key: cord-0954439-pw9aja9p
authors: Kotajima‐Murakami, Hiroko; Takano, Ayumi; Hirakawa, Shinya; Ogai, Yasukazu; Funada, Daisuke; Tanibuchi, Yuko; Ban, Eriko; Kikuchi, Minako; Tachimori, Hisateru; Maruo, Kazushi; Kawashima, Takahiro; Tomo, Yui; Sasaki, Tsuyoshi; Oi, Hideki; Matsumoto, Toshihiko; Ikeda, Kazutaka
title: Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double‐blind, placebo‐controlled trial
date: 2022-01-23
journal: Neuropsychopharmacol Rep
DOI: 10.1002/npr2.12232
sha: a3ae2cd19fe76f018e7c8ecdf40c06989484e6ca
doc_id: 954439
cord_uid: pw9aja9p

AIM: No effective pharmacological interventions have been developed for patients with methamphetamine use disorder. Ifenprodil is a blocker of G protein‐activated inwardly rectifying potassium channels, which play a key role in the mechanism of action of addictive substances. We conducted a randomized, double‑blind, exploratory, dose‐ranging, placebo‐controlled trial to examine the clinical efficacy of ifenprodil for the treatment of methamphetamine use disorder. METHODS: Participants were assigned to three groups: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. The drug administration period was 84 days. The primary outcome was the use or nonuse of methamphetamine during the drug administration period in the placebo group vs 120 mg/d ifenprodil group. We also assessed drug use status, relapse risk based on the Stimulant Relapse Risk Scale (SRRS), drug craving, and methamphetamine in urine as secondary outcomes. We further evaluated drug use status and SRRS subscale scores in patients who were not taking addiction medications during the study. RESULTS: Ifenprodil did not affect the primary or secondary outcomes. However, the additional analyses showed that the number of days of methamphetamine use during the follow‐up period and scores on the emotionality problems subscale of the SRRS improved in the 120 mg/d ifenprodil group. The safety of ifenprodil was confirmed in patients with methamphetamine use disorder. CONCLUSION: The present findings did not confirm the efficacy of ifenprodil for methamphetamine use disorder treatment based on the primary or secondary outcomes, but we found evidence of its safety and efficacy in reducing emotionality problems. CLINICAL TRIAL REGISTRATION: The study was registered at the University Hospital Medical Information Network Clinical Trial Registry (no. UMIN000030849) and Japan Registry of Clinical Trials (no. jRCTs031180080). The main registration site is jRCT (https://jrct.niph.go.jp/).

Methamphetamine is an addictive psychostimulant drug that causes aberrant physiological and psychological status. 1 In East Asia, South-East Asia, and North America, methamphetamine dominates drug markets. Methamphetamine use significantly increased between 2013 and 2016 in North America. 2 In Japan, methamphetamine is the most popular psychostimulant. Approximately 80% of drugrelated crimes are associated with methamphetamine. 3, 4 Effective pharmacological interventions for methamphetamine use disorder

have not yet been developed.

G protein-activated inwardly rectifying potassium (GIRK) channels are implicated in the mechanisms of action of various addictive substances. Functional GIRK channel subunits have four heterotetramers. 5-7 GIRK1, GIRK2, and GIRK3 subunits have been shown to be expressed in brain regions that are associated with addiction in rodents. 8, 9 GIRK channels are activated by the activation of G protein-coupled receptors that couple with G αi/o proteins 10, 11 and are important for regulating cellular activity. Alcohol can directly open GIRK channels without the participation of G protein-coupled receptors. 12 Weaver mutant mice with a missense mutation at the channel pore in the GIRK2 subunit did not exhibit methamphetamine-induced conditioned place preference or priming effects. 13 A single nucleotide polymorphism of the Kcnj6 gene, which encodes GIRK2, could serve as a marker to predict susceptibility to nicotine dependence in humans. 14 Therefore, GIRK channels are crucial in the mechanism of action of addictive substances.

Ifenprodil is a blocker of α 1 -adrenergic and GluN2B subunitcontaining N-methyl-D-aspartate receptors 15, 16 and inhibits GIRK channels. 17 Ifenprodil is approved as a treatment for dizziness after brain ischemia (≤60 mg/d). 18 High-dose ifenprodil is used as an analgesic in Japan. 19 Pretreatment with ifenprodil reduced morphineinduced conditioned place preference in mice, 20 and ifenprodil inhibited amphetamine-induced potentiation of excitatory postsynaptic currents in rat midbrain dopamine neurons. 21 Ifenprodil (60 mg/d) treatment for 3 months improved alcohol use scores in patients with alcohol dependence. 22 Ifenprodil (120 mg/d) also suppressed craving in a patient who was addicted to the cough medicine Bron ® and a patient with alcohol dependence. 23 Fluoxetine and paroxetine have been reported to inhibit GIRK channels. 24 Ifenprodil does not have serious adverse effects. 25 Paroxetine can cause several serious adverse effects, such as serotonin syndrome, 26 and fluoxetine use is not yet approved in Japan. These studies suggest that ifenprodil may be an effective treatment for substance use disorder. We conducted an exploratory, randomized, double-blind, placebo-controlled trial to investigate the clinical safety and efficacy of ifenprodil for the treatment of methamphetamine use disorder in Japanese patients. The study protocol was previously published as a protocol article. 27 2 | ME THODS

This randomized, double-blind, exploratory, dose-ranging, placebocontrolled trial was conducted in a single center (National Centre Hospital, National Centre of Neurology and Psychiatry [NCNP], Japan). Patients were randomly assigned to the following three groups: placebo, 60 mg/d ifenprodil, and 120 mg/d ifenprodil (1:1:1 allocation ratio). The patients orally took either placebo or ifenprodil use status and SRRS subscale scores in patients who were not taking addiction medications during the study.

Results: Ifenprodil did not affect the primary or secondary outcomes. However, the additional analyses showed that the number of days of methamphetamine use during the follow-up period and scores on the emotionality problems subscale of the SRRS improved in the 120 mg/d ifenprodil group. The safety of ifenprodil was confirmed in patients with methamphetamine use disorder.

The present findings did not confirm the efficacy of ifenprodil for methamphetamine use disorder treatment based on the primary or secondary outcomes, but we found evidence of its safety and efficacy in reducing emotionality problems.

Clinical trial registration: The study was registered at the University Hospital Medical Information Network Clinical Trial Registry (no. UMIN000030849) and Japan Registry of Clinical Trials (no. jRCTs031180080). The main registration site is jRCT (https://jrct. niph.go.jp/).

days of methamphetamine use, G protein-activated inwardly rectifying potassium channel, ifenprodil, methamphetamine use disorder, randomized-controlled trial over the 84-day administration period and were followed up for 84 days. The study was performed according to the tenets of the Declaration of Helsinki 28 and approved by the Ethics Committee of NCNP and Tokyo Metropolitan Institute of Medical Science. All patients provided written informed consent. Further methodological details of the protocol were published previously. 27 The following can be found in the Appendix S1: blood tests, dropout criteria, data management, access to data, harms, data monitoring, and data auditing.

Outpatients were recruited at the National Centre Hospital, NCNP, from January 2018 to March 2019. The inclusion criteria were the following: (a) outpatients who were diagnosed with methamphetamine use disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), 1 (b) outpatients who used methamphetamine in the past year, and (c) outpatients who were >20 years old when informed consent was obtained. The exclusion criteria were the following: (a) patients with severe physical diseases, (b) patients with a high risk of suicide, (c) patients with severe symptoms of substance-induced psychotic disorder, (d) patients with impairments in cognitive function, (e) patients who did not wish to be notified of their functional magnetic resonance imaging results, (f) patients who were determined to be ineligible to participate in the study by their attending psychiatrists, and (g) patients who took the GIRK channel blocker paroxetine. We screened for eligible patients who met the inclusion criteria using the in-hospital computer system.

The clinical research coordinator (CRC) and authors of the present study explained the study in detail to the participants and obtained informed consent from all patients, stating that participation was voluntary and that participants could withdraw from the study at any time. The CRC and authors of the present study collected information about sociodemographic characteristics, self-reported drug use status using a self-report calendar format based on the timeline follow-back (TLFB) method, relapse risk based on the Stimulant Relapse Risk Scale (SRRS), 29 and drug craving based on a numerical rating scale (NRS) after patients signed the informed consent form.

The NRS consisted of a numerical rating scale from 0 to 10. Higher scores indicated a greater magnitude of craving for methamphetamine. These self-administered questionnaires were applied at baseline and during visits every 4 weeks until day 168 (ie, the end of the study period). On day 0, all participants underwent urine and blood tests. The urine tests were conducted at all visits. The blood tests were conducted on days 0, 28, and 84 to monitor safety. The primary physicians, CRC, and authors of the present study checked for adverse events (AEs) at all visits.

We used Cerocral fine granules 4% (20 mg ifenprodil tartrate/0.5 g;

SANOFI-Nichi-Iko) as the study medication. Placebo consisted of granules without ifenprodil tartrate. Cerocral granules were ground to a consistency that was similar to fine lactate in the Pharmaceutical Department at NCNP. Patients received the medication during the drug administration period three times daily.

Patients were randomized to the three groups using the minimization method at the Translational Medical Centre (TMC), NCNP. The following prognostic factors were considered: sex, DSM-5 diagnostic criteria met (<4 criteria = mild, ≥4 criteria = moderate to severe), and methamphetamine use within the past 28 days. The allocation staff at the TMC received information from the CRC via a passwordprotected email, and they sent the allocation results to unblinded pharmacists via a password-protected email. The primary physicians, CRC, patients, and authors of the present study were blinded.

We assessed the use vs nonuse of methamphetamine during the 84-day ifenprodil or placebo administration period in the placebo and 120 mg/d ifenprodil groups as the primary outcome. A selfmonitoring calendar format, based on the TLFB method, was used to evaluate methamphetamine use over the past 28 days at baseline and the follow-up assessments, every 28 days. The patients checked one of three categories (0, 1, or 2) in the self-monitoring calendar format. The categories represented the participants' drug use status: 0 (no drug use), 1 (use of other drugs and/or alcohol, absence of methamphetamine use), and 2 (methamphetamine use). When the category 2 was checked during the administration period, we defined that methamphetamine was used (ie, the presence of methamphetamine use) and calculated the ratio of patients who used methamphetamine during the administration period in both the placebo and 120 mg/d ifenprodil groups.

We also assessed the use vs nonuse of methamphetamine during the 84-day ifenprodil or placebo administration period in the placebo vs 60 mg/d ifenprodil groups and in the 60 mg/d ifenprodil vs 120 mg/d ifenprodil groups as secondary outcomes. We set the days of methamphetamine use during the drug administration period and followup period in the placebo and 120 mg/d ifenprodil groups, in the placebo vs 60 mg/d ifenprodil groups, and in the 60 mg/d ifenprodil vs 120 mg/d ifenprodil groups as secondary outcomes. The days of methamphetamine use during the drug administration and follow-up periods were calculated using the TLFB method. The days when category 2 of the TLFB was selected were defined as days of methamphetamine use. The number of days of methamphetamine use that was calculated for each patient was cumulated in each group, and comparisons were made among groups. The positivity rate of urine methamphetamine (ie, percentage of those who had at least one positive urine test, number of positive urine tests) during the 84-day administration period was assessed. Relapse risk during the 84-day administration period was assessed using the SRRS. The SRRS was composed of the following five subscales: anxiety and intention to use the drug (AI), emotionality problem (EP), compulsivity for drug use (CD), positive expectancies and a lack of control over drug use (PL), and a lack of negative expectancy for drug use (NE). The total score ranged from 30 to 90. Subscale scores ranged from 8 to 24

for AI, 8 to 24 for EP, 4 to 12 for CD, 6 to 18 for PL, and 4 to 12 for NE. Higher total and subscale scores indicated a higher relapse risk.

Finally, drug craving during the 84-day administration period was assessed using the NRS. For the above parameters, the following comparisons were performed: placebo vs 120 mg/d ifenprodil groups, placebo vs 60 mg/d ifenprodil groups, and 60 mg/d ifenprodil vs 120 mg/d ifenprodil groups.

All P-values were two-tailed. The 95% confidence interval (CI) was computed along with P-values.

We evaluated the primary outcome according to a per-protocol analysis. The frequency of methamphetamine use during the drug administration period in the placebo vs 120 mg/d ifenprodil groups Secondary outcomes during the follow-up period were compared between groups as in the drug administration period using Fisher's exact test for categorical variables and Welch's t test for continuous variables. These statistical test results were interpreted using Bonferroni-Holm adjustment for multiple comparisons.

Multiple comparison tests were conducted twice for the presence or absence of methamphetamine use during the follow-up period.

Multiple comparison tests were also conducted three times for the days of methamphetamine use during the follow-up period. Box-Cox data transformation was performed when appropriate. All statistical analyses were conducted on a per-protocol basis.

Patient characteristics at baseline and safety data were assessed among groups using one-way analysis of variance (ANOVA). The frequency and proportion of each AE in the three groups were recorded.

The sample size was calculated using G*power 3.1. 31 The settings for the analysis of covariance were the following: effect size = 0.4, a = 0.05, 1−b = 0.8, number of groups = 3. These numbers were based on a previous study that investigated ifenprodil treatment in patients with alcohol dependence. 22 This analysis showed that the required number of patients in the present study was 52. A sample size of 80 was considered appropriate based on the number of patients at the NCNP. The number of new outpatients who were examined for drug dependence at the NCNP for 1 year was 60-90. We expected 20 patients to drop out based on the dropout rate of 10%-30% that was reported in previous studies. [32] [33] [34] [35] [36] [37] [38] The administration and follow-up periods in these previous studies ranged from 10 days to 36 weeks. We expected that the ratio of informed consent would be 50%, and 60 patients were expected to be analyzed.

For better analytical accuracy, we excluded patients who took other medications for addiction during the study. Two patients took varenicline (smoking-cessation aid), and one patient took Cerocral (ie, ifenprodil). The subsequent analysis included the following patient groups: placebo (n = 9), 60 mg/d ifenprodil (n = 11), and 120 mg/d ifenprodil (n = 10). We focused on the following outcomes: days of methamphetamine use and interindividual SRRS subscale scores.

The sample size in the categories varied because we excluded the patients with missing data. The days and percentage of days of methamphetamine use during the drug administration and followup periods were calculated using the TLFB method. The ratio of days of methamphetamine use was calculated by using the days of the administration and follow-up periods (each period was 84 days) in each group as the denominator and the number of days of methamphetamine use as the numerator. Figure 1 shows the results of study-arm (group) assignment and retention. Thirty-nine patients met the eligibility criteria, of which four did not participate in the present study because of personal reasons.

Thirty-five patients were randomized and assigned to the three groups. One patient who was assigned to the placebo group did not participate after providing informed consent. One patient who was assigned to the 120 mg/kg ifenprodil group withdrew because of personal reasons. Similarly, one patient who was assigned to the 60 mg/kg ifenprodil group withdrew because of personal reasons.

In the primary and secondary analyses, the number of participants was the following: placebo group (n = 10), 60 mg/d ifenprodil group (n = 11), and 120 mg/d ifenprodil group (n = 11). For the safety data, we included the one patient who had withdrawn because of personal reasons. Therefore, the number of patients per group was the following: placebo group (n = 10), 60 mg/d ifenprodil group (n = 12), and 120 mg/d ifenprodil group (n = 12). There were no significant differences in patient characteristics ( Table 1 ). All patients were diagnosed with either moderate or severe methamphetamine use disorder.

We evaluated the presence or absence of methamphetamine use during the drug administration period between the placebo and 120 mg/d ifenprodil groups as the primary outcome. Table 2 lists F I G U R E 1 Flow chart of participants. Thirty-nine patients were assessed according to the eligibility criteria. Thirty-five patients were randomly assigned to the following three groups: placebo (n = 11), 60 mg/d ifenprodil (n = 12), and 120 mg/d ifenprodil (n = 12). In the placebo and 120 mg/d groups, one patient did not attend the study after providing informed consent, and two patients withdrew from participation because of personal reasons, respectively. Ten patients in the placebo group, 12 patients in the 60 mg/d ifenprodil group, and 11 patients in the 120 mg/d ifenprodil group were analyzed for the primary and secondary outcomes (purple box). For the additional analyses, patients who took other medications for addiction were removed from each group (orange box). *The patient in the 60 mg/d ifenprodil group was included in the additional analysis because she completed the drug administration period the primary and secondary outcomes. We calculated the ratio of patients who used methamphetamine during the administration period in both the placebo and 120 mg/d ifenprodil groups (Table 2 in 60 mg/d ifenprodil group; P < .001) and between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P < .001). In the follow-up period, no significant differences in the ratio of urine positive for methamphetamine were found between the placebo and 120 mg/d ifenprodil groups (12.5% vs 20.0%, respectively; P = 1.000), between the placebo and 60 mg/d ifenprodil groups (12.5% vs 28.6%, respectively; P = 1.000), or between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P = 1.000).

In the administration period, no significant differences in the number of positive urine tests were found between the placebo and 120 mg/d ifenprodil groups (6 vs 4, respectively; P = .974), between the placebo and 60 mg/d ifenprodil groups (6 vs 6, respectively; P = 1.000), or between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P = 1.000). In the follow-up period, no significant differences in the number of positive urine tests were found between the placebo and 120 mg/d ifenprodil groups (1 vs 1, respectively; P = 1.000), between the placebo and 60 mg/d ifenprodil groups (1 vs 4, respectively; P = .542), or between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P = .787).

In the administration period, no significant differences in total SRRS scores were found between the placebo and 120 mg/d ifenprodil 

In the administration period, no significant differences in NRS scores were found between the placebo and 120 mg/d ifenprodil groups 

3.4.1 | Days of methamphetamine use during the drug administration and follow-up periods Table 3 shows the results of the additional analyses. There were no significant differences in the frequency of days of methamphetamine use during the drug administration period between the placebo and 120 mg/d ifenprodil groups (2.4% vs 3.3%, respectively; P = .952), between the placebo and 60 mg/d ifenprodil groups (2.4% vs 2.2%, respectively; P = 1.000), or between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P = .952). For this outcome, the analysis included the following groups: placebo (n = 7), 60 mg/d ifenprodil (n = 8), and 120 mg/d ifenprodil (n = 8). The sample size varied because patients with missing data were excluded.

Significant differences in the ratio of days of methamphetamine use during the follow-up period were found between the placebo and 120 mg/d ifenprodil groups (3.1% vs 0.0%, respectively; P < .001), between the placebo and 60 mg/d ifenprodil groups (3.1% vs 5.8%, respectively; P = .016), and between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P < .001). For this outcome, the analysis included the following groups: placebo (n = 8), 60 mg/d ifenprodil (n = 9), and 120 mg/d ifenprodil (n = 4). The sample size varied because patients with missing data were excluded.

subscale scores from baseline to the end of the drug administration and follow-up periods Table 3 shows these results. There were no significant differences in intraindividual changes in EP subscale scores from baseline to the 

subscale scores from baseline to the end of the drug administration and follow-up periods Table 3 shows these results. There were no significant group differences in changes in EP subscale scores from baseline to the end of the drug administration period between the placebo and 120 mg/d ifenprodil groups (P = .222), between the placebo and 60 mg/d ifenprodil groups (P = .827), or between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P = .084). Significant group differences in interindividual changes in EP subscale scores from baseline to the end of the follow-up period were found between the placebo and 120 mg/d ifenprodil groups (P = .017) and between the 120 mg/d ifenprodil and 60 mg/d ifenprodil groups (P = .043). No significant group differences were found between the placebo and 60 mg/d ifenprodil groups (P = .482). Additional analyses of other outcomes are reported in the Details of the Results of Additional Analyses in the Appendix S1 (Table S1 ). Table S2 .

The present findings showed that ifenprodil is safe for the treatment of methamphetamine use disorder, but we found no evidence of efficacy with regard to the primary or secondary outcomes.

Nonetheless, the additional analyses showed that the days of methamphetamine use during the follow-up period were lower and SRRS EP subscale scores improved after treatment with 120 mg/d ifenprodil compared with both placebo and 60 mg/d ifenprodil. These results suggest that beneficial outcomes can be achieved with ifenprodil for the treatment of methamphetamine use disorder.

We set the use vs nonuse of methamphetamine, days of methamphetamine use, urine positivity, SRRS scores, and NRS scores as primary and secondary outcomes, but none of these outcomes supported the efficacy of ifenprodil for the treatment of methamphetamine use disorder. Although these outcomes have been previously used to investigate the efficacy of drug treatment and cognitive therapy for methamphetamine use disorder, 30 However, only three of the 35 participants in this study dropped out.

This dropout rate suggests our study protocol was appropriate for these patients with methamphetamine use disorder.

Groups: the days of methamphetamine use/total days, (%) Significance P The present study has limitations. First, the number of patients was low, and the target sample size was not achieved. It is difficult for patients with methamphetamine use disorder to access medical institutions in Japan. Future studies should have a longer recruitment period to study larger cohorts. Second, self-administered questionnaires and self-reports of methamphetamine use were not objective indicators. Third, we conducted this study in a single center in Japan. Multicenter studies are needed that include a larger number of patients.

Overall, this was the first clinical trial on the treatment of methamphetamine use disorder with ifenprodil. Our findings confirmed the safety of ifenprodil, and ifenprodil at the highest dose exerted slight efficacy. Future studies with more patients are needed to further compare the effects of placebo and 120 mg/d ifenprodil to more definitively determine whether ifenprodil is effective for the treatment of methamphetamine use disorder. Clinical Research Unit, NCNP) for assistance with patient and investigational product management. We thank Michael Arends for proofreading the manuscript. All authors read and approved the final manuscript to be published.

The Institutional Review Board of the National Center of Neurology and Psychiatry and Tokyo Metropolitan Institute of Medical Science approved the study.

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All participants provided written informed consent.

We do not share individual de-identified participant data. All data generated or analyzed during this study are included in this published article and its supplementary information file Data S1.

https://orcid.org/0000-0001-5228-4699Yuko Tanibuchi https://orcid.org/0000-0002-1690-6793Hisateru Tachimori https://orcid.org/0000-0001-6401-2885Kazutaka Ikeda https://orcid.org/0000-0001-8342-0278

Additional supporting information may be found in the online version of the article at the publisher's website.