Drug and Alcohol Dependence , 32 (1993) 231- 237 Elsevier Scientific Publishers Ireland Ltd.
Neuropsychological deficits in abstinent cocaine abusers: preliminary findings after two weeks of abstinence James Berry, Wilfred G. van Gorp, David S. Herzberg, Charles Hinkin, Kyle Boone, Lynne Steinman and Jeffery N. Wilkins Alcohol and Drug Treatment Program, West Los Angeles VA Medical Center, Brentwood Division, 11.901 Wilshire Boulevard, Los Angeles, CA 90073 (USA) (Accepted January 9, 1993) Sixteen subjects hospitalized for treatment of cocaine dependence were administered a battery of neuropsychological tests within 72 h of last cocaine use and again approximately 2 weeks later. Twenty-one non-cocaine using control subjects, matched for age, gender, ethnicity and education, also received neuropsychological testing. Abstinence from mood altering substances during the 2-week study period was verified for both groups on three occasions using quantitative urine analysis. The results suggest that recent cocaine use is associated with impairment in memory, visuospatial abilities, and concentration during the acute phase of withdrawal, independent of withdrawal-related depression. Furthermore, many of these deficits appear to persist at least 2 weeks beyond cessation of cocaine use. Key words: neuropsychology;
cocaine abuse; cognition
Introduction Although many studies have examined the long-term neuropsychological effects of chronic alcohol abuse, there has been surprisingly limited research to date on the neuropsychological sequelae of chronic cocaine abuse. Such a dearth of research is especially noteworthy in light of the widespread use of cocaine in the United States and other countries. A recent review of the literature revealed only 5 extant studies of the neuropsychological sequelae of cocaine abuse, of which most were preliminary reports of short-term cognitive dysfunction in cocaine abusers. Melamed (1987) documented the deleterious effects of cocaine on neuropsychological function both at the point of acute abstinence and 10 days later, with some improvement observed at Correspondence to: W.G. van Gorp, West Los Angeles VA Medical Center, Brentwood Division, 11301 Wilshire Blvd., Los Angeles, CA 90073, USA. 0376-8716/93/$06.00 0 1993 Elsevier Scientific Publishers Printed and Published in Ireland
the second assessment. Visuomotor tracking, cognitive flexibility and speed of information processing were found to be particularly affected. These findings must be interpreted with caution, however, since the study did not include a non-cocaine using control group. Manschreck et al. (1990) studied performance on a battery of experimental cognitive tasks in a sample of 33 abstinent cocaine abusers in which the length of abstinence varied considerably (mean = 59 days) and in a control group (iV = 21) matched for age, sex and education. The authors found deficiencies in short-term memory in the cocaine group, but because subjects were tested only once and length of abstinence among the cocaine users was not reported, no definitive conclusions can be drawn regarding the persistence of these short-term memory difficulties. Herning et al. (1990) reported short-term memory deficits to persist up to at least four weeks in a sample of 12 males seeking treatment for cocaine abuse, though the investigators did not control for length of time since last cocaine use. Ireland Ltd.
O’Malley and Gawin (1990) found concentration, memory, non-verbal problem solving and abstraction ability to be affected in 20 recently abstinent inpatient cocaine abusers. Length of abstinence was significantly associated with neuropsychological improvement, suggesting at least some degree of recovery of neuropsychological function over time. In a second study, 25 abstinent outpatient cocaine abusers were compared with 25 age-, education-, raceand sex-matched controls. The authors report the outpatients to have been abstinent for an average period of 135 days, but no independent, objective means used to verify abstinence were reported. The cocaine abusers did not perform as well as controls on measures assessing psychomotor skill, pure motor skill and verbal and performance IQ scores. However, the former group’s scores, although statistically poorer than controls, were still largely ‘in the normal range’ (p. 186). Finally, Ardila et al. (1990) studied 37 abstinent freebase cocaine users and found deficits in short-term verbal memory and attention. However, no control group was used and analyses were conducted by comparing subjects’ scores to published normative data. These authors also found a correlation between amount of cocaine used over the lifespan and magnitude of neuropsychological impairment. The preceding studies suggest that memory, psychomotor speed, problem solving and abstraction abilities are often affected by chronic cocaine abuse, at least during the acute phase of withdrawal. However, the lack of appropriate control groups and longitudinal follow-up must temper the conclusions that may be drawn. The present study was designed to explore whether acute and short-term residual deficits in neuropsychological functioning were present in a sample of acutely abstinent cocaine abusers, with abstinence verified objectively by urine drug screens. Method Subjects
The sample consisted of 16 individuals admit-
ted to a 21-day inpatient program for treatment of cocaine dependence and 21 non-cocaine using community volunteers, who served as normal controls. All subjects in the cocaine group met DSM-IIIR criteria for cocaine dependence, reported that they had abused the drug for a minimum of 6 months prior to their inpatient admission and were assessed within 72 h of their last reported use and then reassessed 14 - 18 days later. Subjects were excluded if they reported having used phencyclidine (PCP) more than 10 times over their lifetime, or if they drank more than 100 fl. ozs of alcohol or smoked more than 28 g of marijuana in the previous month. Individuals with a history of head injury with loss of consciousness over one minute, or a current or past diagnosis of bipolar affective disorder, psychosis, seizure disorder, malnutrition, liver dysfunction, or learning disability were also excluded. Control subjects met the same inclusionlexclusion criteria as the cocaine subjects, with the exception that they were considered eligible only if they had no reported history of drug or alcohol abuse or dependence as defined by DSM-III-R criteria. These subjects were individually matched with the cocaine subjects on race and gender and matched at the group level on age, education and socioeconomic status. As can be seen in Table I, there were no significant differences between groups on age (F (1,35) = 0.32; P = NS), education (F (1,35) = 0.04; P = NS), gender (x2 = 0.04; d.f. = 1; P = NS), or ethnicity (x2 = 0.13; d.f. = 2; P = NS). Objective determination
of recent substance me
Urine samples were taken at admission to validate subjects’ self report of recent cocaine use. Urinalysis results were compared with selfreported time of last use and amount of recent use of licit and illicit substances. Urine samples were quantitatively analyzed for six common drugs of abuse: cocaine (in the form of its major metabolite, benzoylecgonine), marijuana (in the form of delta-9_tetrahydrocannabinol), opiates (in the form of morphine), barbiturates, amphetamines and phencyclidine (PCP). The assays were performed by fluorescence polarization
233 Table I. Demographic and normal controls.
of cocaine abusers
Cocaine abusers (n = 16)
Normal controls (n = 21)
Sex Male Female Mean age
15 1 34.5
20 1 33.2
Ethnicity Black Caucasian Hispanic Mean years of education
12 2 1 14
18 2 1 14.1
Level of income $00 - $12,000 $12,001-$18,000 $lS,OOl-$30,000 $30,001-$45,000 $45,001- $60,000 $60,001-$75,000 $75,001 or greater Mean days between testing NART at Time 1: mean (SD) BDI at Time 1: mean (SD) BDI at Time 2: mean (SD)
7 2 4 3 0 0 1 14.1
*Significant difference using family-wise alpha correction, P < 0.01.
immunoassay (FPI), using the Abbott Diagnostic ADX and TDX systems. Quality control for the FPI was performed through crossconfirmation of results by gas liquid chromadetography (GLC) with nitrogen-phosphorus tection or high pressure liquid chromatography (HPLC). Minimal detectable concentrations in urine were: morphine, 30 ng/ml; benzoylecgonine, 30 nglml; delta-9-tetrahydrocannabinol, 10 ng/ml; amphetamines, 90 mglml; barbiturates, 60 ng/ml and PCP, 10 ng/ml. Given these parameters, the benzoylecgonine sensitivity allows detection of significant cocaine use over the previous week. In addition to the admission urine, 3 urine
samples were randomly obtained from each subject during the .2I-day hospitalization period and analyzed as described above. Urine samples were also taken from the normal controls on both testing occasions. Blood alcohol breath samples were also obtained from both groups prior to each assessment using an instrument capable of calculating blood alcohol content from traces of alcohol contained in respirations (Department of Transportation, 1976). All of the cocaine users tested positive for cocaine by urine analysis at admission, but none tested positive by urine or breath analysis for any substance of abuse at any other point during the study period. None of the normal controls tested positive by urine or breath analysis for any substance of abuse at any point in the study. Neuropsychological measures Cocaine subjects were assessed with a battery of neuropsychological measures within 72 h of their last reported use and again 14 - 18 days later. Control subjects also received two assessments separated by 14- 18 days. The following tests were administered: (i) Trail Making Test, parts A and B (Reitan, 1958). This measure assesses psychomotor speed and cognitive set shifting. (ii) Rey-Osterrieth Complex Figure Test, copy and recall at 3 min (Lezak, 1983). This measure assesses visuospatial construction and nonverbal recall. (iii) Controlled Oral Word Fluency Test (FAS, Lezak, 1983). This measure assesses word list generation, which is often affected in individuals with impairment to the frontallsubcortical axis of brain function (Cummings, 1990). (iv) Digit Symbol (WA%-R subtest; Wechsler, 1981). This subtest has been shown to be the most sensitive measure to central nervous system impairment of the WAIS-R subtests, including chronic substance abuse including alcoholism (Lezak, 1983). (v) Block Design (WAIS-R subtest; Wechsler, 1981) to assess visuospatial construction. (vi) Rey Auditory-Verbal Learning Test, trials 1 - 5, total score (RAVLT; Lezak, 1983). This measure, consisting of 15 unrelated words presented over five trials, was included to assess verbal learning and memory. (vii) Paced Auditory
dent variables. Because of the elevated BDI scores of the cocaine subjects at Time 1, subjects’ BDI scores at the initial testing were used as the covariate. As shown in Table III, MANCOVA revealed a trend toward significance for group (F (10,25) = 1.95; P = 0.09), a significant effect for time (F (10,26) = 19.86; P < 0.0001) and a significant group x time interaction (F (10,26) = 3.62; P = 0.004), suggesting differential rates of change over time for the cocaine vs. control groups. Follow-up univariate analyses of covariance (ANCOVA), again using BDI score at Time 1 as the covariate, revealed that the cocaine group performed significantly poorer than the control group at initial testing on measures of visuospatial construction (Rey-Osterrieth Complex Figure copy [F (1,34) = 4.16; P < 0.051, WATS-R Block Design [F (1,34) = 11.56; P = O.OOZ]), verbal memory (RAVLT, sum of recall on trials 1- 5 [F (1,34) = 6.65; P = O.Ol]) and concentration (PASAT total score trials 1 and 2 [F (1,34) = 4.71; P c 0.051). Trends toward significance were observed on measures of visual memory (Rey-Osterrieth Complex Figure, 3 min delayed recall [F (1,34) = 3.35; P = 0.081) and psychomotor speed (Digit Symbol [F (1,34) = 2.88; P < 0.101). At time 2, ANCOVA (using subjects’ BDI score at Time 1 as the covariate) revealed the cocaine subjects to still perform poorer than the controls on a
Serial Addition Test, total score trials 1 and 2 (PASAT; Cronwall & Sampson, 1974) was included to assess divided attention. (viii) Stroop Color Word Interference Test. This measure assesses sustained attention and response inhibition and has been shown to be sensitive to impairment in the frontal/subcortical axis of brain function (Lezak, 1983). (ix) New Adult Reading Test - Revised (NART-R; Nelson, 1982). This measure consists of a series of phonetically irregular words and is considered a reliable estimate of premorbid intellectual ability. (v) Beck Depression Inventory (BDI; Beck, Ward, Mendelson, Mock, & Erbaugh, 1961). This self-report measure was included to assess the subject’s current level of depression. Results
As shown in Table I, there were no significant differences between the 2 subject groups in premorbid IQ as estimated by the NART-R. Subjects in the cocaine group scored significantly higher than the normal controls on the Beck Depression Inventory at Time 1 and Time 2. Table II shows the group means and standard deviations of the neuropsychological test scores. Table III presents the results of a repeatedmeasures, 2-factor multivariate analysis of covariance (MANCOVA) (group x time) with the neuropsychological test scores as the depen-
of cocaine abusers and normal controls: mean (SD).
Cocaine abusers at Time 1
Cocaine abusers at Time 2
Normal controls at Time 1
Normal controls at Time 2
Trails A Trails B Rey-Osterrieth Complex Figure Rey-Osterrieth Delay FAS Block Design (raw score) Digit Symbol (raw score) RAVLT Trials 1 - 5 Total PASAT Total Stroop Color Interference Test
34.0 92.5 27.5 10.3 42.4 23.3 47.7 44.3 58.2 119.9
24.9 84.7 29.8 15.6 51.6 28.9 52.8 49.8 72.2 120.0
28.0 79.0 32.1 16.7 41.6 32.3 59.7 50.4 70.4 115.4
24.4 56.2 32.6 24.9 50.0 36.6 59.7 62.6 78.9 114.4
(12.2) (51.2) (6.5) (6.6) (8.3) (6.9) (8.3) (7.9) (19.6) (33.1)
(6.5) (41.9) (4.6) (7.7) (12.7) (7.4) (7.6) (11.5) (17.8) (27.9)
(7.3) (27.8) (2.7) (7.1) (10.7) (8.4) (9.5) (8.2) (17.8) (15.3)
(5.5) (18.2) (3.5) (8.2) (13.2) (7.7) (9.5) (9.7) (12.8) (19.3)
235 Table III.
Repeated measures MANCOVA on NP test scores, BDI at Time 1 as covariate. Group x Time
Trails A Trails B Rey-Osterrieth Complex Figure Rey-Osterrieth Delay FAS Block Design (raw score) Digit Symhol (raw score) RAVLT Trials l-5 Total PASAT Total Stroop Color Interference Test
1.4 4.67 5.93 13.32 0.82 13.97 2.7 9.64 6.43 0.24
NS 0.04 0.02 c 0.001 NS c 0.001 0.11 < 0.01 0.02 NS
27.66 6.47 3.78 36.37 35.56 27.53 15.11 47.96 50.32 0.01
5.1 1.55 1.76 1.65 0.07 0.5 0.93 7.04 3.11 0.01
0.03 NS NS NS NS NS NS 0.01 0.09 NS
0.02 0.06 co.oo1
d.f. = 1,35 for all analyses
psychomotor task requiring set shifting (Trail Making Test B [F (1,34) = 6.00; P < 0.02]), visuospatial function (Rey-Osterrieth Complex Figure [F (1,34) = 5.22; P < 0.031 and Block Design [F (1,34) = 12.36; P = O.OOl]) and visual so 80 70
\ 60 E 50
Trails A - Abusers
Trails A - Controls
and verbal memory (Rey-Osterrieth delayed recall [F (1,34) = 23.37; P < O.OOOl] and RAVLT-total recall for trials l- 5 [F (1,34) = 9.38; P = 0.0041). As Table III shows, both groups demonstrated significant improvement on most neuropsychological measures from Time 1 to Time 2, but the cocaine group exhibited less improvement than the control group on measures of psychomotor speed (Trails A) and memory (RAVLT, trials l-5, total score). Similarly, a trend toward significance was observed for a measure of concentration and divided attention (PASAT total score trials 1 and 2), again with less improvement shown at Time 2 by the cocaine group than by the controls. Figure 1 illustrates the differential change over time of the cocaine abusers and normal controls on these measures. Discussion
Time 1 Time 2 TESTING
Fig. 1. Performance of the cocaine abusers and normal controls on three neuropsychological measures at Time 1 and two weeks later (Time 2).
These results suggest that recent cocaine use results in specific neuropsychological impairment during the acute phase of withdrawal. Further, this impairment does not appear to be attributable to withdrawal-related depression, which is common at this phase and was evident in this sample. The results indicate that memory, visuospatial abilities and concentration were most affected by cocaine use within 72 h of
testing. Following two weeks of abstinence, validated by independent physiological indices, from all substances that could be expected to alter mood or cognitive function, the cocainedependent group failed to demonstrate the expected degree of neuropsychological recovery in comparison to the control group on measures of psychomotor speed, memory and concentration. This finding suggests that selective cognitive deficits are identifiable at least 2 weeks beyond the cessation of cocaine use, at least in this clinical sample. Because cocaine-dependent and control subjects were carefully matched for age, race and education, and since subjects in both groups were tested via urinary benzoylecgonine analysis to rule out significant cocaine use during the past week, it is unlikely that these factors could account for these observed deficits. One important caveat must be noted. This study performed careful assessment of recent substance use to exclude any subject meeting DSM-III-R criteria for current polysubstance dependence or for abuse or dependence of any substance other than cocaine. In addition, any subject whose clinical laboratory analyses showed evidence of liver dysfunction was excluded, thereby ensuring that subjects with liver dysfunction secondary to chronic past alcohol abuse were not enrolled. However, our assessment of past abuse of substances other than cocaine extended only over the 6-month period prior to enrollment. Because of this, our conclusions must be tempered somewhat since the findings could have been influenced by subjects’ use of other substances in the remote past. The sample in this study consisted largely of African-American males, in both the clinical and control samples. The inclusion of only one female and two other ethnic group members does not allow a determination of how our results might have differed in other ethnic groups. Further research is needed to explore the gender and ethnic specificity of these findings. Any attempt to postulate a neurochemical basis for the cognitive deficits observed in this study should take into account the distinction between the short- and long-term effects of cocaine on neurotransmitter function in the
central nervous system. Acute administration of cocaine has been demonstrated to block reuptake of dopamine and cause increased firing in mesolimbic and mesocortical dopaminergic tracts in the brain (Gawin, 1991) as well as reduce cortical and subcortical metabolic function (London et al., 1990). On the other hand, chronic abuse of cocaine is thought to produce chronic dopamine depletion, as neurons adapt to acute increases of dopamine in the synapse (due to blockade of reuptake) by down-regulating synthesis and release of dopamine (Mule, 1984; Dackis and Gold, 1985). Dopamine depletion may represent, at least in part, a physiologic substrate for the observed short-term neuropsychological deficits found during the acute phase of cocaine withdrawal. These persisting deficits in memory, psychomotor speed and concentration are consistent with the neuropsychological deficits seen in other dopamine depletion disorders, such as Parkinson’s disease and progressive supranuclear palsy (Cummings, 1990). In addition, altered dopaminergic activity in tracts projecting to the limbic system may partially explain mood symptomatology, including depression and agitation, that is commonly associated with cocaine withdrawal. In our study, it is noteworthy that at initial assessment, 10 of the 16 subjects in the cocaine group scored above 16 on the BDI, which is generally accepted as the cutoff point for assessing the presence of clinical depression. Future research is needed to better delineate the nature of the recovery of neuropsychological function over time in chronic cocaine abusers. Although our data suggest that deficits are present at least 2 weeks following cessation of cocaine, it is not known if these deficits persist for many weeks or even months after cessation. In addition to longer periods of longitudinal followup, future studies should employ larger sample sizes in order to increase the power of statistical analysis. Acknowledgments This research was supported by the Department of Veterans Affairs Medical Research
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