Addictive Behaviors 28 (2003) 437 – 448

A pilot trial of piracetam and ginkgo biloba for the

treatment of cocaine dependence
Kyle Kampmana,b,*, Maria Dorota Majewskac, Karen Touriand,
Charles Dackisa, James Cornisha,b, Sabrina Poolea,b, Charles O’Briena,b
a
Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
b
Department of Veterans Affairs Medical Center, Philadelphia, PA, USA
c
National Institute on Drug Abuse, Bethesda, MD, USA
d
The Belmont Center, Philadelphia, PA, USA
Accepted 12 November 2001

Abstract

Background: Chronic cocaine use is associated with cognitive deficits that may reduce the
effectiveness of psychosocial treatment and promote relapse in newly abstinent cocaine-dependent
patients. Nootropic agents, such as piracetam and ginkgo biloba, may improve cognitive function and
reduce the incidence of relapse in these patients. Methods: This was a 10-week, double-blind,
placebo-controlled pilot trial involving 44 cocaine-dependent subjects. Subjects received either
piracetam (4.8 g/day), ginkgo biloba (120 mg/day), or placebo. Subjects were required to attain
abstinence from cocaine during a 2-week baseline phase demonstrated by providing at least one
benzoylecgonine (BE)-negative urine toxicology screen. Outcome measures included treatment
retention, urine toxicology screens, Clinical Global Impression (CGI) scores, and results from the
Addiction Severity Index (ASI). Results: Ginkgo biloba was not superior to placebo in any outcome
measure. Piracetam was associated with more cocaine use and lower CGI scores compared to placebo.
Conclusions: Neither piracetam nor ginkgo biloba appears to be a promising medication for the
treatment of cocaine dependence.
D 2002 Elsevier Science Ltd. All rights reserved.

Keywords: Cocaine; Piracetam; Ginkgo biloba; Clinical trial

* Corresponding author. University of Pennsylvania Treatment Research Center, 3900 Chestnut Street,
Philadelphia, PA 19104, USA. Tel.: +1-215-222-3200x109; fax: +1-215-386-6770.
E-mail address: [email protected] (K. Kampman).

0306-4603/02/$ – see front matter D 2002 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0306-4603(02)00226-5
438 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448

1. Introduction

Despite the decline in the overall numbers of cocaine users in the US since the peak of the
cocaine epidemic in the late 1980s, cocaine use still remains a major public health concern. In
1999, there were 1.5 million regular users of cocaine in the US (Feldman & Rouse, 2000). This
number has changed little since 1992, suggesting that current treatment techniques may not be
adequate to deal with the current population cocaine users. Standard treatment for cocaine
dependence consists of individual and/or group psychotherapy, which requires patients to
attend to the therapist, or group, and assimilate new information. Cocaine-dependent patients,
especially those with chronic heavy use, may not have the cognitive ability to fully benefit from
therapy. High rates of relapse and early dropout may reflect this inability to engage in treatment.
Evidence from both neuropsychological testing as well as imaging studies suggests that
chronic cocaine use results in brain changes that may affect cognitive function. Cognitive
deficits have been found to occur in stimulant abusers and the deficits found often included
deficits in memory and attention (Ardila, Rosselli, & Strumwasser, 1991; Herning, Glover,
Koeppl, Weddington, & Jaffe, 1990; Manschreck et al., 1990; O’Malley, Adamse, Heaton, &
Gawin, 1992; Smelson, Roy, Santana, & Engelhart, 1999; Trites, Suh, Offord, Nieman, &
Preston, 1974). Imaging studies provide further evidence of CNS changes resulting from
chronic cocaine use. Studies with positron emission tomography (PET) and single-photon
emission tomography (SPECT) demonstrated irregularly decreased blood flow in the cerebral
cortex, especially in the frontal and temporal lobes (Ernst, Chang, Oropilla, Gustavson, &
Speck, 2000; Holman et al., 1991; Kosten et al., 1998; Strickland et al., 1993; Tumeh, Nagel,
English, Moore, & Holman, 1990; Volkow et al., 1992). Finally, chronic cocaine users
showed significant degrees of cerebral atrophy on computed tomography compared to first-
time users and nonusers (Pascual-Leone, Dhuna, & Anderson, 1991).
Nootropic medications, such as piracetam and ginkgo biloba, improve cognitive functioning
and may be useful for the treatment of cocaine dependence. Piracetam is widely used in Europe
for treatment of neuropsychological deficiencies associated with aging, brain trauma, ischemia,
and for amelioration of neurological deficits resulting from Alzheimer’s disease, Parkinson’s
disease, and alcoholism (Vernon & Sorkin, 1991). Although its exact mechanism of action is
uncertain, piracetam is thought to improve brain circulation, brain glucose metabolism, and
facilitate neurotransmission of catecholamines, serotonin, acetylcholine, and glutamate (Ver-
non & Sorkin, 1991). It has been shown in a number of studies to improve cognitive functions
and stabilize mood (DeMay & Bande, 1980; Ezzat, Ibraheem, & Makhawy, 1985; Mindus,
Cronholm, Levander, & Schalling, 1976; Sano, Stern, Marder, & Mayeux, 1985; Schmidt,
Brendelmuhl, Engels, Schenk, & Luderman, 1991; Vernon & Sorkin, 1991).
Ginkgo biloba is an herbal product derived from the leaves of the Ginkgo biloba tree. A
number of the chemical constituents of the leaf extract have been isolated and identified
including various terpenoids and flavenoids. It is through these terpenoids and flavenoids that
ginkgo is thought to exert its effects (Kleijnen & Knipschild, 1992). Although the exact
mechanism of action of ginkgo is unknown, possible mechanisms of action include improved
cerebral blood flow due to antagonism of platelet activating factor (Kleijnen & Knipschild,
1992; Sutter & Wang, 1993). In addition, ginkgo may have neuroprotective effects including
 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448 439

anti-inflammatory and antioxidant properties (Calapai et al., 2000; Otani, Chaterjee, Gabard,
& Kreutzberg, 1986; Princemail et al., 1989). In clinical trials, ginkgo biloba has improved
cognitive function in both normal volunteers as well as in patients with dementia (Kanowski,
Herrmann, Stephan, Wierich, & Horr, 1996; Kennedy, Scholey, & Wesnes, 2000; LeBars et
al., 1997; Rai, Shovlin, & Wesnes, 1991; van Dongen, van Rossum, Kessels, Sielhorst, &
Knipschild, 2000; Wesnes, Ward, McGinty, & Petrini, 2000).
Our hypothesis was that nootropic agents, such as piracetam and ginkgo biloba, would
improve cognitive function in newly abstinent cocaine-dependent patients, thus allowing them
to better engage in psychosocial treatment. This would result in lower rates of relapse and less
cocaine use. The current trial was undertaken as part of a larger series of screening trials,
sponsored by the National Institute on Drug Abuse, evaluating novel treatment strategies for
cocaine dependence. It was intended to determine if either of these nootropic agents, piracetam
or ginkgo biloba, showed any promise as a potential treatment for cocaine dependence.

2. Methods

2.1. Subjects

The subjects were 44 DSM-IV cocaine-dependent men and women between the ages of 18
and 60. Psychiatric diagnoses were obtained by Master’s level clinicians using the Structured
Clinical Interview for DSM-IV (First, Spitzer, Gibbon, & Williams, 1996). Medical screening
included a complete medical history and physical examination conducted by a certified nurse
practitioner. Baseline laboratory testing included a chemistry screen, complete blood count,
urinalysis, urine pregnancy testing, prothrombin time, partial thromboplastin time, and a 12-
lead EKG. Women received urinary pregnancy testing prior to starting medications, and at
monthly intervals throughout the study.
Subjects dependent on any additional drug except nicotine, marijuana, and alcohol were
excluded. Cocaine-dependent subjects also dependent on alcohol were excluded if the alcohol
dependence was severe enough to require benzodiazepines for detoxification. Subjects were
required to have self-reported at least US$100 worth of cocaine use in the month prior to entry
and had to have at submitted at least one benzoylecgonine (BE)-positive urine toxicology
screen during that time. Other psychiatric exclusion criteria included psychosis, dementia, and
the use of other psychotropic medications. Medical exclusion criteria included unstable medical
illnesses and a history of hypersensitivity to piracetam or ginkgo biloba. Since ginkgo biloba is
an inhibitor of platelet activating factor and cases of abnormal bleeding have been associated
with its use (Rosenblatt & Mindel, 1997; Rowin & Lewis, 1996), subjects with a history of
abnormal bleeding or subjects using nonsteroidal anti-inflammatory drugs were excluded.

2.2. Measures

The primary outcome measures for this trial were urine toxicology screens obtained three
times weekly. Urine collection was not observed but urine sample temperature was
440 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448

monitored. Samples less than 90
F, or greater than 100
F were not accepted. Samples were
analyzed for BE by fluorescent polarization assay. The concentration of urinary BE in each
sample, measured in nanograms per milliliter, was used for comparison.
Secondary drug use outcome measures included the Addiction Severity Index (ASI)
(McLellan et al., 1992), which was administered three times, at baseline, 4 weeks after
starting medications, and at the end of the trial. The study physician rated illness severity and
improvement weekly using the Clinical Global Impression (CGI) scale (Guy, 1976). Cocaine
craving was measured at each visit using a 100-mm visual analog scale anchored by none,
and the greatest ever.
Mood and anxiety symptoms were measured weekly and at the end of the study using
the Beck Depression Inventory (Beck & Beamsdorfer, 1974) and the Beck Anxiety
Inventory (Beck, Epstein, Brown, & Steer, 1988). Cognitive function was measured at
the start of treatment, at Week 6 and at Week 10 using the Mini-Mental State Exam
(MMSE) (Folstein & Folstein, 1975), and the Symbol Digit Modality Test (SDMT)
(Smith, 1982).

2.3. Procedures

Subjects were treatment-seeking cocaine users recruited at two treatment facilities: the
Addiction Recovery Unit of the Philadelphia Veterans Affairs Medical Center (PVAMC) and
the Intensive Outpatient Treatment Program at the Presbyterian Hospital (IOP). The
Presbyterian Hospital is a member of the University of Pennsylvania Health System. All
patients signed informed consent prior to participation in the trial after trial procedures were
explained to them by an investigator. The study was reviewed and approved by the IRB of
both the PVAMC and the University of Pennsylvania.
Both the ARU and the IOP were used in order to enable us to include women in the sample
and in order to speed completion of this rapid screening trial. Both facilities provided similar
psychosocial treatment with subjects participating in intensive outpatient treatment programs
consisting of 7–9 h of primarily group drug counseling per week. Subjects were seen three
times weekly, usually Monday, Wednesday, and Friday (M, W, F).
Eligible subjects entered a 10-week trial that included a 2-week baseline phase during
which subjects were required to attain abstinence from cocaine demonstrated by providing at
least one BE-negative urine toxicology screen. Patients able to achieve abstinence from
cocaine were then randomly assigned to either piracetam 2.4 g twice daily, ginkgo biloba 120
mg twice daily, or placebo. The ginkgo biloba used in this trial was a standardized
preparation, EGb 761. Subjects were evaluated by a research technician three times weekly
during the trial (M,W,F) and by the study physician weekly.

2.4. Statistical analysis

Comparisons were initially made between subjects treated at the ARU and subjects treated
at the IOP in order to determine if outcomes were affected by treatment program. Then
comparisons were made between medication groups combining subjects from the ARU and
 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448 441

the IOP. Baseline measures were compared first between subjects treated at the ARU and
those treated at the IOP using two-tailed t tests for continuous variables and chi-square tests
for dichotomous variables. Baseline measures between the three medication groups were
compared using ANOVA for continuous variables and chi-square tests for dichotomous
variables. Treatment retention was compared using a log-rank test. Urine toxicology results
were analyzed quantitatively using a linear mixed effects regression model with the baseline
urine toxicology screens included as a covariate. Secondary outcome measures were analyzed
using a linear mixed effects regression model with baseline scores on the various measures as
a covariate. These analyses were done using BMDP-5V (Dixon, 1992) and PROC GENMOD
in SAS (SAS, 1996).

3. Results

3.1. Comparisons between treatment programs

Baseline demographics and drug use variables differed little between subjects treated at the
IOP and subjects treated at the ARU. On average, subjects treated at the ARU were slightly
older, 43.0 versus 39.2 years (t = 2.11, P=.04, df = 41). Subjects treated at the ARU were also
more likely to be men 96% versus 57.8% (c2 = 9.63, P=.002, df = 1) and reported
significantly more days of cocaine use in the 30 days prior to the trial, 10.1 versus 1.05 days
(t = 5.30, P < .001, df = 24.95).
Despite these differences in baseline characteristics, there were no effect of treatment
location on the primary treatment outcome measures. Treatment retention in the ARU and the
IOP was not significantly different (log-rank statistic 0.61, P=.43, df = 1). Likewise, treatment
program assignment was not a significant predictor of mean urinary BE levels (log-
transformed) from all visits during Weeks 3–10 [ F(1,42) = 0.095, P=.76]. Because there
were no significant effect of treatment location in the primary outcome measures, all
subsequent comparisons were made between the three medication groups combining subjects
from the ARU and the IOP.

3.2. Comparisons between medication groups

3.2.1. Baseline demographic and drug use

There was no significant difference between the three medication groups in any of the
baseline demographic or drug use variables (see Table 1). On average, subjects were about 40
years old. Most of the subjects were African American men and most smoked crack cocaine.
On average, subjects had used cocaine between 5 and 9 days in the month prior to treatment
and had spent less than US$400 for drugs.

3.2.2. Treatment retention

Treatment retention between the three medication groups differed at a trend level (log-rank
statistic = 4.63, P=.10, df = 2). The placebo group had the highest percentage of completers,
442 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448

Table 1
Subject characteristics, expressed as percent or mean (standard deviation)
Variable Piracetam Ginkgo biloba Placebo
(n = 18) (n = 12) (n = 14)
Age 42.00 (6.26) 40.58 (5.79) 41.21 (6.25)
Gender
Male 78% 75% 86%
Female 22% 25% 14%
Race
African American 100% 83% 93%
White 0% 17% 7%
Years of education 12.00 (1.46) 11.8 (1.40) 12.8 (1.31)
Dollars spent on drugs in past 30 days 245.59 (381.79) 349.58 (702.56) 173.71 (182.98)
Days of cocaine use in past 30 days 6.06 (8.66) 8.17 (2.50) 5.15 (1.38)
Years of cocaine use, lifetime 10.33 (4.53) 6.91 (4.39) 13.54 (8.39)
Number of prior treatments 1.59 (1.71) 1.33 (1.50) 2.46 (1.71)
Route of cocaine use
Intranasal 11% 0% 7%
Smoked 89% 100% 93%
Other current psychiatric diagnoses
Major depression/dysthymia 6.7% 8.3% 8.3%
Anxiety disorders 13.3% 16.7% 16.7%
Alcohol dependence 13.3% 25% 25%

71.4%, the piracetam group had the lowest percentage of completers, 38.8%, and the ginkgo
biloba group was intermediate, 58.3% (see Fig. 1).

3.2.3. Urine toxicology results

The urine toxicology results were analyzed quantitatively using the concentration of BE as
a continuous measure. Urinary benzoylecognine levels were first log-transformed to reduced
skew. Urine samples were compared between the three medication groups, examining
samples obtained during Weeks 3–10 with baseline samples (Weeks 1 and 2) included as
a covariate. In this analysis, there was a significant effect of time (Wald c2 = 50.78, df = 24,
P=.001). There was also a Group  Time interaction that closely approached significance
(Wald c2 = 64.68, df = 48, P=.054). As shown in Fig. 2, the log-transformed mean urinary BE
levels in the placebo group showed a consistent decline during the trial, whereas in the ginkgo
and piracetam group there was more variability in log-transformed mean urinary BE levels
and a less consistent decline over the 10 weeks of the trial.

3.2.4. Relapse prevention

Since our hypothesis was that nootropic agents would reduce relapse to cocaine use, we
compared the time to relapse to cocaine use using survival analysis. Relapse in this case
was defined as self-reported cocaine use, submission of a positive urine toxicology screen
(>300 ng/ml of BE), or treatment dropout. Time was measured in study weeks. This
 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448 443

Fig. 1. Treatment retention during the 8 weeks of randomized medications.

Fig. 2. Weekly mean urinary BE levels (log-transformed).

444 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448

analysis was done with the subset of subjects who had a negative urine toxicology screen
on the first day of medication treatment. Eleven subjects who achieved abstinence verified
by a clean urine sample during baseline but had relapse immediately prior to randomization
were excluded. Out of the subjects who were abstinent from cocaine on the first day of
medication treatment, 60% of placebo-treated subjects completed the trial without relapse
compared to 36% of piracetam-treated subjects and 22% of ginkgo-treated subjects (log-
rank statistic = 2.89, df = 2, P=.236).

3.2.5. Results from the ASI

Self-reported days of cocaine use declined in all groups over the course of the trial but there
was no group effect or Group  Time interaction (group Wald c2 = 0.84, df = 2, P=.66; time
Wald c2 = 10.99, df = 2, P=.004; Group  Time Wald c2 = 2.47, df = 4, P=.65). Likewise, days
of alcohol use declined in all three groups during the trial but there was no significant group
difference or significant Group  Time interaction (group Wald c2 = 3.84, df = 2, P=.14; time
Wald c2 = 7.94, df = 2, P=.02; Group  Time Wald c2 = 6.89, df = 4, P=.14). ASI composite
scores in the seven subscales showed little change over time and no significant Group  Time
effect except for the ASI composite drug score and the ASI composite alcohol score. Both of
these scores showed significant declines over time in all three groups but there was no
significant Group  Time interaction (ASI composite alcohol score: group Wald c2 = 0.49,
df = 2, P=.78; time Wald c2 = 27.46, df = 2, P < .001; Group  Time Wald c2 = 1.25, df = 4,
P=.86; ASI composite drug score: group Wald c2 = 3.47, df = 2, P=.18; time Wald c2 = 30.43,
df = 2, P < .001; Group  Time Wald c2 = 2.96, df = 4, P=.57).

3.2.6. CGI results

The study physician rated each subject for global improvement weekly on a seven-point
scale that included very much improved, improved, minimally improved, no change, minimally
worse, much worse, and very much worse. Including all subjects who completed at least 1 week
of study medication (n = 38), we compared the percentage of subjects in each study group who
were rated improved or very much improved at their last visit. Only 29% of the piracetam-treated
subjects rated were rated improved or much improved compared to 64% of the placebo-treated
subjects and 70% of the ginkgo-treated subjects (c2 = 5.22, df = 2, P=.07).

3.2.7. Results in craving, mood, and anxiety

At each visit, subjects were asked to rate their highest level of cocaine craving since their
last visit on a 100-mm visual analog scale anchored by none, and the greatest ever. A weekly
mean craving score for each subject was calculated and the weekly mean scores from Weeks
3 to 10 were compared. The mean score from baseline (Week 2) was included as a covariate.
Although craving scores declined significantly in all three medication groups, there was no
difference between groups nor was there a significant Group  Time interaction (group Wald
c2 = 2.45, df = 2, P=.29; time Wald c2 = 16.72, df = 7, P=.02; Group  Time Wald c2 = 14.89,
df = 14, P=.39). There was also a significant decline in Beck Depression Inventory scores in
all three groups. However, there was no significant group difference or a significant
Group  Time interaction (group Wald c2 = 0.79, df = 2, P=.67; time Wald c2 = 30.99,
 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448 445

df = 9, P .001; Group  Time Wald c2 = 13.65, df = 18, P=.75). There was no significant
change in Beck Anxiety Inventory scores during the trial in any of the three groups (group
Wald c2 = 0.83, df = 2, P=.66; time Wald c2 = 15.33; df = 9, P=.08; Group  Time Wald
c2 = 9.64, df = 18, P=.94).

3.2.8. Cognitive measures

Results from the tests of cognitive function showed no effect of medication treatment.
Mean scores on the Folstein MMSE were within normal limits for all three groups at the start
of treatment and did not change significantly over the course of the trial (group Wald
c2 = 0.096, P=.953; time Wald c2 = 3.55, P=.170, Group  Time interaction Wald c2 = 3.44,
P=.486). Likewise mean scores on the SDMT were not significantly different in the three
groups at baseline and did not change significantly during the trial (group Wald c2 = 1.17,
P=.557; time Wald c2 = 1.87, P=.392; Group  Time interaction Wald c2 = 3.12, P=.537).

3.2.9. Adverse events

Both piracetam and ginkgo biloba were very well tolerated. Adverse events were mainly
mild and evenly distributed between the three groups. Overall, there were 127 adverse
events reported, 45 in the placebo group, 52 in the piracetam group, and 30 in the ginkgo
group. The most common adverse events reported during the trial included upper respiratory
tract infection, reported by 36% of the subjects, headache (20%), nausea (20%), fatigue
(11%), and muscle aches (11%). There was one serious adverse event noted and this
occurred in a piracetam subject. The patient was withdrawn from the study due to
abnormally heavy menstrual bleeding. There did not appear to be any specific adverse
events associated with piracetam that could have accounted for the unusually high dropout
rate noted in that group.

4. Discussion

This study was a rapid screening trial intended to determine if either piracetam or ginkgo
biloba showed any promise for the treatment of cocaine dependence based on their activity
as nootropic medications. We found that neither medication showed particular efficacy for
the treatment of cocaine dependence. In the primary outcome measure, urine toxicology
results, there was a trend that closely approached statistical significance favoring the placebo
group over both piracetam and ginkgo biloba. In a number of secondary outcome measures,
neither piracetam nor ginkgo biloba showed even a suggestion of superiority over placebo.
These measures included self-reported cocaine use, cocaine craving, mood and anxiety
symptoms, and measures taken from the ASI. Finally, neither piracetam nor ginkgo biloba
showed any measurable effect in improving cognitive function measured by the Folstein
MMSE or by the SDMT.
It is interesting to note that piracetam-treated subjects appeared to do worse compared to
placebo-treated subjects in several outcome measures. First, the dropout rate among piracetam-
treated subjects was very high. In addition, there was trend towards more cocaine use in the
446 K. Kampman et al. / Addictive Behaviors 28 (2003) 437–448

piracetam-treated subjects. Consistent with this result was the finding that piracetam-treated
subjects were less likely to be rated as improved or much improved by the study physician at
their last visit. These results suggest that piracetam may be a particularly poor choice to pursue
as a potential treatment for cocaine dependence.
This study has several weaknesses. The number of subjects included was too small to
definitely assess the efficacy of piracetam or ginkgo biloba. However, this trial was not
intended to definitively assess the efficacy of these two medications. Rather, it was part of a
larger effort to rapidly screen a number of different medications to identify the most
promising agents to include in subsequent fully powered trials. The high dropout rate makes
interpretation of the data difficult since not all cocaine-dependent patients drop out of
treatment due to a lack of treatment efficacy. However, at least in the case of piracetam, there
was evidence to suggest that the high treatment dropout rate was associated with a lack of
clinical improvement. Finally, the cognitive measures used to assess the nootropic capabilities
of piracetam and ginkgo biloba were not very sensitive. In order to fully evaluate the effects
of these medications on cognitive function, more elaborate neuropsychological testing would
have been necessary. Such testing was beyond the scope of this small screening trial.
Despite its flaws, this trial was able to yield important data regarding the ability of these
two nootropic medications to influence outcome in the outpatient treatment of cocaine
dependence. Ginkgo biloba appeared to be well tolerated but showed little benefit over
placebo for preventing relapse to cocaine dependence. Piracetam was also not superior to
placebo in this study. Moreover, piracetam-treated subjects tended to drop out sooner, use
more cocaine, and were less likely to be rated as improved at the end of treatment.

Acknowledgements

The authors would like to acknowledge Maryann Gerhart and Camille Henry for their
assistance in data collection, and Ann Montgomery for her administrative assistance.
This study is supported by NIDA grants YO1 DA30012 and K20 DA00238.

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