Pubdate: Wed, 06 Mar 2002
Source: Journal of the American Medical Association (US)
Issue: Vol. 287, No. 9
Copyright: 2002 American Medical Association.
Contact:  http://jama.ama-assn.org/
Details: http://www.mapinc.org/media/219
Authors: Nadia Solowij, PhD; Robert S. Stephens, PhD; Roger A. Roffman, 
DSW; Thomas Babor, PhD, MPH; Ronald Kadden, PhD; Michael Miller, PhD; 
Kenneth Christiansen, PsyD; Bonnie McRee, MPH; Janice Vendetti, MPH; for 
the Marijuana Treatment Project Research Group
Note: Footnote numbers are in [brackets].

COGNITIVE FUNCTIONING OF LONG-TERM HEAVY CANNABIS USERS SEEKING TREATMENT.

Context

Cognitive impairments are associated with long-term cannabis use, but the 
parameters of use that contribute to impairments and the nature and 
endurance of cognitive dysfunction remain uncertain.

Objective

To examine the effects of duration of cannabis use on specific areas of 
cognitive functioning among users seeking treatment for cannabis dependence.

Design, Setting, and Participants

Multisite retrospective cross-sectional neuropsychological study conducted 
in the United States (Seattle, Wash; Farmington, Conn; and Miami, Fla) 
between 1997 and 2000 among 102 near-daily cannabis users (51 long-term 
users: mean, 23.9 years of use; 51 shorter-term users: mean, 10.2 years of 
use) compared with 33 nonuser controls.

Main Outcome Measures

Measures from 9 standard neuropsychological tests that assessed attention, 
memory, and executive functioning, and were administered prior to entry to 
a treatment program and following a median 17-hour abstinence.

Results

Long-term cannabis users performed significantly less well than 
shorter-term users and controls on tests of memory and attention. On the 
Rey Auditory Verbal Learning Test, long-term users recalled significantly 
fewer words than either shorter-term users (P = .001) or controls (P = 
.005); there was no difference between shorter-term users and controls. 
Long-term users showed impaired learning (P = .007), retention (P = .003), 
and retrieval (P = .002) compared with controls. Both user groups performed 
poorly on a time estimation task (P(.001 vs controls). Performance measures 
often correlated significantly with the duration of cannabis use, being 
worse with increasing years of use, but were unrelated to withdrawal 
symptoms and persisted after controlling for recent cannabis use and other 
drug use.

Conclusions

These results confirm that long-term heavy cannabis users show impairments 
in memory and attention that endure beyond the period of intoxication and 
worsen with increasing years of regular cannabis use.

JAMA. 2002;287:1123-1131

In the current climate of debate about marijuana laws and interest in 
marijuana as medicine, [1] one issue remains unresolved: Does heavy, 
frequent, or prolonged use of cannabis lead to a deterioration in cognitive 
function that persists well beyond any period of acute intoxication? Is the 
functioning of the brain altered in the long term? With over 7 million 
people using cannabis weekly or more often in the United States alone [2] 
and the potential for increased physician recommendations for select 
patients to use cannabis therapeutically, [1] answers to these questions 
are of significant public health concern. [3, 4] Scientific evidence from 
past research clearly showed that gross impairment related to chronic 
cannabis use did not occur but was inconclusive with regard to the presence 
of more specific deficits. [5, 6] Recent studies with improved methods have 
demonstrated changes in cognition and brain function associated with 
long-term or frequent use of cannabis. Specific impairments of attention, 
memory, and executive function have been found in cannabis users in the 
unintoxicated state (and in children exposed to cannabis in utero [7]) in 
controlled studies using brain event-related potential techniques6, [8-10] 
and neuropsychological assessments [11-15] including complex tasks.

Brain imaging studies of cannabis users have demonstrated altered function, 
blood flow, and metabolism in prefrontal and cerebellar regions. [16-19] 
Studies failing to detect cognitive decline associated with cannabis use 
[20] may reflect insufficient heavy or chronic use of cannabis in the 
sample or the use of insensitive assessment instruments. Impairments appear 
to increase with duration and frequency of cannabis use; however, the 
parameters of use that are associated with short-or long-lasting cognitive 
and brain dysfunction have not been fully elucidated. The attribution of 
deficits to lingering acute effects, drug residues, abstinence effects, or 
lasting changes caused by chronic use continues to be debated. [5, 6] 
Animal research suggests an important role for the cannabinoid receptor in 
regulating the neural activity critical for memory processing. [21-24] 
Long-term use of cannabis may result in altered functioning of the 
cannabinoid receptor and its associated neuromodulator systems.

This study investigated the nature of cognitive impairments associated with 
long-term cannabis use employing data collected from a large clinical trial 
of chronic users seeking treatment for cannabis dependence. The study 
compared 102 cannabis users assessed prior to treatment on carefully 
selected neuropsychological tests with 33 nonuser controls. The parameters 
of cannabis use that contribute to impairment were examined. It was 
hypothesized that performance would deteriorate as the number of years of 
regular use increased.

METHODS

Design

A multisite, retrospective, cross-sectional comparison-group design was 
used to compare (1) long-term users with a mean of 23.9 years of regular 
cannabis use; (2) shorter-term users with a mean of 10.2 years of regular 
use; and (3) nonusers of cannabis. Key confounding variables (age, IQ, 
other drug use) were controlled through matching or statistical methods. 
The sample size required for this study was determined by estimating a 94% 
chance of detecting a moderate effect size of 0.5 SD units at a 2-tailed of 
.05.

Recruitment Procedure and Assessment of Drug Use

Sixty-five of the 102 cannabis users were delayed-treatment participants 
from the Marijuana Treatment Project, a multisite US study (Seattle, Wash; 
Farmington, Conn; and Miami, Fla) conducted between 1997 and 2000 of the 
effectiveness of brief treatments for cannabis dependence.25 The remainder 
were recruited through the Marijuana Treatment Project specifically for 
this study. Participants provided written informed consent as approved by 
the ethics committees of the participating institutions and were paid $75 
for completing the cognitive assessments. Controls (n = 33) were recruited 
from the general population through media advertisements at only 1 site. 
The controls were told that the researchers were studying the effects of 
exposure to drugs and alcohol on cognitive functioning, and that at present 
only individuals at the lighter end of the spectrum of drug experience were 
required. The aim was to minimize cannabis use among controls while 
approximating the other characteristics of the cannabis-using sample. 
Assessors were not blinded with regard to group assignment. Self-reported 
drug and alcohol use were assessed by the Addiction Severity Index,26 a 
separate structured interview, and the Time Line Follow Back procedure. 
[27, 28] The Structured Clinical Interview for Diagnostic and Statistical 
Manual of Mental Disorders, 4th Edition (DSM-IV) Axis I Disorders (SCID) 
[29] assessed cannabis dependence. Duration of regular (at least twice per 
month) cannabis use was an averaged composite measure derived from the 
Addiction Severity Index, SCID, and the structured interview. Current 
frequency of cannabis use was calculated from the Time Line Follow Back 
procedure.

Inclusion/Exclusion Criteria

Cannabis users were included if they had used cannabis regularly for at 
least 3 years, were currently using at least once a week, were seeking 
treatment to assist them to cease or reduce their use of cannabis, and were 
willing to participate in the treatment program offered. Participants were 
excluded if they had ever had a serious illness or injury that may have 
affected the brain, any psychotic disorder, met a current DSM-IV diagnosis 
of dependence on any other drug or alcohol, or had a poor command of the 
English language.

Sample Characteristics

Table 1 provides demographic information and cannabis use parameters. 
(acquisition (3 words over 5 trials) was greater among long-term users 
(13.7%) than controls (0%) (P = .007) but not shorter-term users (5.9%). 
The proportion of long-term users recalling fewer than 10 words on trial V 
(27.5%) was more than among shorter-term users (8.5%) or controls (3.0%) (P 
= .002). Significantly more long-term users (23.5%) lost 3 or more words 
over the 20-minute delay between trials VI and VII than shorter-term users 
(4.3%) or controls (3.0%) (P = .003). Long-term users showed a smaller 
primacy effect in the serial position curve than either other group (P = 
.02). Groups did not differ in the recency effect or in words recalled from 
the middle of the list.

Users overall and long-term users recognized fewer words than controls from 
list A (overall, P = .03; long-term, P = .01) and list B (overall, P = .01; 
long-term, P = .04) but long-term users did not differ from shorter-term 
users. More than half of the long-term users (55%) had a recognition score 
for list A of 12 or less compared with 28% of shorter-term users and 21% of 
controls (P = .002). Long-term users misassigned more words (median, 2) 
than shorter-term users and controls (each median, 0) (P(.001). A greater 
proportion of long-term users (13.7%) compared with shorter-term users 
(6.4%) and controls (0%) actually identified fewer words on recognition 
than they had just prior during recall on trial VII (P = .02). Long-term 
users' performance was significantly poorer than published norms [47] for 
the general population on most measures from the RAVLT.

Stroop Test

Cannabis users did not differ significantly from controls after inclusion 
of covariates in any condition or on interference scores. While there were 
no performance differences between Color-Word (CW) and Color-Read (CR) in 
the control group, performance on CR was, however, poorer than on CW in 
both long (P(.001) and shorter-term users (P .03). Color-Read was the 
additional interference condition designed to increase demands on executive 
function.43 There was an inverse relationship between duration of cannabis 
use and number of items completed on CR (partial r, - 0.27; P = .003) and 
CW (partial r, - 0.27; P = .004) after controlling for age and FSIQ. These 
results suggest that cannabis users are vulnerable to task complexity with 
increasing demands creating more sources of interference that adversely 
affect performance.

Wisconsin Card Sorting Test

There were no significant group differences on any Wisconsin Card Sorting 
Test (WCST) measure but a trend on one: long-term users failed to maintain 
the set more often than shorter-term users (P = .05) or controls (P = .07). 
Research suggests that this measure best represents attentional 
dysfunction. [39] There was no evidence of impaired performance with 
increasing years of cannabis use after controlling for covariates.

Alphabet Task and Omitted Numbers

Groups did not differ in the time taken to complete any trial of the 
Alphabet Task or in the number of items correct in the Omitted Numbers 
task. The log time to complete the alternating trial of the Alphabet Task 
increased as a function of duration of cannabis use (partial r, 0.26; P = 
.006), as did the square root difference between times taken to complete 
the alternating and loud trials, an index of interference and lack of 
flexibility (partial r, 0.26; P = .006).

Time Estimation Tasks

Cannabis users differed from controls (P(.001) in Time Estimation Task A 
where they estimated the time taken to complete the preceding (Omitted 
Numbers) task. Both long- and shorter-term users underestimated the time by 
about one third of the actual time taken (64.4 seconds) and differed 
significantly from controls (P = .01 and P(.001, respectively). Groups did 
not differ in the simple and brief warned passive Time Estimation Task B or 
Time Production, where they could use strategies such as counting. Time 
estimation measures did not correlate with duration of cannabis use.

Auditory Consonant Trigrams

Long-term users recalled significantly fewer items than shorter-term users 
(P = .007), controls (P = .002), and published norms [48] on only the 
9-second delay condition. The number of items recalled did not correlate 
with duration of cannabis use. In the general population, the greater the 
delay interval the worse the performance. In cannabis users, this general 
pattern was apparent, though there was greater interference at the 
shorter-delay interval than would be expected.

Paced Auditory Serial Addition Test

Long-term users had slower processing rates than shorter-term users on 
trial 1 (P = .007), with trends on trial 2 (P = .03) and the total 
processing rate across all trials (P = .02). Group differences on all other 
measures failed to reach significance but the performance of the long-term 
users was poorer in comparison with one set of norms49 but not another. [50]

Pure Effects Attributable to Cannabis Use and Effects of Recent vs Chronic Use

Excluding all participants with histories of regular other drug or alcohol 
use, dependence or treatment, and controls with any history of regular 
cannabis use within the past 20 years reduced the sample to 27 long-term 
users, 33 shorter-term users, and 26 controls. Despite the reduction in 
power to detect differences between groups, there remained a significant 
difference with = .05 between long-term users and controls on RAVLTsum (P = 
.03), recognition of lists A (P = .004) and B (P = .01), and between users 
overall and controls on the unwarned Time Estimation task (P = .02). These 
results support the hypothesis that impaired memory function and time 
estimation are specific to chronic use of cannabis.

In a separate analysis, exclusion of users whose urinary cannabinoid 
metabolite levels exceeded those from the night before testing by 50 ng/mg 
or more (n = 18) still resulted in significant differences between long- 
and shorter-term users, and long-term users and controls on RAVLT sum (P = 
.002 and P = .002, respectively), on recognition of lists A (P = .005 and P 
= .006) and B (P = .01 and P(.001), on the 9-second delay of the Auditory 
Consonant Trigrams test (P = .02 and P = .03), and users still differed 
from controls on time estimation (P = .005). When the sample was split at 
the median for time since last use or level of urinary cannabinoid 
metabolite on the day of testing and analyzed by ANCOVA, there were no 
differences on any measure between those who had used cannabis within the 
past 17 hours and those who had used cannabis 17 or more hours ago, or 
those with high vs low levels of urinary metabolites and no interactions 
with duration of cannabis use. Including measures of recent use as 
covariates in ANCOVA did not change the significance of differences between 
long- and shorter-term users. These results support the hypothesis that 
impaired performance is not a consequence of recent use prior to testing or 
the extent of cannabinoid residues present.

To explore further the influences of duration of cannabis use and recency 
of use, semipartial correlations were calculated using the following 
predictors: FSIQ, age, duration of cannabis use, and hours since last use 
of cannabis. As shown in Table 4, the unique contribution of duration of 
cannabis use to the variance of each test variable was superior or at least 
equivalent to that of recency of use in all 6 test variables that had 
significant contributions from at least 1 cannabis use parameter. Recent 
use contributed only to performance on the memory tests. The fact that a 
minority of the sample, primarily shorter-term users, reported experiencing 
mild withdrawal symptoms, yet shorter-term users' performance was not 
impaired, supports the interpretation of the cognitive impairments observed 
as a long-term consequence of cannabis use and not a manifestation of 
overtly experienced withdrawal.

COMMENT

The results of this study have confirmed and extended previous findings of 
cognitive impairments among chronic heavy cannabis users.

Acknowledgment: We are grateful to Aimee Balmer-Campbell, BA, Kara Brennan 
Dion, BA, David Duresky, MA, Dave Ghany, BA, Brian Glidden, BA, Cara 
Gluskoter, MS, Cher Gunby, BA, Jennifer Haley, BA, Heather Haynes, RN, 
Patricia Holkon, MA, Elise Kabella, PhD, Priscilla Morse, MA, Joe Picciano, 
MS, Sam Schwartz, MSW, Megan Swan, MA, Debbie Talamini, AS, and Anna Wolfe, 
BA, for input and assistance with data collection and trial management, 
Peter Caputi, BA, GradDip, for statistical advice, Brin Grenyer, PhD, for 
comments on the manuscript, Eva Congreve, DipLib, for library assistance, 
and to all participants in this research.

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