Long-Term Outcome of Repetitive Transcranial Magnetic Stimulation in a Large Cohort of Patients With Cocaine-Use Disorder: An Observational Study

Abstract

Background: Cocaine is a psychostimulant drug used as performance enhancer throughout history. The prolonged use of cocaine is associated with addiction and a broad range of cognitive deficits. Currently, there are no medications proven to be effective for cocaine-use disorder (CocUD). Previous preliminary clinical work suggests some benefit from repetitive transcranial magnetic stimulation (rTMS) stimulating the prefrontal cortex (PFC), involved in inhibitory cognitive control, decision-making and attention. All published studies to date have been limited by small sample sizes and short follow-up times. Methods: This is a retrospective observational study of 284 outpatients (of whom 268 were men) meeting DSM-5 criteria for CocUD. At treatment entry, most were using cocaine every day or several times per week. All patients underwent 3 months of rTMS and were followed for up to 2 years, 8 months. Self-report, reports by family or significant others and regular urine screens were used to assess drug use. Results: Median time to the first lapse (resumption of cocaine use) since the beginning of treatment was 91 days. For most patients, TMS was re-administered weekly, then monthly, throughout follow-up. The decrease in frequency of rTMS sessions was not accompanied by an increase in lapses to cocaine use. Mean frequency of cocaine use was <1·0 day/month (median 0), while serious rTMS-related adverse events were infrequent, consistent with published reports from smaller studies. Conclusions: This is the first follow-up study to show that rTMS treatment is accompanied by long-lasting reductions in cocaine use in a large cohort.

Full text

BRIEF RESEARCH REPORT
published: 28 February 2020
doi: 10.3389/fpsyt.2020.00158
Frontiers in Psychiatry | www.frontiersin.org 1February 2020 | Volume 11 | Article 158
Edited by:
Simona Pichini,
Higher Institute of Health (ISS), Italy
Reviewed by:
Mark J. Ferris,
Wake Forest School of Medicine,
United States
Deena Marie Walker,
Icahn School of Medicine at Mount
Sinai, United States
*Correspondence:
Luigi Gallimberti
luigigallimberti.novellafronda@
gmail.com
Specialty section:
This article was submitted to
Addictive Disorders,
a section of the journal
Frontiers in Psychiatry
Received: 05 December 2019
Accepted: 19 February 2020
Published: 28 February 2020
Citation:
Madeo G, Terraneo A, Cardullo S,
Gómez Pérez LJ, Cellini N, Sarlo M,
Bonci A and Gallimberti L (2020)
Long-Term Outcome of Repetitive
Transcranial Magnetic Stimulation in a
Large Cohort of Patients With
Cocaine-Use Disorder: An
Observational Study.
Front. Psychiatry 11:158.
doi: 10.3389/fpsyt.2020.00158
Long-Term Outcome of Repetitive
Transcranial Magnetic Stimulation in
a Large Cohort of Patients With
Cocaine-Use Disorder: An
Observational Study
Graziella Madeo 1, Alberto Terraneo 1, Stefano Cardullo 1, Luis J. Gómez Pérez 1,
Nicola Cellini 2,3 , Michela Sarlo 2,3 , Antonello Bonci 4and Luigi Gallimberti 1
*
1Novella Fronda Foundation, Padua, Italy, 2Department of General Psychology, University of Padua, Padua, Italy, 3Padova
Neuroscience Center, University of Padua, Padua, Italy, 4Global Institutes on Addictions, Miami, FL, United States
Background: Cocaine is a psychostimulant drug used as performance enhancer
throughout history. The prolonged use of cocaine is associated with addiction and a
broad range of cognitive deficits. Currently, there are no medications proven to be
effective for cocaine-use disorder (CocUD). Previous preliminary clinical work suggests
some benefit from repetitive transcranial magnetic stimulation (rTMS) stimulating the
prefrontal cortex (PFC), involved in inhibitory cognitive control, decision-making and
attention. All published studies to date have been limited by small sample sizes and
short follow-up times.
Methods: This is a retrospective observational study of 284 outpatients (of whom 268
were men) meeting DSM-5 criteria for CocUD. At treatment entry, most were using
cocaine every day or several times per week. All patients underwent 3 months of rTMS
and were followed for up to 2 years, 8 months. Self-report, reports by family or significant
others and regular urine screens were used to assess drug use.
Results: Median time to the first lapse (resumption of cocaine use) since the beginning
of treatment was 91 days. For most patients, TMS was re-administered weekly, then
monthly, throughout follow-up. The decrease in frequency of rTMS sessions was not
accompanied by an increase in lapses to cocaine use. Mean frequency of cocaine
use was <1·0 day/month (median 0), while serious rTMS-related adverse events were
infrequent, consistent with published reports from smaller studies.
Conclusions: This is the first follow-up study to show that rTMS treatment is
accompanied by long-lasting reductions in cocaine use in a large cohort.
Keywords: cocaine use disorder (CocUD), transcranial magnetic stimulation (TMS), left dorsolateral prefrontal
cortex (l-DLPFC), long-term follow up, addiction

Madeo et al. Long-Term Outcome of rTMS in CocUD
INTRODUCTION
Cocaine is a psychostimulant drug generally used as enhancer
of cognitive performances, confidence, sociability, energy, and
wakefulness. However, cocaine has been a focus of attention
on a global scale for the serious harms related to its use,
including addiction and cognitive dysfunctions. Currently, no
medications have been proven to be effective for cocaine
use disorder (CocUD). The traditional strategy has been
to develop medications or psychological interventions to
attenuate drug reward, which is mainly mediated by the
dopaminergic pathway from the ventral tegmental area (VTA)
to the nucleus accumbens. This approach has not resulted
in effective therapeutic interventions for cocaine addiction.
Recently, repetitive transcranial magnetic stimulation (rTMS)
has received increasing attention as a potential treatment
for CocUD (1). As we and others have suggested, rTMS of
left dorsolateral prefrontal cortex (l-DLPFC) may represent a
human translation of preclinical findings that cocaine-seeking
is attenuated by optogenetic activation of specific prefrontal
circuits (2,3). Both preclinical and clinical findings suggest that
DLPFC has a key role in top-down modulation of emotional
and behavioral processes relevant to addiction (4,5). Thus,
exogenously increasing the neuronal excitability of DLPFC via
high-frequency rTMS might help reduce craving and prevent
lapse∗1to cocaine use.
Clinical confirmation that rTMS is effective for CocUD
awaits results from randomized controlled trials that are now
in progress. Studies published to date are limited by small
sample sizes and short duration of follow-up. In almost half
the published studies using rTMS or a similar intervention for
CocUD, there was, strictly speaking, no follow-up: responses
(e.g., cocaine craving) were assessed only within the laboratory on
the day of stimulation (6–9). In 6 studies that assessed real-world
outcomes, follow-up durations ranged from 5 days to 6 months
(median 39 days), and the number of cocaine users receiving
stimulation ranged from 6 to 36 (median 14) (10–15).
Here we report results from a cohort of 284 cocaine users
who received rTMS and were then followed for up to 2 years, 8
months (median 164 days). This is a retrospective chart review,
with all the attendant limitations thereof. However, it is also
unprecedented in its size and duration. Until there are results
from large randomized trials, the data we report here provide
the strongest evidence to date that rTMS is well-tolerated and
possibly effective in people with CocUD.
METHODS
Study Design and Participants
Patients signed informed consent on the day of clinic intake
and agreed that their data could be used for research. Patients
1The terms lapse and relapse each refer to a resumption of drug use during some
period of deliberate abstinence. A lapse is any such resumption of drug use,
however brief; a relapse is a resumption that is prolonged and problematic. Neither
term has a standardized operational definition. In this paper, we refer to any
resumption of cocaine use as a lapse. Thus, some of the lapses in our participants
could probably be characterized as relapses.
were informed that the data collected would be processed in
accordance with the law on privacy and in compliance with
Legislative Decree No. 196 of June 30, 2003, “Personal Data
Protection Code,” ensuring anonymity. The data were extracted
from patient clinical records and anonymized for analysis. All
subjects gave their informed consent for inclusion before they
participated in the study. This was a retrospective chart review
of data from 284 men and women who were treated from 2013
to 2017 and followed for at least 12 weeks after the first week
of rTMS sessions. The protocol, limited to the retrospective
chart review, was approved by the Ethical Committee for the
Psychological Research, Departments of Psychology, University
of Padua (Protocol 2551) and the study was conducted in
accordance with the Declaration of Helsinki. The total of 284
includes 58 patients who were lost to follow-up within the
first 12 weeks (i.e., this was an intent-to-treat sample) but
excludes 44 patients for whom 12 weeks had not yet elapsed
when data analysis started. All patients voluntarily underwent
treatment for CocUD in an rTMS protocol at a clinic center
for addiction treatment in Padua, Italy. At intake, each patient
was assessed by a psychiatrist and a psychologist with expertise
in the treatment of addiction. A complete family, physiological,
remote pathological and near pathological history was collected,
in addition to a detailed psychiatric, toxicological and clinical
history. Patients were between 18 and 70 years of age and met
DSM-5 criteria for CocUD. A published screening form was
administered to all the patients to exclude contraindications
to rTMS (16). Each patient underwent rTMS using a medical
device (MagPro R30) targeting the l-DLPFC. The stimulation
parameters, in accord with international recommendations for
patient safety and ethics (16), were: frequency 15 Hz, intensity
100% of the motor threshold, 60 impulses per stimulation
train, inter-train interval 15 s, and 40 total trains, for a
session duration of 13 min. For the first 5 days, patients
received two rTMS sessions per day (on either an inpatient
or outpatient basis, reflecting the patient’s needs). rTMS was
then administered on an outpatient basis at weekly intervals
(twice per day on each session day) for 11 consecutive weeks,
as in our published pilot study (15). rTMS was re-administered
throughout follow-up on an individualized basis to patients who
reported lapses to cocaine use, and to patients whose clinical
evaluations showed ongoing cocaine craving, including stress-
induced craving.
Measures
The primary outcome measure was lapse to cocaine use during
follow-up. Cocaine use was assessed through a combination of
urine screening, self-report, and reports by collateral informants
(typically family members). As in our published pilot study
(15), the “zero” day for follow-up monitoring was set at 8
days after the initial 5-day course of rTMS (for consistency
in outcome analysis, this was done regardless of whether the
initial sessions were inpatient or outpatient.) After that 8-day
grace period (during which only 29 of 284 patients tested
positive for cocaine), any indications of cocaine use (whether by
urine or by report) was coded as a lapse. Of the 284 patients,
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Madeo et al. Long-Term Outcome of rTMS in CocUD
147 maintained regular contact with the clinic through follow-
up visits and phone calls, allowing us to reliably trace their
precise patterns of cocaine use and abstinence during follow-
up. For the other 137 patients, we have reliable data only
on the date of initial lapse to cocaine use (if any) or loss
to follow-up.
Statistical Analysis
Because this is a retrospective chart review, results are presented
descriptively. For the sample as a whole, we used Kaplan-
Meier survival analysis (SAS Proc Lifetest) to calculate the
median number of days until the first lapse to cocaine use.
Data were coded as right-censored for patients who were still
abstinent at the end of monitoring (∼44% of censored cases)
or with whom the clinic lost contact (∼56% of censored
cases). To help contextualize the “first lapse” findings, we
display them together with historical control data from an
outpatient cohort of 173 cocaine users in the US who
were undergoing group and/or individual psychotherapy after
discharge from inpatient treatment (17,18)2. The two samples
are not intended to be directly comparable, but they share
important characteristics: both had just been discharged from
an inpatient stay, and both continued to receive treatment
as needed during a lengthy outpatient follow-up. For the
subset of our 147 patients who were regularly followed, we
created a case-by-case display of the relationship between
booster sessions of rTMS and stretches of abstinence from
cocaine. We know of no published data set to which this can
be compared.
Role of the Funding Source
The funders of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of the
report. The corresponding author had full access to all the
anonymized data in the study and had final responsibility for the
decision to submit for publication.
RESULTS
Patient Characteristics
Demographic and drug-use data are shown in Table 1. Most
patients were male and were using cocaine at least weekly
(typically by nasal insufflation, though in some cases by smoking)
before initiation of rTMS.
First Lapse to Cocaine Use in the Sample
as a Whole
For the 284 patients in the whole sample, the duration of follow-
up ranged from 4 to 989 days (2 years, 8 months); median
2The results from the comparison cohort were collected ∼15 years ago as part of
a larger data set. The authors who graciously allowed us to use the lapse results
were unable to retrieve raw data such as the demographics of the cocaine-using
subgroup. In the full comparison sample (n=827), which included people in
treatment for dependence on alcohol, marijuana, and heroin, 24% were women,
and race/ethnicity were more heterogeneous than in our patients: 47% were
European American, 40% were African American, another 12% were classified as
Hispanic, and the race of the remaining 1% was classified as “other.” Their mean
age was 30. For more information, see Dodge et al. (17).
TABLE 1 | Sample characteristics.
Total sample
(n=284)
Closely followed
subsample (n=147)
Age (mean, SD) 38.3 (8.4) 36.6 (7.7)
Sex
Male 268 (94%) 139 (95%)
Female 16 (6%) 8 (5%)
Cocaine use before treatment entry*
Daily 45% 30%
Weekly or more (not daily) 45% 51%
Monthly or more (not weekly) 2% 5%
Less than monthly 7% 14%
Cocaine route of administration*
Snorting 90% 86%
Smoking 9% 11%
Both 1% 3%
*Cocaine-use data were available for 126 participants, 43 of whom were in the closely
followed subsample; these are the denominators for the percentages. Some percentages
add up to slightly <100 due to rounding error.
was 164 days (just over 5 months). Time to the first lapse is
shown in Figure 1. Median time to the first use of cocaine was
91 days (95% confidence interval 70–109 days). Of the patients
who had at least 12 months of follow-up, 10 out of 55 (18%)
maintained abstinence throughout. Of the patients who had at
least 18 months of follow-up, 2 out of 6 (33%) maintained
abstinence throughout. In a separate cohort of “treatment as
usual” outpatients, median time to the first use of cocaine was
51 days (95% confidence interval 39-78 days). The difference
between “treatment as usual” patients and rTMS patients seemed
to emerge most clearly around 80 days after discharge from
inpatient treatment.
Patterns of Cocaine Use and Abstinence in
the Closely Followed Subsample
In the 147 closely followed patients, the duration of follow-
up ranged from 84 days (12 weeks) to 974 days (2 years, 8
months); median was 217 days (just over 7 months). Time
courses of rTMS and cocaine use are shown in Figure 2. For most
patients, rTMS (light rectangles) was re-administered weekly,
then monthly. Lapses to cocaine use (black circles) tended to
occur every month or so for most patients, but there were
long stretches of abstinence between lapses. This is shown
in collapsed form in Figure 3, which illustrates more clearly
that the gradual decrease in re-administration of rTMS (green
circles) did not leave patients more vulnerable to lapses to
cocaine use (red rectangles). The mean number of cocaine
uses per patient was <1·0 day/month (median 0). Self-reported
use of other drugs, including alcohol, gave no indication
that patients were substituting other drugs for cocaine (data
not shown).
Adverse Events
Adverse events (AEs) were reported by 41 of the 284 patients.
No patient reported more than one. AEs reported were: headache
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Madeo et al. Long-Term Outcome of rTMS in CocUD
FIGURE 1 | T ime to first resumption of cocaine use in full sample and comparison cohort. Blue line: Proportion of our patients (n=284) remaining abstinent from
cocaine after the first course of rTMS, monitored by urine screening, self-report, and family corroboration. Day 0 is 8 days after the initial course of rTMS. rTMS
continued during follow-up (not shown in this figure). Red line: Proportion of patients in a separate cohort of 173 “treatment as usual (no-rTMS)” outpatients in New
Haven, CT (17). Like our rTMS patients, they achieved initial abstinence and were followed up during ongoing treatment (group and individual psychotherapy) for
cocaine-use disorder.
(n=23), hypomania (n=4), anxiety (n=2) irritability
(n=2), dental pain (n=2), scalp discomfort during the
first 2 weeks of sessions (n=1), angioedema and urticaria
(n=1), distractibility (n=1), dizziness (n=1), nausea
(n=1), nausea and numbness (n=1), seizure (n=1),
and a hypomanic episode (n=1). The seizure occurred in
a 27-year-old woman 66 days after her first rTMS session.
She has used cocaine shortly before; she had not recently
undergone rTMS. The hypomanic episode occurred in a 37-
year-old man, just under 90 days after his first rTMS session.
His family reported that he had begun speaking aloud to
himself without realizing it. rTMS was suspended for medical
examinations, which did not show any abnormalities. Other AEs
were transient and resolved spontaneously or with over-the-
counter medications.
DISCUSSION
This large set of outcome data adds to the evidence that rTMS
can be used to treat CocUD. Our data have all the limitations
inherent in retrospective chart review, but one conclusion we
can draw confidently is that rTMS for CocUD, at least as
administered here, can be considered a long-term rather than
only an acute treatment. Several published discussions have
stated or implied that rTMS might be a time-limited treatment
with lifelong “normalizing” effects on addiction to cocaine or
other drugs (19–21). Our findings do not rule that out; we
tested only one brain site (left DLPFC) and only one set of
stimulation parameters. But at that site, using those parameters,
it was feasible, acceptable, and often seemingly necessary to
continue treatment sessions p.r.n. for months or years, with
adverse events generally few and transient. A similar long-
term role has been proposed for rTMS in treatment of mood
disorders (22–24). Therefore, rTMS for CocUD may find its
place as an additional tool in settings where psychotherapeutic
or behavioral treatments are administered. Meta-analyses have
repeatedly shown that the most effective known treatments
for CocUD are behavioral ones incorporating both tangible
incentives for abstinence and social reinforcement of abstinence
(25). rTMS could readily be integrated into those behavioral
approaches, to be given as needed. Although our data do not
permit strong conclusions about the effectiveness of rTMS, it
is intriguing to see our outcomes side by side with outcomes
in the most comparable cohort we could find. Both cohorts
were receiving ongoing care as needed after becoming abstinent
from cocaine. The survival curves for resumption of cocaine
use indicate a considerably longer duration of abstinence in
our rTMS-treated cohort than in the cohort that received
“treatment as usual (no-rTMS)” in the form of individual and
group psychotherapy.
To our knowledge, there are no available studies in
the literature analyzing the lapse rates related to other
conventional forms of treatment (pharmacological, pharmaco-,
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Madeo et al. Long-Term Outcome of rTMS in CocUD
FIGURE 2 | (A) Maintenance rTMS sessions and time between lapses for closely followed subsample. Green rectangles: Maintenance rTMS sessions after the initial
8-day course of rTMS. For most patients, rTMS was readministered weekly, then monthly. This was done in response to lapses and in anticipation of lapses. Black
circles: Lapses to cocaine use. Lapses tended to occur approximately every month for most patients, but with long stretches of abstinence separating them.
(B) Causes of censoring in closely followed subsample. Blue arrows: Continuously abstinent patients for whom follow-up is ongoing. Open black circles: Continuously
abstinent patients who were lost to further follow-up.
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Madeo et al. Long-Term Outcome of rTMS in CocUD
FIGURE 3 | Maintenance rTMS sessions and lapses in closely followed subsample, month by month. This is a collapsed view of data from Figure 2. Green line: Mean
(SEM) number of rTMS sessions per patient. Red line: Mean (SEM) number of cocaine lapses per patient.
or psychotherapy) for cocaine addiction, especially when
considering large cohorts of patients and long period
of observation. Nevertheless, we can argue that clinical
outcomes, including lapse rate, may show a significant
difference compared to conventional treatment for addiction.
Compelling evidence from preclinical and clinical studies
indicates that rTMS influences neural activity in the short
and long term by mechanisms involving neuroplasticity and
resulting in substantial behavioral changes (2,3,26,27).
These rTMS mediated effects have offered a neural
circuit-based treatment for cocaine addiction. Indeed, the
long-term neurophysiological changes induced by rTMS on
frontal brain regions have the potential to affect behaviors
related to drug craving, intake, and relapse and have
been proposed as a significant biomarker for predicting
treatment outcome.
Human laboratory studies with rTMS suggest that the site
we stimulated, left DLPFC, might also be an appropriate target
for people with addictions to heroin (28), methamphetamine
(29,30), nicotine (31), or cannabis (32).
In conclusion, rTMS continues to show promise as
the first neurobiological treatment for CocUD. Our data
add appreciably to the number of patients tested and the
length of follow-up. The crucial next step, already under
way (e.g., ClinicalTrials.gov identifiers NCT03607591,
NCT03333460, and NCT02986438), is represented by sham-
controlled randomized trials with sufficient sample size and
follow-up duration (33).
DATA AVAILABILITY STATEMENT
The datasets for this article are not publicly available to protect
proprietary information. Requests to access the datasets should
be directed to LGa (luigigallimberti.novellafronda@gmail.com).
ETHICS STATEMENT
This study was conducted in accordance with the Declaration
of Helsinki, and the protocol was approved by the Local
Ethics Committee of University of Padua (Protocol 2551,
number code: A0A52E7461375325ABBC1C2D9C54F844). The
patients/participants provided their written informed consent to
participate in this study.
AUTHOR CONTRIBUTIONS
AT and LGa: conceptualization. GM, SC, and LGó: data curation.
SC: formal analysis. SC, GM, and LGó: methodology. AT: project
administration. LGa: supervision. GM, AT, SC, LGó, NC, MS, and
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Madeo et al. Long-Term Outcome of rTMS in CocUD
LGa: validation. GM, SC, LGó, NC, MS, and LGa: visualization.
GM: writing—original draft. GM, AT, SC, LGó, NC, MS, AB, and
LGa: writing—review and editing.
FUNDING
This article was funded by the Novella Fronda Foundation,
Human and Neuroscience Research, Padua, Italy. Novella Fronda
Foundation had no role in data collection, data analysis, data
interpretation, or writing of the report. LGa had full access to all
the anonymized data in the study and had final responsibility for
the decision to submit for publication.
ACKNOWLEDGMENTS
We acknowledge the donors who made liberal donations to
support this study. Also, the authors would like to thank the
Zardi-Gori Foundation for the fellowship bursary.
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2020 Madeo, Terraneo, Cardullo, Gómez Pérez, Cellini, Sarlo, Bonci
and Gallimberti. This is an open-access article distributed under the terms of
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