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Dose-Related Neurocognitive Effects of Marijuana Abuse

  • Johns Hopkins Medicine, Bayview Medical Center

Abstract and Figures

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. 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. A battery of neurocognitive tests was given to 28-day abstinent heavy marijuana abusers. 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. 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.
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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%).
About 7 mil-
lion people in the US population use marijuana at
least weekly.
Because of debate about medicinal
uses and legalization of marijuana, knowing whether
marijuana has persistent effects on the brain is of
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.
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,
it is difficult to determine if the
these observations
were due to drug residues in
the body or to withdrawal symptoms such as anxiety
or irritability.
Second, the quantification of heavy
versus light users may be problematic. Marijuana
users have been grouped by frequency of use
duration of use.
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,
which is associated with poor cogni-
tive performance.
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).
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).
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,
hypothesized that deficits in cognitive performance
would be observed only in the heaviest users of
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 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:
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),
the Addic-
tion Severity Index (ASI,)
and the Diagnostic Interview
Schedule (DIS).
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 DisordersIV (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.
Shipley estimated IQ correlates with the Wechsler Adult
Intelligence ScaleRevised (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.
Verbal memory was assessed by the Logical Memory from
the Wechsler Memory ScalesRevised (WMS-R)
and the
Rey Auditory Verbal Learning Test (RAVLT),
visual memory was assessed using the Rey Osterreith
Complex Figure
and the Symbol Digit Paired Associate
Learning Test.
Attention and concentration were as-
sessed using the Verbal and Non-Verbal Cancellation
for both randomly placed letters and symbols. Exec-
utive functioning was measured with the Digit Symbol
Substitution from the WAIS-R,
Trails A, Trails B,
and the Wisconsin Card Sorting Test (WCST).
Rey Complex Figure (copy), Block Design (WAIS-R),
Judgment of Line Orientation
assessed visuoperception/
visuoconstruction. The California Computerized Assessment
Package (CALCAP)
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 (1837) 24.6 6.1 (1837) 21.9 5.3 (1834) 20.7 2.4 (1825)
Education, y 11.4 1.5 (814) 12.7 0.7* (1214) 10.9 1.5 (812) 10.7 1.5 (812)
Shipley IQ 95.9 10.9 (78115) 101.9 9.9 (86115) 95.0 11.2 (80114) 91 10 (78101)
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 (2117) 10.5 4(214) 42.1 18.2 (1870) 93.9 15.4 (78117)
Days/wk 5.8 1.7 4.4 1.0 5.9 1.9 7.0 0.2
Duration, y 4.8 3.1 (215) 3.4 1.6 (26) 5.4 4.2 (215) 5.3 2.4 (310)
Alcohol use
Days/wk 1.1 1.3 (05) 1.0 1.4 (03) 0.6 0.7 (02) 1.5 1.7 (05)
Drinks/wk 3.2 4.2 (013) 2.4 4.1 (011) 3.1 4.6 (013) 4.1 4.3 (013)
Duration, y 3.8 6.1 (026) 2.3 3.9 (010) 2.0 2.1 (05) 3.0 2.7 (07)
Values are mean SD (range).
*p0.05; Mean difference is between the light and middle and light and heavy groups.
Light group 214 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
and Grooved Peg-
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 (p0.05) 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
and MDMA
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
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; p0.05).
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 timenumber correct, F[1,21]
11.96), and manual dexterity (Grooved pegboardnondomi-
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 CALCAPnumbers
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
RAVLTdelayed recall Joints/wk 0.01 0.27
Symboldigit paired associate learning Joints/wk
Shipley IQ Joints/wk
0.02 0.45
Stroop Joints/wk Shipley IQ Joints/wk 0.01 0.45
WCSTcategories completed Joints/wk 0.02 0.28
Rey complex figurecopy Duration 0.05 0.19
RTsimple Joints/wk
0.01 0.52
RTrepetition of numbers, number correct Joints/wk
Shipley IQ Joints/wk
0.01 0.57
RTnumbers in sequence, false positivesShipley IQ Joints/wk 0.04 0.32
Grooved Pegboardnondominant hand Joints/wk
Shipley IQ Joints/wk
0.02 0.44
* To control for possible confounding effects, these variables were retained in the model if a significant association (p0.05) 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 Figurecopy, 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 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 WCSTcategories
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
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 Pegboardnondomi-
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,
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).
Additionally, our findings
do not confirm previous reports showing resolution of
cognitive effects after 24 days of marijuana absti-
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).
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.
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
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
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 (RAVLTRecognition), 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.
This argument is supported
by observations that individuals exposed to solvents,
and MDMA (Ecstasy)
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.
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
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
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.
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.
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-
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
In rats, morphologic changes are found in the
CA1 region of the hippocampus with acute adminis-
tration of a synthetic THC analogue.
Damage to the
CA1 is also seen after ischemia,
toxin exposure,
traumatic brain injury.
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
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
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.
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.
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
AbstractBackground/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,
p0.001) 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 (p0.007) 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
NEUROLOGY 2002;59:13431349
Cognitive abnormalities commonly occur in patients
with HIV-1 infection.
Among healthy individuals
who are seropositive for HIV, cognitive deficits are
thought to be infrequent
; however, some investiga-
tors suggest that more sensitive measures may be
needed to detect the mild cognitive decline during
the asymptomatic stage.
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
this syndrome has been termed HIV cognitive motor
complex (CMC).
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.
Typical neuropsychological deficits in patients
with HIV include decreased sustained attention,
mental flexibility, general motor speed, and memo-
; in particular, working memory may be
However, little is known about the neu-
roanatomic substrate underlying these neuropsycho-
logical deficits. A variety of functional neuroimaging
techniques, including PET,
and MRS,
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),
HarborUniversity 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:
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
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... In addition, treatment with antagonist reversed the induced attention impairment, although, when administered alone, this compound did not produce any effects on attention [19]. Chronic heavy marijuana use is also associated with impairments in verbal fluency, learning and memory, sustained attention, and executive functioning [20]. ...
... In contrast to these studies, Bolla KI et al. [20] reported minimal or no lasting effects of chronic cannabis use on overall IQ, attention, working memory, and abstract reasoning [20]. Fried et al. [21], prominently, noted that cannabis-induced cognitive impairments may be dependent on the age of onset of cannabis use; in particular, those starting before the age of 17 years have greater impairment. ...
... In contrast to these studies, Bolla KI et al. [20] reported minimal or no lasting effects of chronic cannabis use on overall IQ, attention, working memory, and abstract reasoning [20]. Fried et al. [21], prominently, noted that cannabis-induced cognitive impairments may be dependent on the age of onset of cannabis use; in particular, those starting before the age of 17 years have greater impairment. ...
... Numerosos trabalhos mostraram que os indivíduos com PRS apresentam alterações neuropsicológicas de distinta magnitude inclusivamente depois de períodos prolongados de abstinência (Fernández-Serrano et al., 2011;Lopes et al., 2016;Oliveira et al., 2015). A gravidade dos déficits neurocognitivos têm sido associados com a duração e quantidade de droga usada, sugerindo uma ligação causal entre uso de droga e déficits neurocognitivos (Bolla et al., 2002). Outros estudos sugerem que os déficits neurocognitivos precedem o uso de droga e podem ser um fator de vulnerabilidade para as PRS (Ersche et al., 2012). ...
Cannabis is the most widely used illicit drug in the United States, with 14.6 million current users. Cannabis-dependent individuals presenting for treatment typically report cannabis craving; however, the phenomenon has received little research attention. In the absence of a valid, multidimensional questionnaire to assess cannabis craving, we developed the Marijuana Craving Questionnaire (MCQ). The MCQ consists of four constructs or factors that characterize cannabis craving: compulsivity, emotionality, expectancy, and purposefulness. A separate score is calculated for each factor. The MCQ can be used to measure cue-elicited craving in a research setting or natural craving in cannabis-dependent individuals presenting for treatment. Either the 47-item or 12-item version can be used, and standardized instructions for completion of the MCQ should be given. The MCQ can be administered using a paper and pencil form or a computerized version. In a research setting, the MCQ should be administered immediately after cue presentation and repeated frequently to capture the full time course. In a treatment setting, the MCQ should be administered at intake and during and at the end of treatment.
Background: Prospective memory and response inhibition are interrelated constructs, though studied separately in the drug addiction literature. Also, although sustained attention underlies response inhibition, its role in the relation between these functions has been largely neglected. The limited research on the cognitive effects of methadone-maintenance treatment (MMT) further stresses the importance of investigating these effects. Objective: Therefore, the current study focused on possible effects of MMT combined with long-term drug abuse on all these functions. Thirty five long term opiate/poly-substance users in MMT and thirty four drug-free controls were screened for socioeconomic status, anxiety, depression and general, non-verbal intelligence and then tested on a self-report measure of prospective memory and on the Go/No-Go task. Results: Compared to controls, the MMT group scored worse in all functions assessed. Prospective memory scores were also negatively related to Go/NoGo accuracy scores. Conclusion: As predicted, (a) the MMT participants show impairments in prospective memory, sustained attention and response inhibition and (b) prospective memory, response inhibition and sustained attention are related constructs. The results of this study could inform current rehabilitation and relapse prevention cognitive training practices.
Full-text available
The impact of marijuana on road safety has been the subject of many debates over the years. These debates have intensified in recent years due to initiatives carried out in several jurisdictions aimed at marketing medical cannabis. According to Polish forensic toxicologists, road safety is a key issue, especially following the conferences in November 2012 in Kraków and in 2013 in Augustów (Gieroń et al., 2013), Poland, on the determination of appropriate concentration thresholds. These thresholds, defining the limit for the ‘after use’ and ‘under the influence’ conditions, are still not unambiguous or easy to determine for the Polish government. An unambiguous assessment of the impact of a given concentration of blood Thc on psychomotor performance is very difficult, and will remain so in the foreseeable future. This study used 107 randomly selected blood collection protocols, with 10 protocols for each THC concentration ranging from 1 to 10 ng/ml, on the basis of which thirteen features related to the external appearance and behaviour of the tested individuals were analysed. These features were: facial skin (pale, normal or red), slurred speech, mood and behaviour (cheerful, talkative, rowdy or reticent), heart rate, pupils (normal, dilated or contracted), reaction of pupils to light, the romberg test, the finger-to-nose test, picking up objects from the ground and awareness of time and place. Five of the thirteen features related to the appearance and behaviour of the respondents showed no abnormalities (gait, the romberg test, the finger-to-nose test, picking up objects from the ground, and awareness of time and place). The study found that the symptoms observed and recorded in the protocols are insufficient to make a decision about the impact of Thc on psychomotor performance. The characteristic symptoms (cheerfulness and talkativeness) occurred no more frequently than in 3 out of 10 of the concentrations tested.
Full-text available
Cannabis is one of the oldest crops grown, traditionally held religious attachments in various cultures for its medicinal use much before its introduction to Western medicine. Multiple preclinical and clinical investigations have explored the beneficial effects of cannabis in various neurocognitive and neurodegenerative diseases affecting the cognitive domains. Tetrahydrocannabinol (THC), the major psychoactive component, is responsible for cognition-related deficits, while cannabidiol (CBD), a non-psychoactive phytocannabinoid, has been shown to elicit neuroprotective activity. In the present integrative review, the authors focus on the effects of cannabis on the different cognitive domains, including learning, consolidation, and retrieval. The present study is the first attempt in which significant focus has been imparted on all three aspects of cognition, thus linking to its usage. Furthermore, the investigators have also depicted the current legal position of cannabis in India and the requirement for reforms.
Objective: To explore the feasibility and utility of a tolerance break (T-Break) guide on young adults' cannabis use. Participants: Young adults aged 18-29 (n = 125) who were current cannabis users. Methods: Participants recruited through posters and listservs at various universities were offered the T-Break Guide-daily activities, advice, and encouragement-to help complete a 21-day cannabis break. Bivariate analyses examined associations between Guide use and follow-up measures. Results: Compared to non-Guide users, participants who used the Guide "a lot" were more likely to complete the 21-day abstinence break (84% vs. 57%), revise their personal definition of balance to mean less cannabis (84% vs. 62%), and plan a future break (32% vs. 11%). Conclusion: Use of this self-directed T-Break Guide may help young adults take a break from cannabis use and reduce future use. Further research using more rigorous designs to test the Guide's efficacy and assess longer-term maintenance of effects is needed.
Cannabis is the most used “illicit” drug in the world. As a result of legalization for medical—and, to a lesser extent recreational—use, there is now greater accessibility and social acceptance of marijuana and cannabinoids in the United States. Multiple clinical benefits have been claimed, such as the treatment of nausea, anorexia, chronic pain, seizures, multiple sclerosis, and epilepsy. But its use has also been associated with diminished cognitive-motor skills and with undesirable medical outcomes, such as cognitive impairment, psychosis, pulmonary disease, hyperemesis, myocardial infarction, stroke, and opportunistic infections. Unfortunately, there is a lack of consensus in the transplant community regarding how long, if at all, an individual should abstain from using cannabis prior to transplantation, and opinions differ depending on whether such use is recreational or medicinal. The contemporary transplant psychiatrist is therefore faced with an interesting dilemma in evaluating whether a patient who uses cannabis is an appropriate candidate for transplantation and, more specifically, what to recommend to the transplant team regarding such use. Through a review of the recent literature and an examination of a pertinent case, we aim to illustrate the controversies inherent in such evaluations and provide guidance for performing assessments in individuals who use cannabis.
Full-text available
The purpose of this study is to understand the cause of cannabis abuse and addiction in particular and how it affects a person’s physical, social and psychological well being by studying changes in his behavior and understanding the adjustment problems the subject has been facing, if any since after he started using cannabis. The case study will be conducted on a 25 year old male who hasn’t been diagnosed with any psychological disorder. The study taking place will not be used to form any diagnoses of the subject but merely will be used to assess the causes and effects of drug abuse through already established psychometric tests and by taking interviews of the subject, his sister and his partner.
In this chapter, I summarize the most important facts about recreational drugs and drug use. I start with some basic numbers about use rates, addiction rates, and overdose fatalities, both in the United States and globally. I then go on to look at the different effects of different drugs. Not all drugs are the same, so we need to compare different drugs in terms of their harmfulness, especially their overdose potential, addictiveness, and acute and long-term health risks. This includes the legal drugs alcohol and nicotine, which are more addictive and destructive than many illegal drugs. The chapter ends with important facts about addiction and its causes. Drugs are less addictive than people tend to think. Only about 25% of heroin users are dependent, and it is the most addictive drug besides nicotine. There are also good reasons to doubt the pharmacological model of addiction, which claims that addiction is caused primarily by repeated exposure to a substance. Though use is obviously a necessary condition for addiction, users who come to develop dependency typically suffer from traumatic upbringing or highly stressful environments.
Background: While depression is known to involve a disturbance of mood, movement and cognition, its associated cognitive deficits are frequently viewed as simple epiphenomena of the disorder. Aims: To review the status of cognitive deficits in depression and their putative neurobiological underpinnings. Method: Selective computerised review of the literature examining cognitive deficits in depression and their brain correlates. Results: Recent studies report both mnemonic deficits and the presence of executive impairment--possibly selective for set-shifting tasks--in depression. Many studies suggest that these occur independent of age, depression severity and subtype, task 'difficulty', motivation and response bias: some persist upon clinical 'recovery'. Conclusions: Mnemonic and executive deficits do no appear to be epiphenomena of depressive disorder. A focus on the interactions between motivation, affect and cognitive function may allow greater understanding of the interplay between key aspects of the dorsal and ventral aspects of the prefrontal cortex in depression.
A new interview schedule allows lay interviewers or clinicians to make psychiatric diagnoses according to DSM-III criteria, Feighner criteria, and Research Diagnostic Criteria. It is being used in a set of epidemiological studies sponsored by the National Institute of Mental Health Center for Epidemiological Studies. Its accuracy has been evaluated in a test-retest design comparing independent administrations by psychiatrists and lay interviewers to 216 subjects (inpatients, outpatients, ex-patients, and nonpatients).
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.