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

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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.
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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
lapse1to 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 (69). 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) (1015).
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,
Frontiers in Psychiatry | www.frontiersin.org 2February 2020 | Volume 11 | Article 158
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 (1921). 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 (2224). 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
Frontiers in Psychiatry | www.frontiersin.org 6February 2020 | Volume 11 | Article 158
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
the Creative Commons Attribution License (CC BY). The use, distribution or
reproduction in other forums is permitted, provided the original author(s) and the
copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
Frontiers in Psychiatry | www.frontiersin.org 8February 2020 | Volume 11 | Article 158
... After removing duplicates, titles, and abstracts, 200 references were screened and 29 full-text articles were assessed for eligibility. Finally, 12 studies were included in this SR [13,15,17,20,[41][42][43][44][45][46][47][48]. A list of ongoing studies can be found in Table S3. Figure 1 shows the PRISMA flowchart of the study selection process. ...
... Table 2 shows the selected studies' characteristics. Five of the included studies were RCT [13,15,41,42,44], one was an nRCT [47] and six were case-series [17,20,43,45,46,48]. None of the studies identified by this SR reported data on cost-effectiveness. ...
... None of the studies identified by this SR reported data on cost-effectiveness. Two different therapeutic protocols were identified within the studies: conventional high frequency (10-15 Hz) [13,17,20,41,[43][44][45][46] and continuous or intermittent TBS [15,41,42,44]. Sample sizes ranged from 11-147 (median = 22.5). ...
Article
Full-text available
Long-term cocaine use is associated with cognitive deficits and neuro-psychiatric pathologies. Repetitive transcranial magnetic stimulation (rTMS) is an emerging therapeutic strategy relating to changes in brain activity. It stimulates the prefrontal cortex and is involved in inhibitory cognitive control, decision making and care. This systematic review aims to evaluate and synthesize the evidence on the safety, effectiveness, and cost-effectiveness of rTMS for the treatment of cocaine addiction. A systematic review of the literature was carried out. The following electronic databases were consulted from inception to October 2020: MEDLINE, Embase, CINAHL, PsycINFO, Cochrane Central Register of Controlled Trials and Web of Science. Randomised controlled trials, non-randomised controlled trials and case-series and full economic evaluations were included. Twelve studies were included. No identified study reported data on cost-effectiveness. Significant results of the efficacy of TMS have been observed in terms of the reduction of craving to consume and the number of doses consumed. No serious adverse effects have been observed. Despite the low quality of the studies, the first results were observed in terms of reduction of cocaine use and craving. In any case, this effect is considered moderate. Studies with larger sample sizes and longer follow-ups are required.
... On the other hand, all the remaining studies were not double-blinded, nor sham-controlled or randomised [1,[11][12][13]. Interestingly, these studies have underlined the effectiveness of rTMS in craving control [1,11,12,14,24], and two studies which measured cocaine urinalysis showed a better outcome in the rTMS group [14,25]. Nonetheless, these older studies showed insufficient quality and lacked adequate power in rTMS enrolled patients and other limitations such as the sample size/treatment duration [11], missing controls, and low numbers of cases. ...
... However, the survival curves did initially differentiate between the groups, and the average time to negativisation was shorter with the active therapy. The frequency of patients with urine negativisation was significantly higher in the same group, indicating an early effect of rTMS in this experimental setting and probably confirming the need for a subchronic rTMS treatment [25]. ...
... Positive results were found by using a swimmer plot analysis following an interview about daily cocaine use. We chose this type of analysis since it reflects a better picture of the cocaine pattern of use reported day by day, similarly to Madeo and co-workers [25]. Interestingly, the results are very comparable to the most recent RCT rTMS/CUD report [23], and both study confirm the same pattern of results. ...
Article
Full-text available
Background: Cocaine use disorder (CUD) is a global health issue with no effective treatment. Repetitive Transcranial Magnetic Stimulation (rTMS) is a recently proposed therapy for CUD. Methods: We conducted a single-center, randomised, sham-controlled, blinded, parallel-group research with patients randomly allocated to rTMS (15 Hz) or Sham group (1:1) using a computerised block randomisation process. We enrolled 62 of 81 CUD patients in two years. Patients were followed for eight weeks after receiving 15 15 Hz rTMS/sham sessions over the left dorsolateral prefrontal cortex (DLPFC) during the first three weeks of the study. We targeted the DLFPC following the 5 cm method. Cocaine lapses in twice a week urine tests were the primary outcome. The secondary outcomes were craving severity, cocaine use pattern, and psychometric assessments. Findings: We randomly allocated patients to either an active rTMS group (32 subjects) or a sham treatment group (30 subjects). Thirteen (42%) and twelve (43.3%) of the subjects in rTMS and sham groups, respectively, completed the full trial regimen, displaying a high dropout rate. Ten/30 (33%) of rTMS-treated patients tested negative for cocaine in urine, in contrast to 4/27 of placebo controls (p = 0.18, odd ratio 2.88, CI 0.9-10). The Kaplan-Meier survival curve did not state a significant change between the treated and sham groups in the time of cocaine urine negativisation (p = 0.20). However, the severity of cocaine-related cues mediated craving (VAS peak) was substantially decreased in the rTMS treated group (p<0.03) after treatment at T1, corresponding to the end of rTMS treatment. Furthermore, in the rTMS and sham groups, self-reported days of cocaine use decreased significantly (p<0.03). Finally, psychometric impulsivity parameters improved in rTMS-treated patients, while depression scales improved in both groups. Conclusions: In CUD, rTMS could be a useful tool for lowering cocaine craving and consumption.
... Long-lasting rTMS-induced changes may impact behavioral manifestations of addictive disorders as craving, intake, or relapse (29). Preliminary clinical studies have shown reductions in cocaine craving and intake after rTMS treatments (30)(31)(32)(33)(34)(35). In addition, it was reported a positive effect of rTMS on other symptoms connected to substance use and deeply related to the fronto-striatal functioning (36). ...
... To best identify the L-DLPFC [Montreal Neurological Institute (MNI) coordinates x: −50, y: 30, z: 36], we used an optical TMS navigator (Localite, St. Augustin, Germany) and a magnetic resonance image (MRI) template. Treatment characteristics are the same described in our previous studies (30,34): twice-daily rTMS sessions for the first five consecutive days of treatment, followed by twice-daily rTMS sessions once a week over eleven weeks. The time interval between the two sessions within each day was 45-60 min. ...
... Firstly, we considered the lapse to cocaine use. In this analysis, for consistency with our previous works (30,34), the "zero" day for follow-up monitoring was set at 8 days after the initial 5-day course of rTMS. After that 8-day grace period, any indication of cocaine use was coded as a lapse. ...
Article
Full-text available
Background: Adult attention-deficit/hyperactivity disorder (ADHD) is associated with high comorbidity with other psychiatric diseases, including cocaine use disorder (CocUD). Given the common fronto-striatal dysfunction, ADHD patients often use cocaine as self-medication for ameliorating symptoms by increasing striatal dopamine release. Yet, comorbidity with ADHD is related to poor treatment outcomes. CocUD has been treated with transcranial magnetic stimulation (TMS), but no studies investigated the outcomes in patients comorbid with ADHD. Methods: Twenty-two ADHD/CocUD and 208 CocUD-only participants received a high-frequency (15Hz) rTMS treatment stimulating the left-DLPFC. We investigated whether both groups of patients shared similar demographic and clinical characteristics at baseline. Then, we monitored the effect of treatment testing for potential differences between groups. Results: At baseline demographic, toxicology and clinical features were not different between the two groups except for global severity index (GSI from SCL-90): patients of ADHD/CocUD group reported higher general symptomatology compared to the CocUD-only group. Concerning the effect of treatment, both groups significantly improved over time regarding cocaine use, craving, and other negative affect symptoms. No differences were observed between groups. Conclusions: To our knowledge, this is the first study comparing the demographic characterization and rTMS clinical improvements of patients with a dual diagnosis of ADHD and CocUD against CocUD-only patients. Cocaine use and common self-reported withdrawal/abstinence symptoms appear to benefit from rTMS treatment with no differences between groups. Future studies are needed to further investigate these preliminary results.
... This approach has been associated to clinically relevant behavioral changes in patients with addictive disorders (Ekhtiari et al., 2019), affecting craving, intake and relapse (Diana et al., 2017). To date, high-frequency rTMS protocols over the dorsolateral prefrontal cortex, a key node for the executive control network (Shirer, Ryali, Rykhlevskaia, Menon & Greicius, 2012), are effective in reducing craving, substance consumption and withdrawal symptoms of SUD, including alcohol (Addolorato et al., 2017;Mishra, Nizamie, Das & Praharaj, 2010;Mishra, Praharaj, Katshu, Sarkar & Nizamie, 2015), tobacco (Amiaz, Levy, Vainiger, Grunhaus & Zangen, 2009;Eichhammer et al., 2003;Hayashi, Ko, Strafella & Dagher, 2013;Johann et al., 2003;Li et al., 2013), cocaine Hanlon et al., 2015;Madeo et al., 2020;Pettorruso et al., 2019;Politi, Fauci, Santoro, & Smeraldi, 2008;Sanna et al., 2019;Steele, Maxwell, Ross, Stein, & Salmeron, 2019;Terraneo et al., 2016), methamphetamine (Liang, Wang & Yuan, 2018;Su et al., 2017) and heroin (Shen et al., 2016). Preliminary findings also suggest that these protocols might ameliorate gambling disorder symptoms (Cardullo et al., 2019;Pettorruso et al., 2020). ...
... Notably, the clinical recovery persisted at 1-year followup after the treatment although both patients experienced unpleasant situations, recognized as triggers for inducing craving for gaming or porn watching in the past. This longlasting clinical improvement over the addictive behaviours with no relapses in both patients is in support of a minimized placebo response and is in line with our previous findings showing that rTMS treatment is accompanied by long-lasting reductions of substance consumption behaviours in a large cohort of patients with cocaine use disorder clinically followed-up for 2 years and 8 months (Madeo et al., 2020). ...
Article
Full-text available
Background Several behaviors, besides consumption of psychoactive substances, produce short-term reward that may lead to persistent aberrant behavior despite adverse consequences. Growing evidence suggests that these behaviors warrant consideration as nonsubstance or “behavioral” addictions, such as pathological gambling, internet gaming disorder and internet addiction. Case presentation Here, we report two cases of behavioral addictions (BA), compulsive sexual behavior disorder for online porn use and internet gaming disorder. A 57-years-old male referred a loss of control over his online pornography use, started 15 years before, while a 21-years-old male university student reported an excessive online gaming activity undermining his academic productivity and social life. Both patients underwent a high-frequency repetitive transcranial magnetic stimulation (rTMS) protocol over the left dorsolateral prefrontal cortex (l-DLPFC) in a multidisciplinary therapeutic setting. A decrease of addictive symptoms and an improvement of executive control were observed in both cases. Discussion Starting from these clinical observations, we provide a systematic review of the literature suggesting that BAs share similar neurobiological mechanisms to those underlying substance use disorders (SUD). Moreover, we discuss whether neurocircuit-based interventions, such as rTMS, might represent a potential effective treatment for BAs.
... TMS studies looking at cocaine primarily all demonstrated decreased craving compared to the control group [52,[78][79][80][81][82][83]. Several demonstrated reduced intake and craving and a single study looked at treatment of 11 weeks leading to an elongated latency to the first relapse [52,81,82,84]. Finally, one single theta burst study performed three sessions a day for 10 days and demonstrated a reduction in overall days cocaine was used by 70% and a 78% reduction in weekly cocaine consumption spending based in dollars [85]. TMS looking at opioid use disorder treatment remains quite limited. ...
Article
Full-text available
Substance use, misuse and use disorders continue to be major problems in society as a whole and athletes are certainly not exempt. Substance use has surrounded sports since ancient times and the pressures associated with competition sometimes can increase the likelihood of use and subsequent misuse. The addiction field as a whole has very few answers to how to prevent and secondarily treat substance use disorders and the treatments overall do not necessarily agree with the role of being an athlete. With concerns for side effects that may affect performance coupled with organizational rules and high rates of recidivism in the general population, newer treatments must be investigated. Prevention strategies must continue to be improved and more systems need to be in place to find and treat any underlying causes leading to these behaviors. This review attempts to highlight some of the data regarding the field of substance misuse and addiction in the athletic population as well as explore possible future directions for treatment including Neuromodulation methods and Ketamine. There is a need for more rigorous, high-quality studies to look at addiction as a whole and in particular how to approach this vulnerable subset of the population.
... Further protocols could also evaluate the efficacy of maintaining rTMS sessions after successful response to initial stimulations, as proposed in depression [123] or in a recent multicenter randomized control trial in tobacco use disorder [124]. Long-term positive results of these protocols have also been suggested by an observational study in a large cohort in cocaine use disorder [125]. ...
Article
Full-text available
Addiction is a mental disorder with limited available treatment options. The therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) on it, by targeting craving in particular, has been explored with heterogenous results. This meta-analysis uses updated evidence to assess overall rTMS efficacy on craving, differential effects between addiction types clustered into three groups (depressant (alcohol, cannabis, opiate), stimulant (nicotine, cocaine, methamphetamine), and behavioral addiction (gambling, eating disorder)), and stimulation settings. Studies on substance use, gambling, and eating disorders are included, with unrestricted stimulation settings, by searching the PubMed, Embase, PsycINFO, and Cochrane databases up to 30 April 2020. A total of 34 eligible studies (42 units of analysis) were identified. Because of highly significant heterogeneity in primary results, a sensitivity analysis was performed on a remaining sample of 26 studies (30 units of analysis). Analyses performed using random effects model revealed a small effect size favoring active rTMS over shamTMS stimulation in the reduction in craving. We found a significant difference between addiction types, with a persistent small effect only for stimulant and behavioral groups. In these groups we found no difference between the different combinations of target and frequency of stimulation, but a significant correlation between number of sessions and craving reduction. In conclusion, efficacy of rTMS on craving in stimulant and behavioral addiction was highlighted, but recommendations on optimal stimulation settings and its clinical application await further research.
... Fisioter., Salvador, 2020 Dezembro;10(supl 1):23-30 http://dx.doi.org/10.17267/2238-2704rpf.v10i5.3581 | ISSN: 2238-2704 Quadro 1. Ensaios experimentais de dados usando rTMS em dependentes de cocaína[5][6][7][8][9][10][11] ...
Article
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CUD, like other addictions, is a chronic disease characterized by a high rate of relapse and drop-out (DO) from medical and behavioral treatment programs, which is positively correlated with relapse. Repetitive transcranial Magnetic Stimulation (rTMS) protocols have shown therapeutic potential in addiction in the short term, but only a few studies have explored their long-term efficacy, so far. This study explores the long-term outcome of bilateral intermittent theta-burst stimulation (iTBS) of the prefrontal cortex (PFC) in cocaine use disorder (CUD) and the possible influence of maintenance treatment in improving abstinence and decreasing DO rates. Eighty-nine treatment-seeking CUD patients were exposed to 20 sessions of iTBS. At the end of the treatment 61 (81%) abstinent patients underwent a 12 months follow-up. Among these, 27 patients chose to follow a maintenance treatment (M), whereas 34 patients chose not to adhere to a maintenance treatment (NM). Overall, among patients reaching the 12 months follow-up endpoint, 69.7% were still abstinent and 30.3% relapsed. In NM-patients the DO rate was significantly higher than in M-ones (58.82 vs. 29.63%). The present observations show the long-term therapeutic effect of bilateral PFC iTBS to decrease cocaine consumption. Moreover, they underline the importance to perform a maintenance protocol to consolidate abstinence and decrease DO rates over time.
Article
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Background Cocaine use disorder (CUD) is a chronic and relapsing brain disorder with no approved treatments. Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in open label and single-blind studies, reducing cocaine craving and consumption. Although, large randomized, double-blind, controlled trials are still missing. Objective This multi-center, randomized, double-blind, sham-controlled study was designed to evaluate the safety and efficacy of multiple sessions of active rTMS compared to sham stimulation in patients with CUD. Methods rTMS (15 Hz, 2 daily sessions for 5 days/week,for a total of 20 stimulation sessions) was delivered over the left DLPFC for two weeks of continuous treatment followed by 12 weeks of maintenance (1 day/week, twice a day), in a double-blind, randomized sham-controlled design. Our primary outcomes included self-reported cue-induced craving and cocaine consumption, as measured by percentage of negative urine tests. Our secondary outcomes included: 1) changes in depressive symptoms; 2) changes in cocaine withdrawal symptoms; and 3) changes in self-reported days of cocaine use. Results Forty-two outpatients with CUD were enrolled in the active rTMS group and 38 patients in the sham group. We observed a significant decrease in self-reported cue-induced cocaine craving and consumption in both the active rTMS and sham, whereas no main effect of treatment was found. However, the active rTMS group showed greater changes in depressive symptoms. The improvement on depressive symptomatology was particularly marked among patients receiving a total number of rTMS sessions greater than 40 and those reporting more severe depressive symptoms at baseline. Conclusions A significant improvement of CUD symptoms during active rTMS treatment was observed. However, we did not observe significant differences in cocaine craving and consumption between treatment groups, highlighting the complexity of factors contributing to CUD maintenance. A significant improvement in depressive symptoms was observed in favour of the active group. Clinical trial registration details: clinicaltrials.gov identifier NCT03333460
Article
Introduction: A significant proportion of patients with Parkinson's disease (PD) display a set of impulsive-compulsive behaviors at some point during the course of illness. These behaviors range from the so-called behavioral addictions to dopamine dysregulation syndrome, punding and hoarding disorders. These behaviors have been consistently linked to the use of dopaminergic medications used to treat PD motor symptoms (dopamine agonists, levodopa, and other agents) and less consistently to neuromodulation techniques such as deep brain stimulation (DBS). Since there are still no approved treatments for these conditions, their pharmacological management is still a big challenge for clinicians. Methods: We conducted an extensive review of current pharmacological and neuromodulation literature for the management of impulsive-compulsive disorders in PD patients. Results: Pharmacological treatment approaches for impulsive-compulsive behaviors and DDS in PD patients include reduction of levodopa (LD), reduction/cessation of dopamine agonist (DA), and initiation of infusion therapies (apomorphine infusion and duodopa). Also, atomoxetine, a noradrenergic agent approved for the treatment of attention deficit hyperactivity disorder, showed some interesting preliminary results but there is still a lack of controlled longitudinal studies. Finally, while DBS effects on impulsive-compulsive disorders are still controversial, non-invasive techniques (such as transcranial magnetic stimulation and transcranial direct current stimulation) could have a potential positive effect but, again, there is still a lack of controlled trials. Conclusion: Managing impulsivity and compulsivity in PD patients is still a non-evidence-based challenge for clinicians. Controlled trials on promising approaches such as atomoxetine and non-invasive neuromodulation techniques are needed.
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Background Clinical guidelines recommend psychosocial interventions for cocaine and/or amphetamine addiction as first-line treatment, but it is still unclear which intervention, if any, should be offered first. We aimed to estimate the comparative effectiveness of all available psychosocial interventions (alone or in combination) for the short- and long-term treatment of people with cocaine and/or amphetamine addiction. Methods and findings We searched published and unpublished randomised controlled trials (RCTs) comparing any structured psychosocial intervention against an active control or treatment as usual (TAU) for the treatment of cocaine and/or amphetamine addiction in adults. Primary outcome measures were efficacy (proportion of patients in abstinence, assessed by urinalysis) and acceptability (proportion of patients who dropped out due to any cause) at the end of treatment, but we also measured the acute (12 weeks) and long-term (longest duration of study follow-up) effects of the interventions and the longest duration of abstinence. Odds ratios (ORs) and standardised mean differences were estimated using pairwise and network meta-analysis with random effects. The risk of bias of the included studies was assessed with the Cochrane tool, and the strength of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We followed the PRISMA for Network Meta-Analyses (PRISMA-NMA) guidelines, and the protocol was registered in PROSPERO (CRD 42017042900). We included 50 RCTs evaluating 12 psychosocial interventions or TAU in 6,942 participants. The strength of evidence ranged from high to very low. Compared to TAU, contingency management (CM) plus community reinforcement approach was the only intervention that increased the number of abstinent patients at the end of treatment (OR 2.84, 95% CI 1.24–6.51, P = 0.013), and also at 12 weeks (OR 7.60, 95% CI 2.03–28.37, P = 0.002) and at longest follow-up (OR 3.08, 95% CI 1.33–7.17, P = 0.008). At the end of treatment, CM plus community reinforcement approach had the highest number of statistically significant results in head-to-head comparisons, being more efficacious than cognitive behavioural therapy (CBT) (OR 2.44, 95% CI 1.02–5.88, P = 0.045), non-contingent rewards (OR 3.31, 95% CI 1.32–8.28, P = 0.010), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13–14.69, P = 0.031). CM plus community reinforcement approach was also associated with fewer dropouts than TAU, both at 12 weeks and the end of treatment (OR 3.92, P < 0.001, and 3.63, P < 0.001, respectively). At the longest follow-up, community reinforcement approach was more effective than non-contingent rewards, supportive-expressive psychodynamic therapy, TAU, and 12-step programme (OR ranging between 2.71, P = 0.026, and 4.58, P = 0.001), but the combination of community reinforcement approach with CM was superior also to CBT alone, CM alone, CM plus CBT, and 12-step programme plus non-contingent rewards (ORs between 2.50, P = 0.039, and 5.22, P < 0.001). The main limitations of our study were the quality of included studies and the lack of blinding, which may have increased the risk of performance bias. However, our analyses were based on objective outcomes, which are less likely to be biased. Conclusions To our knowledge, this network meta-analysis is the most comprehensive synthesis of data for psychosocial interventions in individuals with cocaine and/or amphetamine addiction. Our findings provide the best evidence base currently available to guide decision-making about psychosocial interventions for individuals with cocaine and/or amphetamine addiction and should inform patients, clinicians, and policy-makers.
Article
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Background Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex may serve as a potential treatment for cocaine use disorder (CUD), which remains a public health problem that is refractory to treatment. The goal of this pilot study was to investigate the effect of rTMS on cocaine self-administration in the laboratory. In the self-administration sessions, CUD participants chose between cocaine and an alternative reinforcer (money) in order to directly measure cocaine-seeking behavior. The rTMS was delivered with the H7 coil, which provides stimulation to the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). These brain regions were targeted based on previous imaging studies demonstrating alterations in their activation and connectivity in CUD.Methods Volunteers with CUD were admitted to an inpatient unit for the entire study and assigned to one of three rTMS groups: high frequency (10 Hz), low frequency (1 Hz), and sham. Six participants were included in each group and the rTMS was delivered on weekdays for 3 weeks. The cocaine self-administration sessions were performed at three time points: at baseline (pre-TMS, session 1), after 4 days of rTMS (session 2), and after 13 days of rTMS (session 3). During each self-administration session, the outcome measure was the number of choices for cocaine.ResultsThe results showed a significant group by time effect (p = 0.02), where the choices for cocaine decreased between sessions 2 and 3 in the high frequency group. There was no effect of rTMS on cocaine self-administration in the low frequency or sham groups.Conclusion Taken in the context of the existing literature, these results contribute to the data showing that high frequency rTMS to the prefrontal cortex may serve as a potential treatment for CUD.
Article
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Substance use disorders (SUDs) are one of the leading causes of morbidity and mortality worldwide. In spite of considerable advances in understanding the neural underpinnings of SUDs, therapeutic options remain limited. Recent studies have highlighted the potential of transcranial magnetic stimulation (TMS) as an innovative, safe and cost-effective treatment for some SUDs. Repetitive TMS (rTMS) influences neural activity in the short and long term by mechanisms involving neuroplasticity both locally, under the stimulating coil, and at the network level, throughout the brain. The long-term neurophysiological changes induced by rTMS have the potential to affect behaviours relating to drug craving, intake and relapse. Here, we review TMS mechanisms and evidence that rTMS is opening new avenues in addiction treatments.
Article
Background Cocaine use disorder (CUD) is very common and has psychological and physical consequences. Patients with CUD present hypoactivity of the prefrontal cortical area. Thus, excitatory repetitive transcranial magnetic stimulation (rTMS) targeting the premotor cortex/dorsolateral prefrontal cortex (PMC/DLPFC), given its ability to increase prefrontal area excitability and to modulate cortico-limbic activity, could result in a decrease in cocaine intake. Methods We designed a protocol for a monocentric, randomized, double-blind, placebo-controlled, parallel-group pilot trial, with the principal aim of assessing the efficacy of rTMS on the reduction of cocaine intake. Patients with CUD will be recruited according to inclusion and exclusion criteria, and then randomized to undergo active or sham rTMS. Our rTMS protocol will consist of 15 days of 15 Hz rTMS targeting the left PMC/DLPFC. Toxicological and psychiatric assessments, urine drug tests, the Cocaine Craving Questionnaire (CCQ) and the Visual Analogic Scale (VAS) will be used to assess changes from baseline in cocaine intake and craving, mood and quality of life. Discussion Only a few studies have evaluated the efficacy of rTMS for CUD treatment in humans, with limitations concerning small sample size, short treatment duration, different rTMS protocols and the absence of a placebo-controlled group. Our study will attempt to overcome these shortcomings and will provide data that can be used for future larger studies of non-invasive left PMC/DLPFC stimulation as a treatment for CUD.
Article
Although the last 50 years of clinical and preclinical research have demonstrated that addiction is a brain disease, we still have no neural circuit-based treatments for substance dependence or cue reactivity at large. Now, for the first time, it appears that a noninvasive brain stimulation technique known as transcranial magnetic stimulation (TMS), which is Food and Drug Administration approved to treat depression, may be the first tool available to fill this critical void in addiction treatment development. The goals of this review are to 1) introduce TMS as a tool to induce causal change in behavior, cortical excitability, and frontal-striatal activity; 2) describe repetitive TMS (rTMS) as an interventional tool; 3) provide an overview of the studies that have evaluated rTMS as a therapeutic tool for alcohol and drug use disorders; and 4) outline a conceptual framework for target selection when designing future rTMS clinical trials in substance use disorders. The manuscript concludes with some suggestions for methodological innovation, specifically with regard to combining rTMS with pharmacotherapy as well as cognitive behavioral training paradigms. We have attempted to create a comprehensive manuscript that provides the reader with a basic set of knowledge and an introduction to the primary experimental questions that will likely drive the field of TMS treatment development forward for the next several years.
Article
Background Elevated frontal and striatal reactivity to drug cues is a transdiagnostic hallmark of substance use disorders (SUDs). The goal of the present experiments was to determine if it is possible to decrease frontal and striatal reactivity to drug cues in both cocaine users and heavy alcohol users through continuous theta burst stimulation (cTBS) to the left ventromedial prefrontal cortex (VMPFC). Methods Two single-blinded, within-subject, active sham-controlled experiments were performed wherein neural reactivity to drug/alcohol cues vs. neutral cues was evaluated immediately before and after receiving real or sham cTBS (110% RMT, 3600 pulses, FP1 location) (n=49 participants; 25 cocaine users (experiment 1), 24 alcohol users (experiment 2); 196 total fMRI scans). Generalized psychophysiological interaction (gPPI) and three-way repeated-measures analysis of variance were used to evaluate cTBS-induced changes in drug cue-associated functional connectivity between the left VMPFC and 8 regions of interest (ROIs): ventral striatum, bilateral caudate, bilateral putamen, bilateral insula, and anterior cingulate cortex (ACC). Results In both experiments, there was a significant interaction between treatment (real/sham) and time (pre/post). In both experiments, cue-related functional connectivity was significantly attenuated following real cTBS vs. sham cTBS. There was no significant interaction with ROI for either experiment. Conclusions This is the first sham-controlled investigation to demonstrate, in two populations, that VMPFC cTBS can attenuate neural reactivity to drug and alcohol cues in frontal-striatal circuits. These results provide an empirical foundation for future clinical trials that may evaluate the efficacy, durability, and clinical implications of VMPFC cTBS to treat addictions.
Article
Background: Cannabis use disorder (CUD) is a common condition with few treatments. Several studies in other substance use disorders have found that applying repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) decreases cue-elicited craving and possibly decreases use. To date, there have been no studies attempting to use rTMS in CUD. Objectives: This study was conducted to determine if rTMS could be feasibly delivered to a group of non-treatment seeking CUD participants. Secondarily, the study aimed to estimate the effect of rTMS on craving. Methods: In a double-blind, sham-controlled, crossover design, a single session of active or sham rTMS (Left DLPFC, 10 Hz, 110% rMT, 4000 pulses) was delivered during a validated cannabis cue paradigm. Participants crossed over to complete the other condition one week later. The feasibility and tolerability were measured by the rate of retention, and the percentage of participants able to tolerate full dose rTMS, respectively. Craving was measured using the Marijuana Craving Questionnaire (MCQ). Results: Eighteen non-treatment seeking CUD participants were recruited from the community; 16 (three women) completed the trial (89% retained for the three study visits). All of the treatment completers tolerated rTMS at full dose without adverse effects. There was not a significant reduction in the total MCQ when participants received active rTMS as compared to sham rTMS. Conclusion: rTMS can be safely and feasibly delivered to CUD participants, and treatment is well tolerated. A single session of rTMS applied to the DLPFC may not reduce cue-elicited craving in heavy cannabis users.
Article
Objective: Cocaine use disorder is a very common condition that represents a substantial public health problem, and no effective pharmacological or psychological therapies have been identified to date. Urgent therapeutic alternatives are therefore needed such as neurostimulation techniques. The purpose of this review is to describe and discuss studies that have evaluated the safety and efficacy of these techniques for the treatment of cocaine dependence. Methods: The electronic literature on repetitive transcranial magnetic stimulation, theta-burst stimulation, deep transcranial magnetic stimulation, transcranial direct current stimulation, magnetic seizure therapy, electroconvulsive therapy, cranial electro-stimulation, and deep brain stimulation in the treatment of cocaine addiction were reviewed. Results: Most of these studies which are few in numbers and with limited sample sizes found that some of these neurostimulation techniques, particularly transcranial magnetic stimulation, and transcranial direct current stimulation are safe and potentially effective in the reduction of craving to cocaine. Although deep brain stimulation showed some good results in one patient, no conclusion can be drawn so far concerning the efficacy and safety of this approach. Conclusion: Given the somewhat promising results of some of the studies, future controlled studies with larger samples, and optimal stimulus parameters should be designed to confirm the short- and long-term safety and efficacy of neurostimulation techniques to treat cocaine addiction.
Article
Objective: To provide expert recommendations for the safe and effective application of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD). Participants: Participants included a group of 17 expert clinicians and researchers with expertise in the clinical application of rTMS, representing both the National Network of Depression Centers (NNDC) rTMS Task Group and the American Psychiatric Association Council on Research (APA CoR) Task Force on Novel Biomarkers and Treatments. Evidence: The consensus statement is based on a review of extensive literature from 2 databases (OvidSP MEDLINE and PsycINFO) searched from 1990 through 2016. The search terms included variants of major depressive disorder and transcranial magnetic stimulation. The results were limited to articles written in English that focused on adult populations. Of the approximately 1,500 retrieved studies, a total of 118 publications were included in the consensus statement and were supplemented with expert opinion to achieve consensus recommendations on key issues surrounding the administration of rTMS for MDD in clinical practice settings. Consensus process: In cases in which the research evidence was equivocal or unclear, a consensus decision on how rTMS should be administered was reached by the authors of this article and is denoted in the article as "expert opinion." Conclusions: Multiple randomized controlled trials and published literature have supported the safety and efficacy of rTMS antidepressant therapy. These consensus recommendations, developed by the NNDC rTMS Task Group and APA CoR Task Force on Novel Biomarkers and Treatments, provide comprehensive information for the safe and effective clinical application of rTMS in the treatment of MDD.