Systematic Review

1. 1 Interdisciplinary Group of Alcohol and Drug Studies (GREA), Department and Institute of Psychiatry, Medical School, São Paulo University, São Paulo 05403-010, SP, Brazil
2. 2 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510, USA
3. 3 Department of Neuroscience, Medical School, ABC Health University Center, Santo André 09060-870, SP, Brazil
4. 4 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA

* Correspondence: [email protected]; Tel.: +55-11-26617892

Citation: Lassi, D.L.S.; Malbergier, A.; Negrão, A.B.; Florio, L.; De Aquino, J.P.; Castaldelli-Maia, J.M. Pharmacological Treatments for Cocaine Craving: What Is the Way Forward? A Systematic Review. Brain Sci. 2022, 12, 1546. https://doi.org/ 10.3390/brainsci12111546

Academic Editors: Fabrizio Schifano and Oliver M. Schlüter

Received: 20 July 2022 Accepted: 10 November 2022 Published: 14 November 2022

Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Abstract: Background: cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving efficacy of pharmacotherapies tested for cocaine use disorder, in the context of randomized-controlled clinical trials. Objectives: we assessed the databases of the U.S. National Library of Medicine, Google Scholar, and PsycINFO, without date restrictions up to August 2022, to identify relevant studies. Study eligibility criteria, participants, and interventions: we included double-blinded randomized-controlled trials investigating pharmacotherapies for cocaine craving and/or cocaine use disorder whose outcomes included cocaine craving. Study appraisal and synthesis methods: Two authors screened studies’ titles and abstracts for inclusion, and both read all the included studies. We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study set-ting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes. Results: Overall, we appraised 130 clinical trials, including 8137 participants. We further considered the drugs from the studies that scored equal to or greater than six points in the quality assessment. There was a correlation between craving and cocaine use outcomes (self-reports, timeline followback or urinary benzoylecgonine) in the vast majority of studies. In the short-term treatment, acute phenylalanine-tyrosine depletion, clonidine, fenfluramine, meta-chlorophenylpiperazine (m-CPP) and mecamylamine presented promising effects. In the long term, amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol in the short term; amantadine, aripiprazole, bromocriptine, citicoline, ketamine, modafinil, olanzapine, topiramate in the long term. The remaining 52 medications had no positive anti-craving outcomes. Limitations: Our review was limited by high heterogeneity of craving assessments across the studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence and retention in treatment as the main outcomes, whereas craving was a secondary outcome and some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity. Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy. Conclusions: There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment, and amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone in the long-term treatment.

Brain Sci. 2022, 12, 1546. https://doi.org/10.3390/brainsci12111546 https://www.mdpi.com/journal/brainsci

Keywords: craving; cocaine; pharmacological treatment; review; target

Cocaine use disorder causes a host of medical, psychological, and social problems worldwide, including cardiovascular disease, infection, violence, and crime. The United Nations Office on Drugs and Crime [1] estimates that, in 2018, 19 million people used cocaine, a number that is expected to grow against the backdrop of the socioeconomic crisis caused by SARS-CoV-2 pandemic. Yet, despite decades of clinical research, thus far no pharmacological treatments for cocaine use disorder have been established. One of the most critical barriers to abstinence and relapse prevention is craving [2], a core symptom of cocaine use disorder, and one whose clinical relevance is underscored by its inclusion as a diagnostic criterion to diagnose stimulant use disorders in the 5th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [3].

At the neurobiological level, prolonged cocaine use can cause brain circuitry modifications and progressively sensitize dopamine systems, leading to recurrent and intense urges—or craving—to use cocaine. Craving is defined as “a more intense, urgent abnormal desire characterized by longing, yearning and physiological need for drug” [4]. The shift from “wanting” to use a drug to “craving” it occurs due to a progressive salience attributed to drug-related stimuli, even when negative cognitions are attributed to drug use itself [5]. Craving can be elicited by cocaine cues—such as paraphernalia and places/situations related to cocaine use—by acute withdrawal, by cocaine, and by stress, which makes feasible to evaluate in a naturalistic way with an ecological momentary assessment or in laboratory studies with the induction of craving.

Distinct biological and psychological mechanisms are believed to contribute to various types of craving [6]. Some evidence indicates that specific types of craving may be particularly amenable to pharmacological interventions, such as the craving for compulsive use in early abstinence [7].

Although the precise pathophysiology of craving remains elusive, some of its neural substrates have been identified, including progressive alterations in limbic, striatal and cortical systems. The amygdala plays a critical role in learning the relationship between significant stimuli and the signals that anticipate them; the anterior cingulate connects to the amygdala and subserves mood regulation and emotional responsivity; the nucleus accumbens mediates the reinforcing properties of cocaine [6]; and the basal ganglia are believed to underlie compulsive component of addiction. Altogether, the shift of cognitive and emotional aspects of cocaine-related memory can lead to compulsive drug-seeking behavior [8].

Converging functional neuroimaging studies involving persons who use cocaine show cue-elicited increases activity in limbic regions, such as the amygdala and anterior cingulate, cerebellum, and prefrontal cortex, as well as decreased activity in subcortical regions, such as the basal ganglia [6,8–10]. Another study with positron emission tomography (PET) [9] using personalized cues and autobiographical memories found a decreased activity in the prefrontal cortex, lending support to previous findings showing a disruption of prefrontal activity during craving [4].

Although multiple clinical trials have investigated pharmacological interventions for cocaine use disorder, thus far few of them have included craving as a treatment efficacy outcome. Given the clinical relevance of craving as a potential mediator of return to using cocaine, there is growing interest in studying stimulants, antidepressants, and anticonvulsants as anti-craving pharmacotherapies, as reviewed in recent metanalysis [11–14].

As craving is strongly associated with compulsive cocaine use [15,16] and is a significant predictor of relapse [2], it is an important treatment target for persons with cocaine use disorder. Hence, we have summarized and appraised findings from randomized trials investigating anti-craving medications for this clinical population. To our knowledge,

this is the first systematic review to specifically synthesize and appraise the evidence for anti-craving effects of pharmacological interventions for cocaine use disorder.

1. 2.1. Eligibility
2. 2.2. Information Sources
3. 2.3. Search Strategy
4. 2.4. Study Selection
5. 2.5. Assessment of Methodological Quality
6. 2.6. Data Collection Process
7. 2.7. Data Items

We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study setting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes.

Brain Sci. 2022 12, x FOR PEER REVIEW of 51

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram.

Figure 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram.

1. 2.5. Assessment of Methodological Quality
2. 2.6. Data Collection Process
3. 2.7. Data Items

1. 3.1. Distribution
2. 3.2. Participants
3. 3.3. Assessments

We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study setting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes.

1. 3.1. Distribution
2. 3.2. Participants

Ninety-three percent of the included studies used the Diagnostic and Statistical Manual of Mental Disorders criteria for cocaine abuse or dependence (20% DSM-III, 71% DSM-IV, 2% DSM-5). The other 7% included criteria from International Classification of Diseases (ICD-10) and unstructured self-report measures.

Craving was assessed by single or multi-factorial craving scales. Approximately 51% of the studies used a Visual Analog Scale (VAS), either alone or in combination with another semi-structured assessments. The most frequent semi-structured assessments were: The Addiction Severity Index (ASI) (39%); the Cocaine Craving Questionnaire (CCQ) (20%); the Brief Substance Craving Scale (BSCS) (20%); the Minnesota Cocaine Craving Scale (MCCS) (16%); and the Cocaine Selective Severity Assessment (CSSA) (12%). These measures are summarized in Table S1, in the Supplementary Materials Section.

1. 3.4. Quality Assessment
2. 3.5. Interventions and Outcomes

Setting: 74%, 21% and 5% of the studies were conducted in the outpatient, inpatient, and hybrid settings, respectively.

Duration of intervention: The duration of the intervention ranged from single-dose/oneday intervention to 16 weeks. The most prevalent duration of intervention was 12 weeks (21% of studies). Most (92%) studies compared a pharmacological agent to placebo, and 8% of studies compared two or more active drugs, directly and indirectly.

Adjuvant interventions: Over 60% of trials (74) offered—in addition to the study intervention—treatment as usual, such as individual counseling, cognitive behavioral counseling, or 12-step based approaches.

Efficacy: The majority of trials—46% or 60 studies—found no significant improvement in craving measures by time or group intervention. In approximately 21% of trials, or 27 studies, the active drug intervention suppressed craving and differentiated from placebo.

A total of 84 studies evaluated both craving and cocaine use as outcomes, 76% of them

(64) presented a direct correlation between craving and cocaine use after the treatment. The other studies (20) showed divergent results.

First, we separated the studies into two large groups according to the duration of intervention: Acute interventions when up to 7 days and Sub-Acute interventions for more than 7 days. Within each large group, pharmacotherapies were divided into pharmacological classes: antidepressants, antipsychotics, psychostimulants, and other drugs. Detailed data is depicted in Tables 1–5.

Table 1. Characteristics and main findings of the studies included in the systematic review–Antidepressants.

Dependence; Route of Cocaine Use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

N (Sample); Age (Mean); Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Pharmacotherapy and Duration; Non-Pharmacological Intervention

Outcomes (AG: Active Group; PG: Control/Placebo Group)

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Craving Assessment Instrument

Author, Year, Country

CCS: The time effect for the strength of craving score was significant for the placebo group [F(10,91.2) =

4.6, p < 0.0001], but not for the mirtazapine group (Baseline: PBO: 52.6 (29.8), MTZ: 51.1 (22.8);endpoint: PBO: 30.4 (27.3), MTZ: 45.0 (15.5)); CCQ: neither the

Oral mirtazapine (MTZ) 45 mg or placebo (PBO) daily for 12 weeks; weekly hour-long sessions involving (manual guided) relapse prevention counseling

Cocaine dependence and major depression (DSM-IV); S, I; C

Cocaine Craving Scale (CCS); Cocaine Craving Questionnaire (CCQ)

Afshar et al., 2012, USA [19]

24; 45; 17:7; NA; O; 12 weeks

NA; NA

treatment effect nor the treatment × time interaction was significant, and the within-group time effects were also insignificant (Baseline: PBO: 168.6 (56.9), MTZ: 184.6 (96.0); endpoint: PBO: 140 (57.4), MTZ: 156.4 (35.2))

CCS: Cocaine craving dropped significantly from 13 to 8 (on a scale of 1 to 20), but there was no significant difference between groups (Baseline: PBO: 12, DSP: 13; endpoint: PBO: 7, DSP: 8)

Oral desipramine (DSP) 250–300 mg or placebo (PBO) daily and regular methadone treatment for 12 weeks; NA

Cocaine dependence (DSM-III) among methadone-maintained patients; S, I, IV; C

79; 41; 79:0; NA; O; 12 weeks of intervention + contacts after 6 months

Cocaine Craving Scale (CCS)

Arndt et al., 1992, USA [20]

25% (20); NA

QCI: No differences in craving were found between the two groups over weeks

Oral fluoxetine 40 mg or placebo daily for 12-week; NA

Cocaine dependence (DSM-IIIR); S, IV; C

Quantitative Cocaine Inventory (QCI)

Batki et al., 1996, USA [21] 32; 34; 21:11; Y; O; 12 weeks

59% (19); NA

VAS (100-mm line where 0 indicated that the chances were nil and 100 indicated that they were certain they would use cocaine)

VAS: a significantly greater craving decline after fenfluramine administration (p <0.05) compared to placebo

Single dose of oral fenfluramine 60 mg or placebo; NA

Buydens-Branchey et al., 1998, USA [22]

Cocaine dependence (DSM-IV); NA; A

NA; NA

19; NA; 19:0; Y; I; 1 day

Hal-DIRS: subjects improved over time, but there was no statistically significant difference between groups

Oral desipramine 200 mg, carbamazepine 800 mg or placebo daily for 8 weeks; therapy

Cocaine abuse (Psychiatric Diagnostic Interview-Revised- PDI-R); NA; NA

Halikas-Crosby Drug Impairment Rating Scale (Hal-DIRS)

Campbell et al., 2003, USA [23]

146; 33; 102: 44; NA; O; 8 weeks

65% (95); Y;

CCS: significant reduction in craving strength for both groups (<0.0001), but more for nefazodone (p = 0.049). Decrease in intensity was significant in both nefazodone (p < 0.0001) and placebo (p < 0.0001) groups

cocaine dependence and had Hamilton Depression Scores of 12 or higher (DSM-IV); S, I, IV; C

Oral nefazodone 400 mg daily or placebo for 8 weeks; individual counseling

Ciraulo, Knapp et al., 2005, USA [24]

69; 40; 49:20; NA; O; 8 weeks

Cocaine Craving Scale (CCS)

26% (18)

S1: oral paroxetine 20 mg daily or pentoxifylline 400 mg three times a day or riluzole 50 mg twice daily or placebo twice daily for 8 weeks; cognitive behavioral counseling; S2: oral venlafaxine (50 mg three times a day) or pramipexole (0.5 mg three times a day) or placebo, three times daily for 8 weeks; cognitive behavioral counseling

S1 and S2: BSCS: Changes between baseline and end-point values were not found to differ among the placebo and the active medication groups, but significant within-group decreases in mean scores in all groups

S1: 65; 40; 47:18; NA; O; 8 weekS2: 60; 43; 43:17; NA; O; 8 weeks

S1: 11% (7); S2: 36.6% (22); NA

Ciraulo, Sarid-Segal et al., 2005, USA [25]

Cocaine dependence (DSM-IV); NA; C

S1 and S2: Brief Substance Craving Scale (BSCS)

Cocaine Use Inventory and Craving Scale (−10 represents no craving; 0, about the usual craving; and 10, more craving than ever)

Oral desipramine hydrochloride 2,5 mg/Kg or lithium carbonate 600 mg or placebo daily for 6 weeks; weekly individual psychotherapy

Craving: statistically significant differences in craving appearing in the desipramine-treated subjects by week 4 (p < 0.0001)

Gawin et al., 1989, USA [26]

Cocaine dependence (DSM-III-R); S, I, IV; C

72; 29; 55:17; Y; O; 6 weeks

54% (39); NA

S1: DUDI: scores being highest at intake and diminishing during treatment (F = 10.9, df = 3147, p < 0.01). Fluoxetine produced no significant effect on “desire to use drug” over time by dose (f ratio < 1.0); S2: DUDI: Fluoxetine produced no significant decrease in craving in any medication group

1. S1: Oral fluoxetine 0, 20, or 40 mg daily or placebo; NA.
2. S2: oral fluoxetine 20 mg or placebo, in addition to and

S1: cocaine-dependent (DSM-III); S2: cocaine and opiate dependent in methadone maintenance treatment (DSM-III-R); NA; NA

S1: 155; 32; 112:43; 2-week runup+ 12-week intervention; S2: 21; 39; 16:5; NA; O; 2-week stabilization + 8 weeks of intervention

S1 and S2: Desire to Use Drugs Inventory (DUDI)

Grabowski et al., 1995, USA [27]

S1: 55% (85); S2: 43% (10); NA

65 to 80 mg of methadone daily; individual therapy sessions

VAS: Desire to use: no significant difference between groups; Likely to use: significant increase (p < 0.03) for de fluoxetine group

Within Session Rating Scale (VAS 100 mm: “desire to use” and “likely to use”)

Oral fluoxetine 40 mg or placebo daily for 11 weeks; NA

29; 40; 20:2; NA; M; 11 weeks

Cocaine dependence (DSM-IV); NA; NA

24% (7); N

Harris et al., 2004, USA [28]

Craving: significantly reduced over time in all three groups. However, there were no differences between groups on these measures (Time effect: F18.519 df 12/228 p <0.01; Group effect: F 0.9321 df 2/19 p N.S.)

Oral desipramine 200 mg or amantadine 200 mg or

Cocaine dependence in methadone maintenance clients (DSM-III-R); S, IV; C

Self-report craving (0=“Not at all” to 20= “More than ever” over past 7 days)

22; 35; 19:3; NA; O; 12 weeks

Kolar et al., 1992, USA [29]

32% (7); NA

placebo for 12 weeks; weekly counseling sessions

Oral amantadine hydrochloride300 mg or desipramine hydrochloride 150 mg or placebo daily for 12 weeks; weekly group relapse prevention therapy

VAS (analogue scale, with scores ranging from 0 (no craving) to 20 (most craving in life))

VAS: Craving showed little change over the course of this trial and no difference across medication groups

Opioid and cocaine dependence (DSM-III-R); NA; NA

Kosten et al., 1992, USA [30]

94; 32; 45:49; NA; O; 12 weeks

21% (20); NA

Oral desipramine up to 300 mg or placebo daily for 12 weeks; weekly individual manual-guided relapse prevention therapy

TLFB: no significant differences between the treatment groups in self-reported cocaine craving

Cocaine dependence and major depression or dysthymia (DSM-III-R); S, I, IV; NA

111; 36; 83:28; Y; O; 1-week single blind lead-in placebo

Self-report cocaine craving (TLFB)

McDowell et. al, 2005, USA [31]

58% (64); Y

+ 12 weeks of intervention

CCQ: group treated with mirtazapine showed a significant decrease in mean craving compared to the placebo group (p < 0.01)

Oral mirtazapine 30 mg/kg or plcebo daily for 12 weeks; NA

Nanni- Alvarado et al., 2021, Mexico [32]

100; 28; 100:0; NA; M; 12 week

DSM-IV criteria for cocaine use disorder; NA; A

Cocaine Craving Questionnaire (CCQ-G)

36% (36); N

VAS: intensity of their desire for cocaine at the time they completed the form as well as in the past week on a scale from 0 (none at all) to 24 (more than ever)

Opioid-dependent and at least one positive cocaine urine and/or reported use of at least 14 g of cocaine over the 3-month period

Oral buprenorphine 8 mg plus either oral desipramine 150 mg, amantadine 300 mg, or fluoxetine 60 mg daily for 12 weeks; weekly group relapse prevention

VAS: craving reduced, but did not differ between groups

Oliveto et al., 1995, USA [33]

21; 33; 11:10; NA; O; 12 weeks

58% (10); NA

immediately preceding; NA; C

Oral nefazodone 300 mg or placebo daily for 10 weeks; weekly individual psychotherapy

VAS: average craving did not differ between groups: 4.13 9 (nefazodone) and 4.17 (placebo)

VAS: rated by the subject from 0 cm (no craving) to

Passos et al., 2005, Brazil [34]

210; 31; 194:16; NA; O; 10 weeks

Cocaine dependence (DSM-IV); NA; NA

79% (166); NA

10 cm (maximum craving)

CCS: Cocaine craving decreased in both groups during the trial, although there were no statistically significant differences (p = 0.419)

Oral bupropion 300 mg or placebo daily for 16 weeks; cognitive behavioral therapy for 16 weeks

70; 37; 59:11; Y; O; 16 weeks intervention + 4 weeks observation

Cocaine abuse or dependence (DSM-IV); S, I, IV, O; C;

Shoptaw et al., 2008, USA [35]

Cocaine Craving Scale (CCS)

82% (58); Y

145; 38; 79: 66; Y; O; 3 weeks of methadone+ 18 weeks of intervention + 12 weeks observation

Cocaine dependence and opioid dependence in treatment with methadone (DSM-IV); NA; NA

Oral fluoxetine 60 mg or placebo daily for 18 weeks; psychosocial counseling (individual and group)

VAS: There were no statistically significant between-group differences over time for craving scores

Winstanley et al., 2011, USA [36]

VAS

35% (51); Y

S1: study 1; S2: study 2.

Table 2. Characteristics and main findings of the studies included in the systematic review–Psychostimulants.

N (Sample); Age (Mean); Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Dependence; Route of Cocaine use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

Pharmacotherapy and Duration; Non-Pharmacological Intervention

Outcomes (AG: Active Group; PG: Control/Placebo Group)

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Author, Year, Country

Craving Assessment Instrument

VAS: decrease in craving from baseline to end of intervention: F (1,45) = 27,39, p < 0.001; but no significant group differences; QCU: scores were higher in baseline than in the first 2 weeks of trial, but with no interaction with the groups

Oral diethylpropion 25, 50, 75 mg or 75 mg sustained release or placebo daily for 2 weeks; therapy

60; 33; NA; NA; I; 1-week baseline + 2 weeks of intervention

Cocaine dependence (DSM-III-R); S; NA

Questionnaire of Cocaine Urges (QCU); VAS

Alim et al., 1995, USA [37]

16,6% (10); NA

BSCS: craving declined on average within each active arm, and this difference from placebo was nominally significant for 200 mg (p = 0.04) but not for 400 mg (p = 0.90); CCQ: No significant effect on total score was noted, however, the sub-domains “Anticipation” (p = 0.04) and “Relief” (p = 0.03) were significant with treatment of 200 mg modafinil.

Oral modafinil 200 mg or 400 mg or placebo daily for 12 weeks; one hour of individual weekly cognitive behavioral therapy

Anderson et al., 2009, USA [38]

210; 42; 148:59; Y; O; 12 weeks of intervention + 4 weeks of observation

Brief Substance Craving Scale (BSCS); Cocaine Craving Questionnaire (CCQ)

Cocaine dependence (DSM-IV) NA; C

40% (75); NA

VAS (chances they would use cocaine if they were not in the hospital and had unlimited financial resources. They were asked to draw a mark on a 100-mm line where 0 indicated that the chances were nil and 100 indicated that they were certain they would use cocaine)

Oral metachlorophenylpiperazine (m-CPP) 0.5 mg/kg of body weight or placebo for 2 days (separated by 48 h); NA

Craving: Patients’ craving for cocaine was found to decrease significantly (20%) after the administration of m-CPP (drug effect (F [1,1 = 41 2 5.4; p < 0.001))

Buydens-Branchey et al., 1997, USA [39]

31; 37; 31:0; Y; I; 2 days of intervention + 2 days interval

cocaine dependence (DSM-III-R) S, I; A

NA; NA

BSCS: craving reduced over time, but there were no significant differences between the atomoxetine and placebo groups on any days of assessment

Oral atomoxetine up to 100 mg or placebo daily for 2 weeks; NA

20; 40; 18:2; N; I; 2 weeks intervention + observation after 2 weeks

Cocaine abuse or dependence (DSM-IV); NA; C

Brief Substance Craving Scale (BSCS)

Cantilena et al., 2012, USA [40]

20% (4); NA

VAS: neither the main effects nor the time by group interaction approached significance

80; 38; 80:0; Y; O; 2 weeks placebo lead in + 4 weeks intervention + 4 weeks observation

VAS (100-mm line their maximum level of craving over the previous 48-h period)

Oral ritanserin 10 mg or placebo daily for 4 weeks; counseling

Cornish et al., 2001, USA [41]

Cocaine dependence (DSM-IIIR); NA; C

24% (19); NA

Oral modafinil 200 mg, or 400 mg or placebo daily for 4 days; NA

VAS: within each period, there was not a significant treatment effect

Cocaine dependence (DSM-IV); S; C

Dackis et al., 2003, USA [42]

VAS (cocaine craving)

30% (3); NA

10; 44; 10:0; NA; O; 4 days

BCSC, CCQ: no significant treatment group differences in the BCSC, or in the CCQ total score (Z-score140.76, p140.45)

Oral modafinil 400 mg or placebo daily for 8 weeks; twice-weekly cognitive behavioral therapy

62; 44; 44:16; Y; O; 8 weeks intervention + 1-week observation;

Brief Substance Craving Scale (BSCS); Cocaine Craving Questionnaire (CCQ)

Dackis et al., 2005, USA [43]

Cocaine dependence (DSM-IV); S; C

8% (5); Y

Oral modafinil 200 mg or 400 mg or placebo daily for 8 weeks; once-weekly cognitive behavioral therapy

Dackis et al., 2012, USA [44]

210; 45; 157:53; Y; O; 8 weeks

Cocaine dependence (DSM-IV); NA; C

Brief Substance Craving Scale (BSCS)

BSCS: no treatment group differences

11,4% (24); Y

45; 38; 45:0; Y; O; 2 weeks screening + 4 weeks intervention

Oral ritanserin 10 mg or placebo daily for 4 weeks; NA

VAS: ritanserin had no effect on cue-induced craving

Ehrman et al., 1996, USA [45]

Cocaine dependence (DSM-III); S, I; C

VAS: scale of O-10

NA; NA

CUQ: no significant changes in craving scores in the cocaine dependent were present in the modafinil versus the placebo condition (p = 0.39)

Goudriaan et. al, 2013, Netherlands [46]

29; 39; NA; Y; O; single-dose+ 1-week observation

Cocaine dependence (DSM-IV); NA; A

Cocaine Urge Questionnaire (CUQ)

Single dose of modafinil 200 mg or placebo; NA

NA; Y

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

Craving Assessment Instrument

Duration; Non-Pharmacological Intervention

Outcomes (AG: Active Group; PG: Control/Placebo Group)

Author, Year, Country

Oral methylphenidate 45 mg or placebo daily for 11 weeks; therapy sessions 1 h/week

49; 34; 38:11; NA; O; 2-week intake period + 11-week medication trial+ 2-week observation

No significant differences between the two groups

Grabowski et al., 1997, USA [47]

Cocaine dependence (DSM-IIIR); S, I; NA;

51% (25); NA

Self -report craving

Oral d-amphetamine 30 or 60 mg sustained release (SR-AMP) or placebo daily for 3 days, followed by 4 conditions: cocaine (COC 100 mg+ saline), hydromorphone (COC 4 mg +HYD 24 mg), ‘speedball’ (COC 100 mg +HYD 24 mg) and placebo (COC 4 mg + saline); NA

CCQ: IG presented no significant reduction relative to PG (F 3.41 p (0.07)); VAS (Want drug again): IG presented a significant reduction relative to PG (F 8.48 p (0.01)

Cocaine Craving Questionnaire (CCQ); VAS (0–100: Want Drug Again)

Greenwald et al., 2010, USA [48]

Opioid dependence and cocaine dependence (DSM-IV); S; C

38% (5); N

13; NA; 6:2; N; I; 3 weeks

Oral lorcaserin 20 mg or placebo daily for 19 days; NA

VAS: there was a decrease in “I am craving” (p, 0.0001) for lorcaserin

Johns et al., 2021, USA [49]

DSM-5 criteria for cocaine use disorder; S or IV; C

25; 51; 11:2; N; M; 19 days

Visual Analogue Scale (VAS)

48% (12); N

VAS: reduction in craving in 66.4% and 32.5% for the placebo and ritanserin groups, respectively at end of intervention

65; 36; 55:10; Y; O; 2 weeks single-blind+ 4 weeks intervention+ 4 weeks observation

Oral ritanserin 10 mg or placebo daily for 4 weeks; psychoeducational program

Johnson et al., 1997, USA [50]

Cocaine dependence (DSM-IIIR); NA; NA

VAS

27% (18); Y

BSCS: placebo group was significantly more likely to report higher levels of craving than the modafinil group for intensity (OR = 2.04, 95% Ci = (1.06, 3.92), p = 0.03) and duration (OR = 1.89, 95% Ci = (1.06, 3.38), p = 0.03); there was a similar effect for frequency (OR = 1.51, 95% Ci = (0.84, 2.73)

Oral modafinil 300 mg or placebo daily for 8 weeks; weekly individual cognitive behavioral therapy

Kampman et al., 2015, USA [51]

Cocaine dependence (DSM-IV); S; C

Brief Substance Craving Scale (BSCS)

24% (23); Y

94; 47; 76:18; Y; O; 8 weeks

Oral modafinil 400mg/day for 26 days, then 300mg/day for 30 days, and 200mg/day for 31 days or placebo; NA

CCQ: No therapeutic advantage of modafinil 400 mg/day was detected during hospitalization

Cocaine dependence (DSM-IV); NA; C

Cocaine Craving Questionnaire (10-item CCQ brief)

Karila et. Al, 2016, France [52]

27; 38; 27:0; Y; I; 12 weeks

18% (5); NA

VAS: Although both groups significantly reduced their craving severity over time (Z = −5.11, p < 0.001), there were no significant group or group by time differences

Oral sustained-release methylphenidate 40 mg or placebo for 14 weeks; weekly individual cognitive behavioral therapy

Cocaine dependence and attention deficit hyperactivity disorder (ADHD) (DSM-IV); S, I; C

VAS (craving during the last 24 h: “1” (very little) to “100” (very much))

Levin et al., 2007, USA [53]

106; 37; 88:18; Y; O; 14 weeks

56% (59); Y

Oral immediate release (IR) methamphetamine 30 mg or sustained release (SR)methamphetamine 30

CCS: SR group reported less craving than the placebo group, t (36.3) = 2.49, p = 0.0451

mg or placebo daily for 8 weeks; 4 weeks counseling followed by 4 weeks of counseling plus a contingency management procedure

Mooney et al., 2009, USA [54]

Cocaine dependence (DSM-IV); NA; C

82; 36; 54:28; Y; O; 8 weeks

Cocaine craving scale (CCS)

68% (83); Y

VAS: those receiving LDX reported significantly less craving for cocaine than participants receiving placebo F(1, 62.6) = 5.94, p = 0.0176, (Placebo, M = 28.7, SE = 3.21; LDX, M = 17.5, SE = 3.30)

Oral lisdexamphetamine (LDX) 70 mg or placebo daily for 14 weeks; weekly manual-based, cognitive-behavioral therapy (CBT)

Mooney et al., 2015, USA [55]

Cocaine dependence (DSM-IV); NA; C

43; 45; 35:8; Y; O; 14 weeks

VAS

36% (16); Y

Oral sustained-release dexamphetamine 60 mg or placebo daily, in addition to co-prescribed methadone and diacetylmorphine (max 150 mg) for 12 weeks; NA

VAS: significant changes in craving from baseline (Wald = 52·36; p < 0·001), but no significant group differences (Wald = 6·52; p = 0·011)

Cocaine dependence (DSM-IV)

Nuijten et al., 2016, Netherlands [56]

73; 49; 66:7; NA; O; 12 weeks

and heroin assisted treatment; S; C

VAS (0–20)

11% (8); Y

No significant effects were observed in craving: Baseline (Mean (SD)): PBO: 25.38 (29.12) MZD: 28.64 (29.98); Endpoint: PBO:32.14 (35.69) MZD: 13.17 (30.33)

Oral mazindol (MZD) 6 mg or placebo (PBO) daily, in addition to their current antipsychotic medication for 6 weeks; cognitive-behavioral therapy

Schizophrenia or schizoaffective disorder and cocaine abuse or dependence (DSM-III); NA; NA

Perry et al., 2004, USA [57]

16,6% (4); NA

24; 38; 23:1; NA; O; 6 weeks

VAS

Lorcaserin treatment decreased craving following intravenous placebo [F(1, 214) = 15.8, p < 0.001] but not after cocaine

VAS: 100 mm scroll bar marked from 0 (‘not at all’) to 100 (‘extremely) to indicate: ‘How much do you want to use cocaine?’

Two doses of oral lorcaserin 10 mg or placebo, separated by 24 h, followed by intravenous cocaine or placebo; NA

11; 41; 11:0; N; M; 5 days of procedure, health status check 3 days after discharge

Pirtle et al., 2019, USA [58]

Cocaine Use Disorder (DSM-V); S, IV; C

18% (2); N

. S1: found neither positive nor negative influences of methylphenidate on treatment outcome; S2: found neither positive nor negative influences of methylphenidate on treatment outcome

VAS: 100-mm lines ranging from “not at all” to “extremely” for “am craving cocaine,” “desire to use cocaine,” “would use cocaine,” and “want to buy cocaine.”

S1: Oral methylphenidate 45 mg daily dose for 11 weeks; NAS2: Oral methylphenidate (15, 30, and 60 mg) followed by placebo for 1 week; NA

S1: 57, 36, 45:12, NA, 11 weeks; S2:12, 37, 10:2, O, 1 week

Roache et al., 2000, USA [59]

Cocaine dependence (self-report); NA; C

.S1: 58% (33);.S2: NA; NA;

Oral extended release lorcaserin 20 mg or placebo daily for 12 week; NA

Santos et al., 2021, USA [60]

DSM-5 criteria for mild to severe cocaine use disorder; S and I; C

VAS: significant treatment effects in craving (p> 0.09)

22; 39; 22:0; Y; O; 12 weeks

Visual Analogue Scale (VAS)

14% (3); Y

Oral methylphenidate up to 90 mg or placebo daily for 12 weeks; twice-weekly cognitive-behavioral group therapy (CBT)

Attention-deficit/hyperactivity disorder (ADHD) and cocaine dependence (DSM-IV); NA; NA

CCQ: there were no group differences in cocaine craving

Schubiner et al., 2002, USA [61]

Cocaine Craving Questionnaire (CCQ)

48; 36; 43:5; Y; O; 12 weeks

47% (23); NA

VAS: no significant between-group differences; within-group changes were in favor of the treatment group and reached significance for cocaine craving (p < 0.01)

Oral dexamphetamine 60 mg or placebo daily for 14 weeks; NA

Shearer et al., 2003, Australia [62]

30; 28; 16:14; NA; O; 14 weeks

cocaine dependence (DSM-IV); IV; C

64% (19); Y

VAS

VAS: craving was not significantly affected by mazindol (drug: df = 1,41; F = 1.8; p = 0.2, time: df = 6,41; F = 10.4; p = 0.001, drug/time interaction: df = 6,41; F = 0.7; p = 0.6) although a decrease with time is observed

Oral mazindol 2 mg or placebo daily for 6 weeks; weekly group counseling

Cocaine dependence (DSM-IIIR); NA; C

Stine et al., 1995, USA [63]

58% (25); NA

VAS (5-point analog scale)

43; 35; 37:6; NA; O; 6 weeks

CCS: During the trial, there was a significant group×time interaction (F(11,310) = 1.99; p = 0.03) for “All I want to use now is cocaine” and for “Nothing would be better than using coke right now” (F= 2.37; p= 0.008). Examination of the data suggest that these findings were not due to systematic changes over time in craving for either group; rather the placebo group reported slightly higher scores reliably throughout the trial and for one week (Week 11) the atomoxetine group reported higher scores (creating the interaction) which declined the following week. No other differences on craving items were observed.

Oral atomoxetine 80 mg or placebo daily for 12 weeks; weekly counseling + cognitive behavioral therapy

50; 43; 36:14; Y; O; 12 weeks of treatment+ follow up after 12 weeks

Cocaine dependence (DSM-IV); S; C

Walsh et al., 2013, USA [64]

Cocaine Craving Scale (CCS)

44% (22); Y

S1: study 1; S2: study 2.

Table 3. Characteristics and main findings of the studies included in the systematic review–Antipsychotics.

Dependence; Route of Cocaine Use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

N (Sample); Age (Mean); Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Pharmacotherapy and Duration; Non-Pharmacological Intervention

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Outcomes (AG: Active Group; PG: Control/Placebo Group)

Craving Assessment Instrument

Author, Year, Country

Current cocaine and/or marijuana abuse or dependence and schizophrenia or schizoaffective disorder (DSM-IV); S, I; C

Oral olanzapine 5–20 mg or oral risperidone 3–9 mg daily for 10 weeks; weekly psychotherapy

CCR: there were no significant differences between the groups in terms of cocaine craving over time

Cocaine Craving Report (CCR)

Akerele et al., 2007, USA [65]

28; 36; 25:3; NA; O; 14-weeks

43% (12); NA

BSCS: Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5 points subscales, craving intensity decreased by 1.53 ± 0.43 (p < 0.0005) points, craving frequency by 1.4 ± 0.40 (p > 0.0004) points, and craving duration by 1.76 ± 0.44 (p > 0.0001) points

Oral aripiprazole 10–30 mg or perphenazine 12–24 mg daily for 8 weeks; subjects were given the option to attend group behavioral therapy session weekly

44; 48; 31:13; Y; O; 8 weeks of intervention + 2 weeks observation;

Cocaine dependence and schizophrenia (DSM-IV); NA; C

Brief Substance Craving Scale (BSCS)

Beresford et al., 2017, USA [66]

NA; NA

Craving Questionnaire: significant within-subjects (time) effects, but there were no significant differences between the olanzapine and placebo groups

Oral olanzapine 2,5–20 mg or placebo daily for 16 weeks; psychotherapeutic and educational groups

48; 46; 48:0; Y; O; 16 weeks intervention + 4 weeks observation

Hamilton et al., 2009, USA [67]

Cocaine dependence (DSM-IV); S, I, IV, O; C

Craving Questionnaire

NA; NA

BSCS: significant decline over the 12 weeks: duration (t//3.16, p/0.002); frequency (t//2.94, p/0.004), and intensity (t//2.93, p/0.004). There was no medication effect on either duration (t//0.04, p/0.97), frequency (t/0.50, p/0.62), or intensity (t//0.39, p/0.7)

Oral olanzapine 10 mg or placebo daily for 12 weeks; twice-weekly individual cognitive-behavioral

Kampman et al., 2003, USA [68] 30; 40; 22:8; Y; O; 12 weeks

Cocaine dependence (DSM-IV); S, I, IV; C

Brief Substance Craving Scale (BSCS)

10% (3); NA

Intramuscular risperidone 25 mg or placebo every other week for 12 weeks; NA

MCCS: craving reduced in both groups, but with no difference between them

Loebl et al., 2008, USA [69]

31; 43; 31:0; NA; O; 12 weeks

Cocaine dependence (DSM-IV); NA; C

Minnesota Cocaine Craving Scale (MCCS)

NA; NA

Cocaine Use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Craving Assessment Instrument

Duration; Non-Pharmacological Intervention

Outcomes (AG: Active Group; PG: Control/Placebo Group)

Author, Year, Country

Oral aripiprazole 2 or 10 mg or placebo daily for 32 days; NA

Lofwall et al., 2014, USA [70]

No significant group effects were observed

34; 35; 19:2; N; I; 32 days Self-report use; S; C VAS: “Desire for Cocaine”

40% (13); NA

EMA: in randomly prompted EMA entries craving was not reported frequently in either group but tended to be reported more often in the aripiprazole group, F (1,13) = 2.91, p =0.11, effect = 0.43, 95% CI = −0.08–0.76. Almost all participants in the aripiprazole group reported craving at least once

Dependence on opioids, current cocaine use on at least 3 of the last 30 days, lifetime cocaine-use duration of at least one year; S, I, IV; C;

Ecological momentary assessment (EMA): participants answered craving questions with the response options “NO!!”, “no??”, “yes??”, and “YES!!”

Oral aripiprazole 15 mg or placebo daily for 12 weeks; weekly session of individual counseling

18; 45; 17:1; Y; O; 12 weeks intervention + 29 weeks of buprenorphine treatment

Moran et al., 2017, USA [71]

22% (4); Y

CCQ: significant treatment effect (p < 0.05), in which the olanzapine group showed significantly higher craving than placebo at week 8 (p < 0.05); BSCS: scores for cocaine craving decreased in all groups by the end of treatment; however, olanzapine group experienced a weaker reduction in cocaine craving at the last clinic visit (p < 0.05);

Oral olanzapine 10 mg, valproate 1500 mg, coenzyme Q10 200 mg, and L-carnitine 500 mg combination or placebo daily for 8 weeks; cognitive behavioral counseling

Cocaine Craving Questionnaire general (CCQ-general); Brief Substance Craving Scale (BSCS)

Reid, Casadonte et al., 2005, USA [72]

Cocaine dependence (DSM-IV); S, I, IV; C

63; 39; 50:13; Y; O; 8 weeks

42% (29); NA;

VAS: mark on a 100-mm line representing the “greatest degree of craving

Oral olanzapine 10 mg or haloperidol 10 mg daily for 26 weeks; NA

VAS: significant difference in craving over time favoring the patients in the haloperidol group

Sayers et al., 2005, USA [73]

24; 46; 23:1; NA; O; 26 weeks

Schizophrenia and cocaine addiction (DSM-IV); NA; C

for cocaine since your last visit,” with endpoints marked as “NONE” and “MORE THAN EVER.”

42% (10); Y

VCCQ: significant main effect of time for the craving (F = 33.62, p = 0.01). The interaction of treatment group by time, however, was not significant for the craving

Oral risperidone 1 mg or placebo daily for 2 weeks; NA

Smelson et al., 2004, USA [74]

Cocaine dependence (DSM-IV); NA; C

Voris Cocaine Craving Questionnaire (VCCQ)

35; 41; NA; Y; O; 2 weeks

8% (3); NA

Cocaine use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Craving Assessment Instrument

Duration; Non-Pharmacological Intervention

Outcomes (AG: Active Group; PG: Control/Placebo Group)

Author, Year, Country

VCCQ: olanzapine-treated subjects compared with those in the haloperidol group showed significantly less cue-elicited craving: Energy score (M = 39.1, SD = 9.2 vs. M = 27.6, SD = 12.8), t(16) = 2.20, p = 0.04 (2-tailed), d = 0.99, but not on the Intensity (M = 8.5, SD = 5.7 vs. M = 14.4, SD = 11.8), t(16) = 1.39, p = 0.18 (2-tailed), d = 0.64

Oral olanzapine 10 mg or haloperidol 10 mg daily for 6 weeks; enhancement therapy, relapse prevention, psychoeducational skills training, and a 12-step therapy

Cocaine-dependent patients with schizophrenia (DSM-IV); NA; C

Smelson et al., 2006, USA [75]

Voris Cocaine Craving Questionnaire (VCCQ)

42% (13); NA

31; 43; NA; NA; O; 6 weeks

BSCS: did not differ in terms of absence of cravings (34.5% in quetiapine group versus 29.0% in placebo group; Wald statistic = 0.21, df = 1, p = 0.65)

Oral quetiapine 400 mg or placebo daily for 12 weeks;

Tapp et al., 2015, USA [76]

60; 48; 52:8; NA; O; 12 weeks

Cocaine dependence (DSM-IV); NA; C

Brief Substance Craving Scale (BSCS)

68% (41); Y

weekly cognitive-behavioral therapy group session

Table 4. Characteristics and main findings of the studies included in the systematic review–Anticonvulsants.

Dependence; Route of Cocaine Use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

N (Sample); Age (MEAN); Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Pharmacotherapy and Duration; Non-Pharmacological Intervention

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Outcomes (AG: Active Group; PG: Control/Placebo group)

Craving Assessment Instrument

Author, Year, Country

Craving: participants observed a decrease in craving frequency (z = −2.09, 0.04), but there were no significant effects of treatment or level of cocaine use

99; 39; 87:12; NA; O; 2 weeks single-blind placebo lead-in period + 12 weeks intervention +2 weeks lead-out

Oral gabapentin 3200 mg or

Self-reported number of days in which participants experienced cocaine craving

Cocaine dependence (DSM-IV); S, I; C

placebo daily for 12 weeks; weekly individual relapse-prevention therapy

Bisaga et al., 2006, USA [77]

51% (50); Y

Oral lamotrigine 200–400 mg or placebo daily for 10 weeks; NA

Brown et al., 2012, USA [78]

112; 44; 67:45; NA; O; 10 weeks

Cocaine dependence (DSM-IV); S, I, IV; C

Cocaine-Craving Questionnaire (CCQ)

CCQ: no differences between groups (p = 0.53)

35% (42); Y

Cocaine abuse or dependence (DSM-III-R); S, I, IV; C

Oral phenytoin 300 mg or placebo daily for 12 weeks; weekly counseling

MCCS: difference did not approach significance (est = −4.96; SE = 5.69; p = 0.383)

Crosby et al., 1996, USA [79]

44; 34; 35:9; Y; O; 12 weeks

Minnesota Cocaine Craving Scale (MCCS)

73% (32); NA

MCCS: compared with placebo, the 400 mg treatment condition exhibited a reduction in intensity and duration of craving over the course of the study (est= 0.113; p< 0.001)

Oral carbamazepine 400 mg or 800 mg or placebo daily for 12 weeks; psychosocial treatment programming

Halikas et al., 1997, USA [80]

150; 33; 106:44; Y; O; 12 weeks intervention

Cocaine dependence (DSM-III-R); NA; C

Minnesota Cocaine Craving Scale (MCCS)

62% (93); Y

Bidirectional effect: wherein the effects of the highest cocaine dose

VAS (100 mm left to right “not at all” to “extremely”)(“crave”, “desire”, “want cocaine”, and “could refuse cocaine”)

Oral topiramate 200 mg or placebo daily for 5 days followed by 3 days of cocaine IV experiments, repeated after 7 days; NA

24; 34; 19:5; N; I; 10 days intervention + 6 days experiments + 7 days interval

Johnson et al., 2013, USA [81]

Cocaine dependence (DSM-IV); NA; C

(0.65 mg/kg) on VAS-Craving was decreased by topiramate, but not with low cocaine dose (0.325 mg/kg)

NA; NA

BSCS: topiramate vs placebo were

1. 0.499 vs 0.300 (OR, 2.33; 95% CI,
2. 1.15–4.71; p = 0.02) for having

Oral topiramate up to 300 mg or placebo daily for 12 weeks; weekly cognitive-behavioral treatment

“reportedly no craving at all” in terms of the intensity, frequency, and duration of craving in the past 24 h and 0.501 vs 0.271 (OR, 2.70; 95% CI, 1.38–5.29; p = 0.004) for having “reportedly no craving at all” in the intensity of craving on the worst day

Johnson et al., 2013 USA, [82]

142; 44; 103:39; NA; O; 12 weeks;

Cocaine dependence (DSM-IV); S, I; C

Brief Substance Craving Scale (BSCS)

49% (70); Y

Dependence; Route of Cocaine Use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

N (Sample); Age (MEAN); Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Pharmacotherapy and Duration; Non-Pharmacological Intervention

Dropout %(Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Craving Assessment Instrument

Outcomes (AG: Active Group; PG: Control/Placebo group)

Author, Year, Country

Oral topiramate 300 mg or placebo daily for 12 weeks; weekly individual psychotherapy (CBT)

170; 44; 135:35; Y; O; 1-week baseline + 12 weeks intervention

MCCS: declined significantly during the trial in both groups and there were no between-group differences

Cocaine and alcohol dependence (DSM-IV); S; C

Kampman et al., 2013, USA [83]

Minnesota Cocaine Craving Scale (MCCS)

42% (70); Y

Brief Substance Craving Scale (BSCS); VAS: with descriptors “not at all”, “mildly”, “moderately” and “extremely” equally spaced above line from 0 to 100: “how much do you desire to use cocaine right now?”

VAS: “desire to use cocaine now” (F(1,38) = 3.916, p < 0.05), in which cocaine cue-induced craving levels were higher in the valproate condition. BSCS: slightly more cocaine craving (BSCS total score) in the valproate condition (F(1,38) = 2.326, p = 0.103)

20; 44; 16:4; NA; O; 8 days intervention + 11 days observation

Oral valproate up to 1500 mg or placebo daily for 8 days; NA

Cocaine dependence (DSM-IV); NA; C

Reid et al., 2009, USA [84]

15% (3); NA

Oral vigabatrin 3 g or placebo daily for 12 weeks; weekly computerized cognitive behavioral therapy and biweekly individual counseling for 13 weeks

BSCS: both groups reported less craving, but there was no significant medication effect

Somoza et al., 2013, USA [85]

186; 45; 125:61; Y; O; 12 weeks

Cocaine dependence (DSM-IV); S, I, IV; C

Brief Substance Craving Scale (BSCS)

27% (51); Y

Oral topiramate up to 300 mg or placebo daily + methadone treatment (median 100 mg/day); NA

Cocaine dependent methadone maintenance patients (DSM-IV); NA; NA

CSSA: there was no effect of topiramate on craving scores over time

Cocaine Selective Severity Assessment (CSSA)

Umbricht et al., 2014, USA [86]

171; 42; 89:82; Y; O; 12 weeks

34% (58); Y

BSCS: both groups reported significantly less craving over the course of the study, but with no significant difference between the groups as indicated by the non-significant medication by week (Z = 0.09, p > 0.05) and medication (Z = 1.68, p > 0.05) effects

Oral tiagabine 20 mg or placebo daily for 12 weeks; individual cognitive behavioral therapy on a weekly

Winhusen, Somoza, Ciraulo et al., 2007, USA [87]

141; 42; 134: 7; Y; O; 12 weeks

Cocaine dependence (DSM-IV); NA; C

Brief Substance Craving Scale (BSCS)

44% (62); NA

Table 5. Characteristics and main findings of the studies included in the systematic review–Other Drugs.

Dependence; Route of Cocaine Use (S: Smoked, I: Inhaled, IV: Intravenous, O: Oral); Cocaine Use Status (C: Current Use; A: Abstinent)

N (sample); Age (Mean); Gender (M:F); Search for Treatment (Y: Yes; N: No); Setting (O: Outpatient; I: Inpatient; M: Mixed); Follow-up

Pharmacotherapy and Duration; Non-Pharmacological Intervention

Dropout % (Number); Intention to Treat (ITT) Analysis (Y: Yes; N: No)

Outcomes (AG: Active Group; PG: Control/Placebo Group)

Craving Assessment Instrument

Author, Year, Country

CCQ: craving appeared higher in the lidocaine/craving and lidocaine/relax groups relative to saline/craving, but there were no significant differences between treatment groups in craving (Mean scores: Baseline: lidocaine/ craving: 31.7 (±12.6) saline/craving: 17.3 (±9.5 lidocaine/relax: 22.7 (±11.9);Endpoint: lidocaine/ craving: 32.3 (±18.5)saline/craving: 15.8 (±4.8)lidocaine/relax: 20.9 (±15.6))

Single dose of intravenous lidocaine 2 mg/kg immediately following a cocaine craving script (lidocaine/ craving), saline following a craving script (saline/craving), or lidocaine following a relaxation script (lidocaine/relax); weekly cognitive behavioral therapy

Becker et al., 2020, USA [88]

36; 42; 28:8; Y; O; single dose + 4 weeks of observation

Cocaine dependence (DSM-IV); NA; C

Craving Questionnaire (CCQ-10)

14% (5); NA

Craving: no changes between the two treatment groups (X2(1) = 0.41, p = 0.52) or over time (X2(1) = 0.01, p = 0.91)

Oral memantine 40 mg or placebo daily for 12 weeks; individual relapse-prevention therapy

81; 40; 63: 17; NA; O; 2 weeks of placebo lead-in + 12 weeks intervention + 2 weeks placebo

Self-report of weekly proportion of days with craving

Bisaga et al., 2010, USA [89]

Cocaine dependence (DSM-IV); NA; C

40% (32); Y

Cocaine dependence and co-occurring bipolar I disorder (depressed or mixed mood state)

CCQ: no significant group or group-by-time effects were observed (Treatment group F 2.4 df 1, 108 p 0.127; treatment group by time F 1.3 df 1, 101 p 0.249)

Oral citicoline up to 2000 mg or placebo daily for 12 weeks; therapy

Brown et al., 2015, USA [90]

122; 42; 82:40; NA; O; 12 weeks

Cocaine Craving Questionnaire (CCQ)

34% (44); Y

(DSM-IV) S, I, IV; C

VAS (craving scored on a 0 to 10 scale, with 0 indicating no craving and 10 indicating the worst craving ever felt)

Oral L-tryptophan 1 g and L-tyrosine 1 g or placebo for 2 weeks, then 2 weeks crossed over; NA

Chadwick et al., 1990, USA [91]

50; 30; 25:4; NA; I; 4 weeks intervention;

Cocaine dependence (DSM-III) S, I, IV; C

VAS: amino acids did not significantly reduce drug craving

42% (21); NA

VAS: 100 mm scale (the right pole indicating maximal craving, and the left pole indicating no craving)

VAS: the mean (± SD) R value after bromocriptine (16.2 ± 14.7) was significantly greater (t = 1.84, df= 12, p < 0.05) than after placebo (10.2 ± 13.0)

Single dose of bromocriptine 1,25 mg or placebo; NA

Dackis et al., 1987, USA [92]

Cocaine abuse (DSM-III); S, I, IV; C

13; 28; 9:4; NA; I; 2 days

NA; NA

Intravenous ketamine (0.41 mg/kg or 0.71 mg/kg), administered at three doses, during 52-min or lorazepam 2 mg, separated by 48 h; 10-min mindfulness-based exercise

VAS: 100 mm scale corresponding to the intensity of their wanting cocaine, from “none at all” on the left to “extremely” on the right

Dakwar, Levin et al., 2014, USA [93]

11; 47; 7:1; N; I; 9 days intervention+ 4 weeks observation

VAS: reduction in cue-induced craving (p = 0.012) in ketamine group relative to lorazepam group

Cocaine dependence (DSM-IV); S; C

27% (3); N

Intravenous ketamine (0.41 mg/kg or 0.71 mg/kg), administered at three doses, during 52-min or intravenous lorazepam 2 mg, separated by 48 h; NA

VAS: 100 mm scale corresponding to the intensity of their wanting cocaine, from “none at all” on the left to “extremely” on the right

8; 48; NA; N; I; 9 days intervention + 4 weeks observation

Cocaine dependence (DSM-IV); S; C

VAS: mystical-type effects did not mediate cue-induced craving

Dakwar, Anerella et al., 2014, USA [94]

0; NA

VAS: craving significantly reduced initially but not throughout the monitoring period; ketamine led to significant craving reduction (%) prior to discharge (59.6 vs 15.3%, t17 df = 3.44, p < 0.01) but not at subsequent time-points

Intravenous ketamine (0.71 mg kg 1), administered at three doses over 6 days or of the active control midazolam (0.025 mg kg); NA

20; 49; 11:9; N; I; 3 days intervention + 7 weeks observation

Dakwar et al., 2017, USA [95]

Cocaine dependence (DSM-IV); NA; NA

NA; NA

VAS

MCCS: reduction of 19.1% of craving in the placebo group (p = 0.017) and 37.6% in the biperiden group (p < 0.001)

Oral biperiden 6 mg or placebo daily for 8 weeks; brief cognitive-behavioral psychotherapy

Dieckmann et al., 2014, Brazil [96]

111; 32; 111:0; NA; O; 8 weeks

Cocaine dependence (DSM-IV); S, I; C

Minnesota Cocaine Craving Scale (MCCS)

69% (77); Y

VAS: a single horizontal line which represents craving for cocaine on a continuum, starting with 0, representing no cocaine craving, up to 10, which represents the highest degree of cocaine craving

VAS: time effect F = 3.46, p < 0.001; first week: time effect F = 3.84, p < 0.002). Bromocriptine did not seem to reduce cocaine craving more expeditiously or quantitatively than placebo.

Oral bromocriptine up to 10 mg or placebo daily for 18 days; NA

Eiler et al., 1995, USA [97]

63; 36; 63:0; Y; I; 18 days intervention

Cocaine dependence (DSM-III); S, I, IV; C

53% (34); NA

BSCS: difference between the selegiline and placebo groups was not significant (p = 0.96): Mean weekly scores: baseline: PBO: 6.7 (2.7), STS: 6.5 (2.5); endpoint: PBO: 4.1 (3.0), STS: 4.5 (3.0)

Selegiline Transdermal System (STS) 6 mg or placebo (PBO) patches daily for 8 weeks; individual psychotherapy weekly

300; 41; 234:66; Y; O; 2 weeks baseline+ 8 weeks intervention

Cocaine dependence (DSM-IV); S, I; C

Brief Substance Craving Scale (BSCS)

Elkashef et al., 2006, USA [98]

31% (93); NA

1. Fox et al., 2012,
2. Fox et al., 2013, USA [100]

CCQ: progesterone group significantly presented lower levels of cocaine craving compared with placebo (p < 0.05) in both males and females

42; 42; 24:18; Y; I; 1-week baseline + 1-week intervention + 2 weeks observation

Oral progesterone 400 mg or placebo daily for 7 days; 12-Step based Group Drug Counseling Manual

Cocaine dependence (DSM-IV); NA; C

Cocaine Craving Questionnaire-Brief (CCQ)

NA; NA

Cocaine dependence in methadone-maintained treatment (DSM-IIIR); NA; C

VAS: average craving and peak craving for each day scored from zero (not at all) to ten (most ever)

VAS: no difference across medication groups for craving, but there was a reduction overall over time

59; 36; 59:0; NA; O; 1-week single blind placebo+ 8 weeks intervention

Oral amantadine 200 mg or and 400 mg or placebo daily for 8 weeks; NA

Handelsman et al., 1995, USA [101]

13% (8); NA

Cocaine Craving Questionnaires (CCQ); VAS (the average daily craving and perceived resistance to using cocaine, assessed by the use of aloo-mm, non-numerated visual analog scale anchored from 0 (not at all) to 100 (most ever))

Cocaine dependence in methadone-maintained treatment (DSM-III-R-); NA; C

Oral bromocriptine 2,5 mg or placebo daily for 5 weeks; cognitive behavioral therapy

50; 38; 50:0; Y; O; 5 weeks intervention + 3-month psychotherapy;

CCQ and VAS: bromocriptine group did not differ from the placebo group in craving for cocaine

Handelsman et al., 1997, USA [102]

20% (10); NA

VAS: in the placebo group, Crave Cocaine was significantly increased from baseline after both the stress script and the drug-cue script, but not after the neutral script; in the

Cocaine Craving Questionnaire (CCQ); VAS (questions worded, respectively, “Right now, how much do you [crave/want/need] cocaine?”)

1. 0.1-mg group, Crave Cocaine
2. 0.2-mg group, Crave Cocaine did

Self-report of using cocaine for at least 1 year and at least once in the previous 30 days; S, I; C

Jobes et al., 2011, USA [103]

Single dose of oral clonidine 0.1 or 0.2 mg or placebo; NA

59; 41; 50:9; N; O; 1 day

0; NA

not increase after either active script. No significant effects on the VAS measure Need cocaine; CCQ: there was also a significant effect of clonidine dose, with a dose-related decrease in craving scores [F(2,56) = 5.49, p = 0.007]

Cocaine Craving Questionnaire (CCQ), VAS (was worded “Please rate the intensity of your desire to use cocaine AT THIS MOMENT”);

Cocaine-abusing outpatients who were also being maintained on methadone for heroin dependence; NA; C

Intravenous propranolol 40 mg or dextrose placebo intravenously (3 interventions, 1 dose in each); NA

VAS: propranolol acutely increased reactivity to the cocaine; CCQ: increased scores in the propranolol group only

Jobes et al.; 2015; USA [104]

35; 42; 16:17; NA; M; 6 weeks

7% (2); N

Oral isradipine 15 or 30 mg or placebo; plus cocaine HCl 0.325 or 0.650 mg/kg or placebo, for 9 sessions separated by a 2-day interval; NA

Johnson et al., 2004, USA [105]

Cocaine dependence (DSM-IV); NA; NA

VAS: no main isradipine effect in craving

18; 33; 12:6; N; O; 4 weeks

VAS

NA; NA

CCQ: craving decreased for both groups following the introduction of CM and then for the DCS group,

Oral D-cycloserine (DCS)

39; 51; 27:12; Y; O; 2 weeks of induction phase+ 3‘weeks of intervention+ 2 weeks observation

50 mg or placebo daily for 3 weeks; Contingency management (CM) intervention

Johnson et al., 2019, USA [106]

Cocaine dependence (DSM-IV); I; NA

Cocaine Craving Questionnaire-Now (CCQ)

21% (11); N

increased significantly during the posttreatment phase (post hoc pairwise comparison, p 0.01)

CCQ: a change from baseline to endpoint did not reach statistical significance for the pooled group compared with placebo, but reached statistically significance in some visits

Oral metyrapone/ oxazepam 500/20 mg or 1500/20 mg or placebo daily for 6 weeks; NA

26; 42; 17:9; Y; O; 6 weeks of interventions + 2 weeks of observations

Cocaine dependence (DSM-IV); NA; C

Cocaine Craving Questionnaire (CCQ)

Kablinger et al., 2012, USA [107]

51% (23); NA

VAS: decline in cocaine craving during the trial (Wald x2= 24.0, p = 0.001) but there was no significant medication group by

Oral propranolol up to 100 mg or placebo daily for 8 weeks; twice-weekly individual cognitive-behavioral

108; 36; 88:20; Y; O; 1-week placebo lead in + 8-week intervention

Cocaine dependence (DSM-IV); S, I, IV; C

Kampman et al., 2001, USA [108]

47% (51); NA

VAS

time interaction (Wald x2 = 7.4, p = 0.387)

Oral amantadine 300 mg or propranolol 100 mg or combination of amantadine 300 mg + propranolol 100 daily or placebo for

BSCS: significant decline over the trial in all groups but there were no significant group effects or group by time interactions

199; 41; 130:69; Y; O; 2-week baseline phase + 8-weeks of intervention

Kampman et al., 2006, USA [109]

Cocaine dependence (DSM-IV); S, I, IV; C

Brief substance craving scale (BSCS)

41% (82); Y

8 weeks; twice-weekly individual cognitive-behavioral therapy

Oral acamprosate 666 mg 3 times daily or placebo for 8 weeks; weekly individual cognitive behavioral relapse prevention therapy

BSCS: cocaine craving showed a significant decline over the trial in

60; 45; 45:15; Y; O; 1-week baseline + 8 weeks intervention

Kampman et al., 2010, USA [108]

Cocaine dependence (DSM-IV); S, I; C;

Brief Substance Craving Scale (BSCS)

40% (24); NA

both groups (F = 19.89, p < 0.001), with no difference between groups

Oral N-acetylcysteine 1200 mg, 2400 mg or placebo daily for 8 weeks; weekly session of manual-based cognitive therapy

. BSCS: time-related reduction, Wald χ2= 104.1, df = 8, p< 0.001; no difference between groups (among abstinent participants, NAC presented significant less craving rates)

Larowe et al., 2013, USA [110]

Cocaine dependence (DSM-IV); S; C;

Brief Substance Craving Scale (BSCS);

126; 43; 83:28; Y; O; 8 weeks;

44% (55); N

VAS: the effect of OT on desire to use before exposure to cues was small (mean ± SE: OT = 2.57 ± 0.39; PL = 1.91 ± 0.39) but significant (df = 1,22; F = 5.22, p = 0.032), where desire to use was augmented under OT

(VAS): “If your drug of choice was in front of you right now, what’s the likelihood that you would use?”

Intranasal oxytocin (OT) 24 IU or placebo, for 4 sessions; NA

Cocaine dependence (DSM-IV); S; A

Lee at. Al., 2015, USA [111]

23; 38; 22:1; NA; I; 1 week

NA; NA

VAS: cue- and cocaine-induced craving was significantly reduced by APTD and APTD + L-dopa, for the following: want cocaine, F(10, 70) = 3.27, p < 0.002; urge for cocaine, F(10, 70) = 2.10, p < 0.04; and the total craving score, F(10, 70) = 2.25, p < 0.025

Balanced amino acid mixture or acute phenylalanine–tyrosine depletion (APTD), followed by L-dopa/carbidopa (2 × 100 mg/25 mg) or placebo; NA

VAS items: want cocaine, crave cocaine, urge for cocaine, and desire cocaine

Nondependent, regular cocaine users (DSM-IV); NA; C

Leyton et al., 2005, USA [112]

8; NA; 8:0; N; M; 3 days

0; NA

1 (least) and 10 (most)

Cocaine craving decreased during the treatment period for both treatment groups, but not significantly

29; 38; 18:11; N; O; 8 weeks intervention + 4 weeks observation

VAS: ranged from 0 ‘none at all’ to 10 ‘extremely high’ of their desire to use cocaine

Oral citicoline 1000 mg or placebo daily for 8 weeks; weekly group therapy

Licata et al., 2011, USA [113]

Cocaine dependence (DSM-IV); S, I; C

38% (11); NA

VAS: Although craving scores rose considerably over the first week of the study (range 40–50 mm), scores did not differ for any of the 12-week visits for any of the treatment groups

Cocaine dependence and combined cocaine/alcohol dependence (DSM-III-R); NA; C

Oral pergolide 0.10 or 0.50 mg or placebo for 12 weeks; 12-step based group therapies

358; NA; 282:76; Y; O; 12 weeks intervention + 4 months follow up visits

Malcolm et al., 2000, USA [114]

VAS

66% (202); Y

Oral amlodipine 5–10 mg or placebo daily for 12 weeks; 12 standard manual-driven cognitive behavioral therapy sessions

Craving score did not differ significantly between treatment arms

Malcolm et al., 2005, USA [115]

116; 36; 89:27; NA; O; 12 weeks

Cocaine dependence (DSM-IV); S, IV; C

Unclear

81% (90); NA

CCQ-Brief: significant effect of time (F10,230 = 16.174; p < 0.001), but not of treatment (F10,230 = 2.663;

Cocaine Craving Questionnaire–Brief (CCQ-Brief); Minnesota Cocaine Craving Scale (MCCS);

Oral canabidiol (CBD) 300 mg or placebo daily for 10 days; group psychotherapy once a week

p = 0.116) or time/treatment interaction (F10,230 = 0.489; p = 0.897).MCCS: significant effect of time (F10,230 = 16.450; p < 0.001), but not of treatment (F10,230 = 2460

Meneses-Gaya et al., 2020, Brazil [116]

DSM-IV diagnosis of crack-cocaine dependence;

31; 32,9; 31:0; NA; I; 10 days

19% (6); Y

Oral micronized progesterone 400 mg or placebo daily for 7 days; NA

Cocaine dependence (DSM-IV); NA; C

Cocaine Craving Questionnaire-Brief (CCQ)

Milivojevic et al., 2016, USA [117]

CCQ: active group had significantly lower post-imagery cocaine craving

46; 41; 29:17; Y; I; 1 week

NA; NA

VAS: 5- point rating scale that range from ‘none at all’ to ‘extremely’-(‘How strong is your desire for cocaine right now?’); Cocaine Craving Questionnaire (CCQ)

Comorbid alcohol and cocaine abuse/ dependence (DSM-IV); NA; NA

Oral naltrexone 50 mg or placebo daily for 8 weeks; NA

Modesto-Lowe, 1997, USA [118]

VAS/CCQ: there was no effect of medication on the desire for cocaine

26; 36; 23:3; Y; O; 8 weeks

NA; NA

VAS:ranging from 0 to 10; Cocaine Craving Questionnaire-Brief (CCQ-Brief); Cocaine Selective Severity Assessment (CSSA)

Oral cannabidiol (CBD) 800 mg or placebo daily for 12 weeks after 10 days of inpatient detoxification; relapse prevention group session

Mongeau-Pérusse et al., 2021, Canada [119]

78; 45,9; 64:14; NA; M; 12 weeks

DSM 5 criteria for cocaine use disorder; S, I and IV; A

VAS, CCQ, CSSA: CBD did not reduce cocaine craving

37% (28); NA

S1: L-dopa/carbidopa 800/200 mg or placebo daily for 5 weeks; supportive behavioral counseling; S2: L-dopa/carbidopa 800/200 mg or 1600/400 mg or placebo daily for 9 weeks; supportive behavioral counseling

S1: VAS S2: Cocaine subscale of the Brief Substance Craving Scale (BSCS)

S1: 67, S2:122; S1:35, S2:39; S1: 45:22, S2: 103:19; NA; O; S1: 5 weeks, S2: 9 weeks

S1: Craving: no differences between groups; S2: Craving: no differences between groups

Mooney et al., 2006, USA [120]

Cocaine users (DSM-IV); S; C

S1: 62% (45), YS2: 57% (70); Y

CCQ: participants in the no-stress group reported significantly greater craving in response to the cocaine-cue as compared to the neutral cue (p < 0.001), in both the no-stress guanfacine (p < 0.001) and no-stress placebo (p = 0.023) groups. In the stress group, participants in both the guanfacine and placebo groups reported similar craving ratings in response to the cocaine and the neutral cue (p = 0.480)

Single dose of oral guanfacine 2 mg or placebo; NA

Moran-Santa Maria et al., 2015, USA [121]

Cocaine dependence (DSM-IV); NA; C

Cocaine Craving Questionnaire (CCQ)

NA; Y

84; 41; 71:13; N; M; 3 days

Four doses of oral ecopipam or placebo (0, 10, 25, and 100 mg) daily for 1 week; NA

Cocaine dependence (DSM-IV); S, IV; C

VAS: “how much do you desire cocaine?”

VAS: Ecopipam largely failed to alter the desire for cocaine

Nann-Vernotica et al., 2001, USA [122]

NA; NA

10; 38; 9:1; N; I; 1 week

BSCS: results were low and fairly steady over the entire assessment period; VAS: results were similar over the entire assessment period and across treatment groups

29; 40; 23:6; N; NA; 1-day intervention + 6 days observation

Nasser et al., 2014, USA [123]

Cocaine abuse (DSM-IV); NA; C

Brief substance craving scale (BSCS); VAS

Single dose RBP-8000 (100 or 200 mg) or placebo; NA

10% (3); NA

VAS: participants rated “DESIRE” cocaine, anchored at 0 (not at all) and 100 (most ever)

Oral pramipexole up to 3.0 mg or placebo daily for 15 days; NA

Newton at. Al., 2015, USA [124]

Cocaine dependence (DSM-IV-TR); S, IV; NA

VAS: No significant main effects was found for “DESIRE”

0; Y

18; 40; 11:7; N; I; 15 days

Oral disulfiram 250 mg or placebo daily, was placed directly in the methadone for 12 weeks; weekly individual and group counseling

There was a significant decrease in craving over time for the entire sample (Z 5 9.05; p, 0.01), but no significant decrease in craving by treatment group

Cocaine dependence in methadone-maintained opioid-dependent (DSM-IIIR); S, I, IV; C

Petrakis et al., 2000, USA [125]

67; NA; 32:35; NA; O; 12 weeks

Self-report cocaine craving

23% (13)

BSCS: craving showed a significant decline over the trial in both groups (F = 20.34, p < 0.001); CSSA: both varenicline and placebo-treated groups show significant decreases in craving from baseline to end of study (p = 0.004)

Oral varenicline 2 mg or placebo daily for 8 weeks; manual-guided cognitive behavioral therapy

Brief Substance Craving Scale (BSCS); Cocaine Selective Severity Assessment (CSSA)

37; NA; 27:10; Y; O; 1-week baseline + 8 weeks intervention

cocaine dependence (DSM-IV); NA; C

Plebani et al., 2012, USA [126]

NA; NA

Intravenous cocaine (0, 12.5, 25 and 50 mg) was administered 2 h after oral mazindol (0, 1 and 2 mg), 2 times per week for 5 weeks; NA

VAS: rated ‘Desire for Cocaine’ by placing a mark along a 100-mm line marked at either end with none and extremely

VAS: there were no significant main effects of mazindol alone and no significant mazindol/cocaine interactions on any scales on the VAS

cocaine abusers/dependent (DSM-III); IV; C

Preston et al., 1993, USA [127]

55% (10); N

18; 33; 18:0; N; I; 5 weeks

VAS: while baseline craving was not significantly different between groups at the beginning of session one, the session two baseline craving was significantly higher in the DCS-only group as compared to the PBO group and the session three baseline craving was significantly higher in the DCS-only group as compared to both the PBO and the DCS–PBO groups

Oral D-cycloserine 50 mg (DCS) only or D-cycloserine 50 mg +placebo (DSC-PBO) or placebo (PBO), for 3 sessions; NA

32; 44; 22:10; Y,N; O; 3 days of intervention + 12 days observation

Cocaine dependence(DSM-IV); NA; C

Price et al., 2012, USA [128]

VAS

NA; NA

TLFB: there was no significant interaction between medication group and MRI session (p = 0.13; placebo participants’ craving from pre-scan to post-scan: Cohen’s d = −0.37; DCS participants’ craving from pre-scan to post-scan: Cohen’s d = 0.47).

Timeline Follow-back (TLFB): participants were asked to rate their craving, from zero (“none”) to four (“severe”)

Oral D-cycloserine (DCS) 50 mg or placebo for 2 sessions; two sessions of cocaine cue exposure and skills training

Prisciandaro et al., 2013, USA [129]

Cocaine dependence (DSM-IV); A

25; 45; 23:2; NA; O; 2 weeks

18% (4); NA

1. Reid et al., 1998,
2. Reid et al., 1999,

VAS: cue-induced cocaine craving and desire to use cocaine now were significantly lower during the mecamylamine condition

Single dose of oral mecamylamine 2.5 mg or placebo; NA

Cocaine dependence (DSM-IV); S; C

VAS: cocaine craving and desire to use cocaine now

NA; NA

23; 41; 20:3; NA; O; 2 days

USA [85]

BSCS: moderate decrease in craving when comparing baseline with last study visit. However, the change was not significantly different between celecoxib and placebo groups (Baseline CLX 6.3 ± 2.8, PBO

Oral celecoxib 200 mg (CLX) or placebo (PBO) daily for 8 weeks; individual cognitive behavioral counseling

Cocaine dependence (DSM-IV); S, I; C

Brief Substance Craving Scale (BSCS)

Reid, Angrist et al., 2005, USA [130]

23; 45; 18:5; NA; O; 8 weeks

48% (11); NA

6.6 ± 2.6; End-point CLX 4.2 ± 2.3, PBO 5.4 ± 2.8 p= 0.686);

BSCS: Cocaine craving showed moderate improvement in both groups, with a significantly greater reduction in cocaine craving (p < 0.05) in the placebo group

35; NA; NA; NA; O; 8 weeks of placebo + 16 week of active intervention

Methadone maintained subjects and cocaine dependence (DSM-IV); NA; C

Transdermal mecamylamine 6 mg/ or placebo daily for 16 weeks; NA

Reid et al., 2005, USA [131]

Brief Substance Craving Scale (BSCS)

20% (7); Y

CCQ: results revealed a group × condition interaction on the CCQ category, “Lack of control over use” (F1,8 = 6.02, p = 0.040), with citicoline treatment group reporting a decrease in “Lack of control over

use” from pre- to post-treatments. There were no other significant differences in other measures; VAS: placebo group reported greater “Urge for cocaine” than the citicoline

VAS: How strong is your desire not to use cocaine right now? How strong is your urge for cocaine right now? CCQ (Cocaine Craving Questionnaire)

Oral citicoline 500 mg or placebo daily for 14 days; NA

Cocaine dependence (DSM-IV); NA; C, A

Renshaw et al., 1999, USA [132]

group at the post-treatment session, both prior to and following presentation of the crack cocaine cue video (F1,9 = 10.91, p = 0.01, and F1,9 = 16.62, p = 0.002, respectively). A main effect for condition “Desire to use cocaine right now” (F1,8 = 5.57, p = 0.046) was revealed, with subjects reporting a greater desire to use cocaine pre-treatment as compared to post-treatment, regardless of treatment or video presented.

14; 37; 11:3; NA; O; 2 weeks

NA; NA

QCU: significant decreases for all items, but no difference between groups (Baseline (Mean (SD): PBO: 64,8 (32,3), NDP: 60,4 (34,7) Endpoint: PBO: 44,8 (35,0), NDP: 47,3 (40,9)); VAS: craving was not significantly altered by the intervention (Baseline (Mean0–3): PBO: 0,62, NDP: 0,48; Endpoint: PBO: 0,50, NDP: 0,46)

Oral nimodipine (NDP) 90 mg or placebo (PBO) daily for 21 days; intensive 12-step milieu-oriented psychosocial therapy 4 h/day

Questionnaires of cocaine craving and urges (QCU); VAS: rate craving from 0 (none) to 3 (severe)

Rosse et al., 1994, USA [133]

Cocaine dependence (DSM-III); NA; C

66; 33; 66:0; NA; I; 3 weeks

NA; NA

VAS After 24 h: propranolol treated group would evidence significantly lower cue-elicited cocaine craving and reactivity relative to the placebo treated group; after 1 week: craving was lower in the propranolol group, but this difference did not exceed

Craving/Distress/Mood States Scale (CDMS): 100 mm visual analogue scales (VAS), with each being anchored by the adjectival modifiers “not at all” (left side of scale) and “extremely” (right side of the scale). The craving item asked participants to rate the desire to use cocaine “right now”

Single oral dose of propranolol 40 mg or placebo; NA

50; 40; 33:17; NA; I; 2 days of procedure + 1-week observation

Cocaine dependence (DSM-IV); S; C

Saladin et al., 2013, USA [134]

NA; NA

threshold for significance/trend. Propranolol group evidenced significantly lower mean craving than the placebo group (F1,47 = 4.98, p = 0.03)

VAS: Craving was assessed by ‘do you crave cocaine? (from ‘0 = “not at all” -‘10

VAS: craving scores declined in both treatment conditions with differences becoming statistically significant from baseline

2 sessions of D-cycloserine 50 mg or placebo, with 1-week interval; NA

Cocaine dependence (DSMIV); NA; C

Santa Ana et al., 2015, USA [135]

47; 47; 40:7; NA; O; 1 week

2% (1); NA

= “extremely”) of subjective desire to use cocaine

Brief Substance Craving Scale (BSCS); VAS: consisting of 100 mm line, anchored by 0 “not at all” and 100 “extremely,” for cocaine craving right now, craving on average in the past week, and the worst craving in the past week

Oral pioglitazone (PIO) 45 mg or placebo (PBO) daily for 12 weeks; weekly cognitive-behavioral therapy and prize-based contingency management for attendance

BSCS: reduced by a factor of 0.24 for participants receiving PIO compared to 0.09 for participants receiving PBO; VAS: decrease in craving by a factor of 3.84 for PIO versus 1.34 for PBO

Schmitz et al., 2017, USA [136]

Cocaine dependence (DSM-IV); NA; NA

30; 48; 22:8; Y; O; 12 weeks

40% (12); Y

CCS: no differences on craving as a function of time, therapy, or medication. overall mean craving scores were lower at posttreatment (M= 16,1; SD = 24,3) than at intake (M = 29,7; SD = 32,3), consistent with a significant effect of time, F(2;37) = 3,57; p = 0,03

Oral naltrexone 50 mg or placebo daily for 12 weeks; relapse prevention (RP) therapy or drug counseling

85; 34; 62:23; NA; O; 12 weeks of intervention + 1-week observation

Schmitz et al., 2001, USA [137]

Cocaine dependence (DSM-IV); NA; NA

Cocaine Craving Scale (CCS)

51% (43); Y

Oral sustained release levodopa/carbidopa 800/200 mg daily or placebo for 12 weeks; Clinical Management (ClinMan); ClinMan + Cognitive Behavioral Therapy (CBT); or ClinMan + CBT + Voucher-Based Reinforcement Therapy (VBRT)

BSCS: those receiving levodopa reported significantly lower craving scores (levodopa, M = 2.8, SE = 0.30; placebo, M = 3.7, SE = 0.31)

Schmitz et al., 2008, USA [138]

161; 41; 134:27; Y; O; 12 week

Cocaine dependence (DSM-IV); NA; C

Brief Substance Craving Scale (BSCS)

59% (95); Y

Questionnaire for Cocaine Urges (QCU); Obsessive Compulsive Drug Use Scale (OCDUS); Desire for Drug Questionnaire (DDQ); VAS: ranging from 1 to 10 on which participants had to indicate their craving

Laboratory assessment: more positive effects of WM-sessions for the NAC group (B = 0.44 (0.10), p= 0.005) on craving, than for the placebo group (B= 0.04 (0.13), p =0.73). Ecological momentary assessment: no significant effects on craving of the treatment.

Oral N-acetylcysteine (NAC) 2400 mg or placebo daily for 25 days; Working memory (WM) training online

Schulte et al., 2018, Netherlands [139]

Cocaine use disorder (DSM-5); I; NA

37% (14); N

38; 18–55; 38:0; Y; O; 25 days

VAS: placebo group reported craving levels at baseline that were almost two times greater than in amantadine group. This proportionate difference between conditions was maintained to treatment termination with a statistically significant effect of medication condition on craving ratings (F(1,64) = 7.27, p < 0.001) after including baseline ratings as covariates

VAS: (0‘not at all’ to 100‘strongest ever’) that asked participants to mark on a 100 mm line indicating their “most intense craving for cocaine that occurred at any time during the past 24 h”

Oral amantadine hydrochloride 200 mg or placebo daily for 16 weeks; three times weekly, 90-min Matrix Model cocaine counseling sessions

69; 36; 55:14; Y; O; 2 weeks screening +16 weeks intervention + brief follow up after 9 months of intervention

Shoptaw et al.,

Cocaine dependence (DSM-IV); S, I, O; NA

78% (15); NA

1. 2002, USA [140]

Oral baclofen 60 mg or placebo daily for 16 weeks; thrice-weekly cognitive-behavioral drug counseling groups

VAS: “most intense craving for cocaine that occurred at any time during the past 24 h”

VAS: no statistically significant difference between participants

Cocaine dependence (DSM-IV); S, I, IV, O; C

Shoptaw et al.,

76% (53); NA

70; 35; 48:22; Y; O; 16 weeks

1. 2003, USA [141]

VAS: the stress and conditioned craving procedures did not significantly alter participants’ VAS ratings; thus, the potential effects of metyrapone on stress- and cue-induced craving could not be evaluated

Oral metyrapone 750 mg or placebo and infusion (40 mg of cocaine or saline) for 2 days; NA

15; 40; NA; N; I; 2 days intervention+ 2 days observation

Cocaine dependence (DSM-IV); S, IV; C

VAS: 0–100 of desire for drug

Winhusen et al., 2005, USA [100]

20% (3); NA

BSCS: both groups reported significantly less craving over the course of the study, but there was no significant difference between the groups as indicated by the non-significant Medication by Week (Z = −1.15, p > 0.05) and Medication (Z = −0.32, p > 0.05) effects

Oral reserpine 0.5 mg or placebo daily for 12 weeks;

Winhusen, Somoza, Sarid-Segal et al., 2007, USA [142]

119; 41; 84:35; Y; O; 12 weeks

Cocaine dependence (DSM-IV); S, I; C

Brief Substance Craving Scale (BSCS)

34% (40); NA

weekly individual cognitive behavioral therapy

N-acetylcysteine 3600 mg or placebo daily for 1 week and then crossed over for 1 more week; NA

Woodcock et al., 2021, USA [143]

Cocaine use (self report); S; C

Cocaine Craving Questionnaire (CCQ)

12; 48; 11:1; N; I; 2 weeks

CCQ: no impact in craving 0; N

S1: study 1; S2: study 2.

1. 3.6. Acute Interventions
2. 3.7. Sub-Acute Interventions

1. 3.7.1. Antidepressants
2. 3.7.2. Antipsychotics
3. 3.7.3. Psychostimulants
4. 3.7.4. Anticonvulsants

Only one study [80] of two [23,80] comparing carbamazepine to placebo showed a significant decrease in craving. The anticonvulsant topiramate was found to have anticraving effects in two [81,82] out of four trials [81–83,86]. The trials with baclofen [141], gabapentin [77], lamotrigine [78], phenytoin [79], tiagabine [87], valproate [72,84] and vigabatrin [144] reported no significant effect on cocaine craving in comparison with placebo.

1. 3.7.5. Other Drugs

Nicotinergic agonists (nicotine and varenicline) were investigated in two trials, and an antagonist (mecamylamine) in two studies: mecamylamine significantly reduced craving in one trial [85], while in another [131] only the placebo group showed significant reduction; transdermal nicotine significantly increased cue-induced craving in comparison to placebo in one trial [145] while varenicline [126] did not differ from the placebo. Biperiden, a muscarinic antagonist, reduced craving by 37.6%, compared to a 19% change from baseline produced by the placebo [96]. Bromocriptine led to a significant reduction in craving in one study [92], while another two [97,102] did not differentiate from the placebo. The DA precursors levodopa/carbidopa, administered for more than 5 weeks and combined with non-pharmacological therapies, were found to reduce craving in one [138] of two studies [120,138], in which it was administered for a longer period (12 weeks) and combined with cognitive behavioral therapy. The administration of amantadine was found to have anti-craving effects in one [140] of three [101,109,140] studies; as citicoline did in one [132] out of three studies [90,113,132]. Two [100,117] studies in three [100,117,146] comparing 7 days of allopregnanolone to the placebo showed a significant decrease in craving. Ketamine showed a significant craving reduction in one [93] of the three studies [93–95]. The PPAR (Peroxisome proliferator-activated receptor)-Gamma agonist Pioglitazone reduced cocaine craving by a factor of b = 0.24 when compared to a factor of b = 0.09 for participants receiving placebo [136].

Oral naltrexone, an opioid receptor antagonist, did not show any difference in craving in comparison to the placebo [118,137]; as well as the glutamatergic partial agonist D-cycloserine [106,128,129,135]. Propranolol, compared to the placebo, did not reduce craving in long-term studies [104,108,134]. The Calcium Channel Antagonists amlodipine [115], isradipine [105] and nimodipine [133]; acamprosate [147]; the Cocaine esterase RBP- 8000 [123]; the Cox-2 inhibitor celecoxib [130]; disulfiram [125]; ecopipam [122]; Ltryptophan [91]; lidocaine [88]; memantine [89]; the corticosteroids metyrapone [107,110]; N-acetylcysteine [139,143,148]; pergolide [114]; pramipexole [124]; reserpine [142]; riluzole [25], selegiline [98] and cannabidiol [116,119] showed no differences compared to the placebo either. In a study, participants who received oxytocin experienced more severe cocaine craving relative to the placebo [111].

1. 3.8. Treatment Dropout

Attrition varied widely among clinical trials, ranging from 0 to 82%, with an average attrition of 40%. Twenty-seven trials did not report their dropout rate. Among the studies with outpatients, 32% showed more than half of the sample dropped out at the end of intervention, against 14% of the inpatient trials. Half of the studies with 5HT agents had an attrition rate greater than 50%. Notably, studies that included adjuvant nonpharmacological therapies had lower attrition rates.

We sought to systematically review and appraise the evidence base on pharmacological interventions for cocaine craving, an important treatment target for cocaine use disorder. Altogether, we appraised 130 clinical trials examining a wide range of compounds, with several mechanisms of action. From the analysis of the current review, we observed correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary BE) in the vast majority of studies. Therefore, we can consider craving as an intermediate target for achieving abstinence.

We highlighted here the promising drugs presented in the studies that scored equal to or greater than six points in the quality assessment. In the short-term treatment, acute phenylalanine-tyrosine depletion (1 study with significant positive anti-craving effects in 1 study included in the present review), clonidine (1/1), fenfluramine (1/1), and mCPP (1/1), mecamylamine (1/2) presented promising effects. In the long term, lorcaserin (2/2) amphetamine (1/1), biperiden (1/1), carbamazepine (1/1), lisdexamfetamine (1/1),

methamphetamine (1/1), pioglitazone (1/1), progesterone (2/3), guanfacine (1/2), levodopa (1/2), mirtazapine (1/2) and nefazodone (1/2) presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol (1/3) in the short term; amantadine (1/3), aripiprazole (1/3), bromocriptine (1/3), citicoline (1/3), ketamine (1/3), modafinil (2/7), olanzapine (1/4), topiramate (1/4) in the long term.

Craving can be triggered by the drug itself, by cues related to drug use, by stress, and by withdrawal. It may occur in the period of immediate abstinence or in a longer period of abstinence. In the first process, there is an immediate activation of limbic system related to an anticipatory state and reward expectancy, and a disruption of medial prefrontal activity leading to compulsive drug-related behavior [4]. Despite having a low number of studies, clonidine, fenfluramine and m-CPP showed to be promising medications for acute anti-craving effects, based on the experimental studies (i.e., cue-induced, stress-induced) included in this review.

The craving that occurs after a longer period of abstinence, on the other hand, can be better explained by the incubation mechanism, in which even after drug use suspension and exposure to drug cues, there is a progressive increase in craving, remaining high within 3 months of abstinence, with a reduction after 6 months and is related to neuroadaptations and increased brain-derived neurotrophic factor (BDNF) levels [149]. The most promising drugs for such chronic purposes came from the longer randomized controlled trials included in this review. The class of psychostimulants had several options such as amphetamine, lisdexamfetamine, lorcaserin and methamphetamine for chronic cocaine craving. Our findings are in line with a review [150] of 9 clinical trials, of which

1. 4 evaluated craving and one showed a significant anti- craving effect of dexamphetamine. Progesterone was shown to be effective for treating craving in two out of three studies, in cocaine-dependent men and women who used the drug for 7 consecutive days. The antidepressant mirtazapine also showed a significant reduction in craving in 1 of 2 studies with it. Carbamazepine, biperiden and pioglitazone also presented significant anti-craving effects in long term treatments, although each one was evaluated once.

There are currently no approved drugs for the treatment of cocaine use disorder, with psychosocial intervention still being the standard approach. Recommendations of United Nations Office on Drugs and Crime [151] state that stimulant medications, such as amphetamines, may have modest effects on withdrawal and craving suppression for patients with stimulant use disorder. These recommendations refer to stimulants as “replacement” or “substitution therapy” and highlight studies that found evidence of craving suppression following the administration of extended-release formulations of methamphetamine 30 mg/day and lisdexamphetamine 70 mg/day. Findings of this review endorse these recommendations, but not the recommendations of The European Monitoring Centre for Drugs and Drugs Addiction, which stated in a summary of systematic reviews [152] that antipsychotics are the most prominent anti-craving drugs, although this could not be established as effective treatment. Several studies have been conducted to evaluate the efficacy of pharmacotherapies regarding dual substance disorders: some reports indicated that buprenorphine decreases cocaine use [153–155] in opioid-dependent humans who were concurrently abusing cocaine; one in particular [155] evaluated craving and demonstrated a significant reduction in its rate. Recent studies examined the therapeutic potential of orexin receptor antagonists in rodent models of cocaine use disorder, in reducing cocaine seeking behavior [156,157], pointing to future directions in studies in clinical settings.

We found that most studies made direct comparisons of one individual compound to placebo, or indirect comparisons between more than one individual compound and placebo. None of the studies investigated the anti-craving effects of combined pharmacological interventions. This is in stark contrast with the complex, multi-system pathophysiology of craving, which may require a combination of pharmacotherapies with complementary mechanisms [2,4,5]. This is exemplified by a randomized, placebo-controlled trial investigating the combination of topiramate and sustained release amphetamine among

127 persons with cocaine dependence, which found significant anti-craving effects over 12 weeks [158]. A pre-clinical study [159] suggested that the combination of buprenorphine and naltrexone decreases compulsive cocaine self-administration with minimal liability to produce opioid dependence and may be useful as a treatment for cocaine addiction. Hence, multi-function therapies maybe represent a more promising avenue of intervention.

Moreover, as craving is elicited by cues, stress, drug and withdrawal, studies must include, besides laboratory assessment, Ecological Momentary Assessment (EMA) due to the temporal association between exposure to drug cues, or subjective experiences, allowing for a more dynamic investigation of therapeutic effects of anti-craving treatments.

Limitations

To our knowledge, this is the first systematic review of pharmacotherapies targeting cocaine craving. Our review has notable strengths. First, published and widely accepted guidelines to conduct and report systematic reviews were used [17]. A highly sensitive search strategy was used across several electronic databases, which yielded multiple studies providing data on anti-craving efficacy of pharmacotherapies. Further, 2 independent reviewers performed all stages of the review, with good interrater reliability.

Previous reviews [11–14] reported challenges in systematically assessing anti-craving effects across multiple studies, primarily due to a high heterogeneity of craving measures. For instance, some studies used standardized scales whereas other studies used Visual Analogue Scales (VAS), or non-standardized questionnaires, some with unclear psychometrical properties. A study [16] comparing unidimensional and multidimensional craving scales suggested that the latter had higher predictive validity for relapse of cocaine use and for treatment dropout. Further, a review of craving measures [7] even suggests that researchers use different scales within the same study due to its complexity. Still, our review was limited by high heterogeneity of craving assessments across studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence retention as the main outcome in cocaine treatment, whereas craving was a secondary outcome; also, some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy. Nonetheless, the results of the review help bring clarity to the mixed findings on anti-craving pharmacotherapies reported in multiple clinical trials.

There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Given its clinical relevance, future studies aiming to develop pharmacotherapies for cocaine use disorder must consider craving as a therapeutic outcome, employing multimodal and standardized assessments—neurophysiological biomarkers, cue reactivity, ecological momentary assessment—to study this complex experience.

Despite most of the studies evaluate craving as a secondary outcome and having a low number of studies per medication in most of the cases, clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment. In addition, amphetamine, biperiden, carbamazepine, levodopa, lisdexamfetamine, lorcaserin, guanfacine, methamphetamine, mirtazapine, pioglitazone, progesterone, nefazodone exhibited anti-craving effects in long-term treatment. Future trials targeting craving as the main outcome should include these medications trying to replicate their preliminary positive results.

Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/brainsci12111546/s1, Table S1: Structured cocaine craving scales.; Table S2: Results of the quality/bias assessment using the Cochrane Collaboration tool for assessing risk of bias.

Author Contributions: Conceptualization, D.L.S.L. and J.M.C.-M.; methodology J.M.C.-M.; formal analysis, J.P.D.A.; writing—original draft preparation, D.L.S.L.; writing—review and editing, J.P.D.A., A.M., A.B.N.; visualization, L.F.; supervision, J.M.C.-M. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding. Data Availability Statement: All the supporting data are presented in the manuscript. Acknowledgments: There are no relevant financial or non-financial competing interests to report. Conflicts of Interest: The authors declare no conflict of interest. Systematic Review Registration: https://osf.io/f3hym/ (accessed on 10 November 2022).