuscript and Warren
Better, MA, for database support.
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Abnormal brain activation on functional
MRI in cognitively asymptomatic
HIV patients
T. Ernst, PhD; L. Chang, MD; J. Jovicich, PhD; N. Ames, BA; and S. Arnold, MS
Abstract—Background/Objectives: A previous fMRI study demonstrated increased brain activation during working mem-
ory tasks in patients with HIV with mild dementia. The current study aims to determine whether patients who are HIV-1
positive and have normal cognitive function also show increased brain activation on fMRI. Methods: Blood oxygenation
level-dependent (BOLD) fMRI was performed in 10 patients with HIV (CD ⬍500) and 10 age-, sex-, education-, and
handedness-matched seronegative subjects. Each subject performed a battery of neuropsychological tests and fMRI with
three tasks (0-back, 1-back, and 2-back) that required different levels of attention for working memory. Results: Compared
with control subjects, patients with HIV showed greater magnitude of brain activation (BOLD signal intensity changes,
pⱕ0.001) in the lateral prefrontal cortex, with normal performance during fMRI and on a battery of neuropsychological
tests. The patients with HIV also showed increased activated brain volume in the lateral prefrontal cortex (p⫽0.007) but
not in other activated regions, including the posterior parietal cortex, supplementary motor area, thalamus, caudate, and
occipital cortex. The increase in activated brain volume was independent of task difficulty. Conclusion: Increased brain
activation in subjects who are positive for HIV precedes clinical signs or deficits on cognitive tests. Early injury to the
neural substrate may necessitate increased usage of brain reserve to maintain normal cognitive function. BOLD fMRI
appears to be more sensitive than clinical and neuropsychological evaluations for detecting early HIV-associated brain
injury.
NEUROLOGY 2002;59:1343–1349
Cognitive abnormalities commonly occur in patients
with HIV-1 infection.
1
Among healthy individuals
who are seropositive for HIV, cognitive deficits are
thought to be infrequent
2
; however, some investiga-
tors suggest that more sensitive measures may be
needed to detect the mild cognitive decline during
the asymptomatic stage.
3
In later stages of HIV dis-
ease, with CD4 counts ⬍100 cells/L, approximately
20% of patients may develop a more disabling de-
mentia syndrome directly related to HIV infection
4
;
this syndrome has been termed HIV cognitive motor
complex (CMC).
5
Early diagnosis and treatment of
HIV dementia are especially important because pa-
tients with early stages of the dementia may show
reversal of their cognitive deficits and neurochemical
abnormalities after treatment.
6,7
Typical neuropsychological deficits in patients
with HIV include decreased sustained attention,
mental flexibility, general motor speed, and memo-
ry
8,9
; in particular, working memory may be
affected.
10-13
However, little is known about the neu-
roanatomic substrate underlying these neuropsycho-
logical deficits. A variety of functional neuroimaging
techniques, including PET,
14
SPECT,
15,16
and MRS,
17-19
found alterations in cerebral blood flow and metabo-
lism in the brains of individuals infected with HIV.
Although the majority of these studies were performed
in patients with HIV with cognitive impairment or de-
From the Medical Department (Drs. Ernst and Chang, and S. Arnold) and Chemistry Department (Dr. Ernst), Brookhaven National Laboratory, Upton, NY;
Department of Brain and Cognitive Sciences (Dr. Jovicich), Massachusetts Institute of Technology, Cambridge; and Department of Neurology (N. Ames),
Harbor–University of California, Los Angeles Medical Center, Torrance.
Supported by grants from the National Institute on Drug Abuse (Scientist Development Award for Clinicians for L.C., 5 K20 DA00280), National Institute of
Mental Health (1R01 61427-01), and General Clinical Reearch Center (MO1-RR00425).
Received December 3, 2001. Accepted in final form July 17, 2002.
Address correspondence and reprint requests to Dr. Thomas Ernst, Medical Department, Brookhaven National Laboratory, Bldg. 490, Upton, NY, 11973-
5000; e-mail: TErnst@bnl.gov
Copyright © 2002 by AAN Enterprises, Inc. 1343
DOI 10.1212/01.WNL.0000031422.66442.49
2002;59;1337-1343 Neurology
K.I. Bolla, K. Brown, D. Eldreth, et al.
Dose-related neurocognitive effects of marijuana use
This information is current as of November 12, 2002
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