Clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan: Comparison of single and multiple OTC product abusers.

OBJECTIVE: To examine the clinical characteristics of over-the-counter (OTC) drug abusers in psychiatric practice in Japan. METHOD: We examined the attributes, ICD-10 subcategory, and comorbid mental disorders of patients who mainly abuse OTC products and compared the clinical characteristics of single product and multiple products abusers, using the database of the "2022 Nationwide Mental Hospital Survey of Drug-related Disorders." RESULTS: Among the 2468 subjects included in this survey, 273 (11.1%) used OTC products as main drugs. Of these, 209 (78.3%) and 58 (21.7%) were classified into the single product group and the multiple products group, respectively. Six were excluded for unknown ingredients. By comparing these groups, we found that many of the multiple products group consisted of young women who were recently treated for drug problems. Many subjects in the group also had a short treatment period. No differences were observed between the groups regarding the ICD-10 F1 subcategory, but many subjects in the multiple products group fulfilled the criteria of F6 "disorders of adult personality and behavior." CONCLUSION: OTC products are easily accessible drugs of abuse for young women in Japan. The results of this study indicate the necessity to reconsider the educational approach for preventing drug abuse, which has focused on illicit drugs. The study also indicates that some OTC products, which contain ingredients banned overseas due to their harmful effects, are still sold in Japan and that abusers for those products exist. Measures by the government are considered urgently needed.

Ifenprodil for the treatment of methamphetamine use disorder: An exploratory, randomized, double-blind, placebo-controlled trial.

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/).

Risk factors for the onset of dependence and chronic psychosis due to cannabis use: Survey of patients with cannabis-related psychiatric disorders.

AIM: The objective of the current study was to identify risk factors that affect the onset of dependence and chronic psychosis due to cannabis use. METHODS: We examined clinical genetic factors, psychiatric disorders prior to cannabis use, starting age of cannabis use, duration and frequency of cannabis use, types of cannabis products used, combined use of other psychoactive substances, and the psychiatric diagnosis of 71 patients with cannabis-related psychiatric disorders who underwent treatment at nine mental health hospitals in Japan. Information was collected from cross-sectional interview surveys conducted by each patient's attending psychiatrist. RESULTS: For the diagnosis of dependence syndrome due to the use of cannabis, we found associations with the number of years of cannabis use and the use of cannabis products with a high Δ9-tetrahydrocannabinol (THC) content. However, we found no association between diagnosis of residual and late-onset psychotic disorders and clinical genetic factors, presence of preceding psychiatric disorders, duration and frequency of cannabis use, starting age of cannabis use, or combined use of other psychoactive substances; an association was found only for the absence of use of cannabis products other than dried cannabis. CONCLUSION: The onset of cannabis dependence was related to long-term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability. Thus, unknown factors appear to be involved in the onset of chronic psychosis.

Changes of clinical symptoms in patients with new psychoactive substance (NPS)-related disorders from fiscal year 2012 to 2014: A study in hospitals specializing in the treatment of addiction.

AIMS: The use of new psychoactive substances (NPS) has become increasingly widespread over the last decade, in Japan and internationally. NPS are associated with a range of increasingly serious clinical, public, and social issues. Political measures to ameliorate the effects of NPS in Japan have focused on tightening regulation rather than establishing treatment methods. The current study sought to compare the neuropsychiatric symptoms of patients with NPS-related disorders across several years. We examined patients who attended specialized hospitals for treating addiction, to elucidate the impacts of legal measures to control NPS. METHODS: Subjects (n = 864) were patients with NPS-related disorders who received medical treatment at eight specialized hospitals for treating addiction in Japan between April 2012 and March 2015. Clinical information was collected retrospectively from medical records. RESULTS: Among psychiatric symptoms, the ratio of hallucinations/delusions decreased over time across 3 years of study (first year vs second year vs third year: 40.1% vs 30.9% vs 31.7%, P = 0.037). Among neurological symptoms, the ratio of coma/syncope increased over the 3-year period (7.8% vs 11.0% vs 17.0%, P = 0.002), as did the ratio of convulsions (2.8% vs 4.3% vs 9.7%, P = 0.001). CONCLUSION: The symptoms associated with NPS were primarily psychiatric in the first year, while the prevalence of neurological symptoms increased each year. The risk of death and the severity of symptoms were greater in the third year compared with the first year, as regulation of NPS increased.

Study of effects of ifenprodil in patients with methamphetamine dependence: Protocol for an exploratory, randomized, double-blind, placebo-controlled trial.

AIMS: Pharmacotherapy for methamphetamine dependence has not yet been developed in Japan or elsewhere in the world. Ifenprodil is a blocker of G protein-activated inwardly rectifying potassium channels that play a key role in the mechanism of action of addictive substances. Our aim is to examine the safety, efficacy, and outcomes of ifenprodil for the treatment of methamphetamine dependence in a randomized, double-blind, placebo-controlled trial. METHODS: The recruitment of outpatients with methamphetamine dependence began in January 2018. The patients will be randomized into three arms: placebo, 60 mg/d ifenprodil, or 120 mg/d ifenprodil. Placebo or ifenprodil will be taken for 84 days. We will use Cerocral fine granule 4%® (ifenprodil tartrate). Follow-up assessments will be conducted for 84 d after the drug administration period. All of the patients will be assessed by self-administered questionnaires and urine tests. The primary outcome will be the presence or absence of methamphetamine use during the 84-day administration period in the 120 mg/d ifenprodil and placebo groups. Secondary outcomes will include the number of days and percentage of days of abstinence from methamphetamine use, positive urine for methamphetamine, relapse risk, and drug craving. DISCUSSION: This study is the first clinical trial of ifenprodil treatment for methamphetamine dependence and is designed as an intervention test with off-label drug use. The present study is expected to provide evidence of the effects of ifenprodil treatment on methamphetamine dependence. TRIAL REGISTRY: This trial was registered in the UMIN clinical trial registry (UMIN000030849; date of registration: January 17, 2018).

The influence of tightening regulations on patients with new psychoactive substance-related disorders in Japan.

AIMS: This study aimed to investigate the influence of tightened regulations on new psychoactive substances in patients with disorders related to these drugs in Japan. METHODS: We used a biennial nationwide survey on drug-related psychiatric disorders to examine why individuals who had previously used new psychoactive substances as their primary drug (the drug that had the greatest impact on their psychiatric symptoms) had switched to other drugs, how they had used drugs in the last 12 months and what type of drugs they were now using. We compared the clinical features of these individuals with patients who mainly used new psychoactive substances and had used these drugs at least once in the last 12 months. RESULTS: A total of 2262 people were included, and 399 had used new psychoactive substances. Of those, 71 people had switched to another drug as primary drug, mostly stimulant drugs (35.2%), hypnotics and anxiolytics (15.5%), and cannabis (14.1%) and used these drugs during the previous 12 months. The majority, 53.3%, had switched "because new psychoactive substances were no longer available." In total, 25 people mainly used new psychoactive substances. The group that had changed drugs had more experience of using methamphetamine and were more likely to have abused other drugs before using new psychoactive substances. They had often switched to illegal or prescription drugs after regulations had been tightened. CONCLUSION: The number of patients abusing new psychoactive substances decreased after drug regulations were tightened, but new psychoactive substances-related problems still exist. It is therefore not enough to tighten regulations. Drug dependence treatment and recovery support are also needed.

Recent changes in the clinical features of patients with new psychoactive-substances-related disorders in Japan: Comparison of the Nationwide Mental Hospital Surveys on Drug-related Psychiatric Disorders undertaken in 2012 and 2014.

AIM: The aim of this study was to examine changes in the psychosocial backgrounds and clinical features of patients with psychiatric disorders associated with new psychoactive substances (NPS) between 2012 and 2014 in Japan. METHODS: Clinical features of patients with NPS-related disorders were compared using data from the Nationwide Mental Hospital Surveys on Drug-related Psychiatric Disorders undertaken in 2012 and 2014. NPS patients were compared with a control group comprising patients with methamphetamine-related disorders, using data from the same period. RESULTS: In NPS patients, changes were observed in the following three areas between 2012 and 2014: (i) a decrease in the number of employed patients; (ii) an increase in the ratio of patients diagnosed with dependence syndrome; and (iii) a decrease in the ratio of patients diagnosed with psychotic disorder. In methamphetamine patients, only one change was observed: protective custody or arrest record relating to the Pharmaceutical Affairs Act. CONCLUSION: This study suggests that the number of patients dependent upon NPS, and those exhibiting social dysfunction, increased between 2012 and 2014. There is a need to focus future measures against NPS dependence: not only on stopping the supply of drugs, but also on reducing the demand for them.

[Efficacy of the Serigaya Methamphetamine Relapse Prevention Program (SMARPP): for patients with drug use disorder: A study on factors influencing 1-year follow-up outcomes].

PURPOSE: The purpose of this study was to evaluate the efficacy of the Serigaya Methamphetamine Relapse Prevention Program (SMARPP), which is the workbook-based group therapy for individuals with drug dependence, through investigating 1-year follow-up outcomes. METHOD AND SUBJECTS: The sample was drawn from 231 outpatients diagnosed as DSM-IV substance use disorder, who had firstly consulted the drug dependence clinic of the Center Hospital, National Center of Neurology and Psychiatry between September 2009 and June 2013. Of the 231 potential subjects, 79 had participated in SMARPP at least once, and finally 37 who had continued contact this clinic for more than 1 year after due-day of finishing the first SMARPP course were determined as the subjects. We collected the outcome information retrospectively based on clinical records. RESULT: At the 1-year follow-up point, 67.6% of the subjects had continued abstinent at least for a month, and 60% of them had continued full-abstinent for more than 1 year. One of the factors which influenced their abstinence was "having no experience of using new psychoactive substances" (p = 0.029). As for 70.3% of subjects, drug-use frequency decreased and the only factor for their improvement was "participating in SMARPP many times" (p = 0.040). Of the subjects, 23 patients corresponded to methamphetamine use disorder, and 65.2% of them had continued abstinent at least for a month at the 1-year follow-up point. Additionally, 60% of them had continued full-abstinent for more than 1 year. DISCUSSION AND CONCLUSION: Our study demonstrated possible effectiveness of SMARPP for patients with drug use disorder, especially methamphetamine-use-disorder. The factors of abstinence or decrease of drug-use frequency may be to participate in SMARPP many times, not to abuse "not illegal" drugs such as new psychoactive substances or hypnotics/anxiolytics and to continue treatment for more than 1 year after due-day of finishing the program.

Clinical features of patients with designer-drug-related disorder in Japan: a comparison with patients with methamphetamine- and hypnotic/anxiolytic-related disorders.

AIM: The aim of this study was to clarify the clinical features of designer-drug-abusing patients through comparisons with methamphetamine-abusing patients and hypnotics/anxiolytics-abusing patients. METHODS: Information on 126 designer-drug-abusing patients, 138 methamphetamine-abusing patients, and 87 hypnotics/anxiolytics-abusing patients was extracted from the 2012 database of 'The Nationwide Mental Hospital Survey on Drug-related Psychiatric Disorders' and the clinical variables of designer-drug-abusing patients compared with those of the other two groups. RESULTS: Multivariate analysis indicated the following significant differences between designer-drug-abusing patients and the other two types of patients: designer-drug-abusing patients were younger, included more men, had higher education and fewer relationships with antisocial groups, and included more patients meeting ICD-10 F1 sub-classification categories of 'Harmful use' and 'Psychotic disorders' than methamphetamine-abusing patients. Compared with hypnotics/anxiolytics-abusing patients, designer-drug-abusing patients were younger, included more men and more patients meeting criteria for 'Psychotic disorders', and more frequently cited 'peer pressure', 'unable to refuse', and 'seeking stimulation' as reasons for using the drug. CONCLUSION: The advent of designer drugs has created a new class of drug abuse, and abuse of designer drugs may carry a strong psychosis-inducing risk, exceeding that of methamphetamine.

[Response to treatment of patients abusing the "dappou drug" who participated in a group relapse prevention program: a comparison with patients abusing methamphetamine].

In this study, we compared the efficacy of a group relapse prevention program using the cognitive behavioral therapy-based workbook, Serigaya Methamphetamine Relapse Prevention Program (SMARPP), between patients abusing the so-called "dappou drugs" (designer drug in Japan, and those abusing methamphetamine (MAP). Both groups participated in the SMARPP at the Center Hospital, National Center of Neurology and Psychiatry. Results showed that, no significant differences were found in the rates of participation in the program or self-reported frequency of drug or alcohol use between the patients abusing "dappou drugs" or MAP. However, patients using "dappou drugs" reported no significant increase in their confidence in their ability to resist the temptation to use drugs on the self- report drug abuse scales after the SMARPP intervention, while patients abusing MAP reported a significant positive difference in their ability to resist temptation. In addition, insight into substance abuse problems and motivation to participate in further treatment slightly declined in those using "dappou drugs," while there was a significant increase reported by the patients using MAP. These results suggested that the SMARPP might not be as effective for patients abusing "dappou drugs" as for those abusing MAP. The development of a relapse prevention program specifically designed for patients abusing "dappou drugs" is required.

[Clinical characteristics of dappou herb use--disorder patients at the drug dependence clinic: a comparison with methamphetamine use-disorder patients].

BACKGROUND AND PURPOSE: Use of the so-called "dappou herb," a street drug typically produced by mixing herbs with synthetic cannabinoid (estimated to be the pharmacologically effective ingredient), has recently spread to young people in Japan who consider it a new recreational drug. It is not legally regulated because no illicit ingredients have been detected in the drug by conventional screening tests. It is easily obtained via the Internet or from street vendors. As the population abusing this drug has grown, medical problems such as psychosis, disturbances of consciousness caused by acute intoxication, and social problems such as traffic accidents while under the influence of the drug have been increasingly reported. However, few psychiatric symptoms associated with it have been identified, and little is known about the psychosocial features of abusers. The purpose of the present study was to examine the clinical and psychosocial features of outpatients with dappou herb use disorder. METHODS: Subjects were 15 male outpatients with dappou herb use disorder who had their first medical examination at the Drug Dependence Clinic in the Center Hospital, National Center of Neurology and Psychiatry between November 2009 and April 2012. The control group comprised 28 age-matched oupatients who had methamphetamine use disorder, the most serious drug-related problem in Japan since the 1950s. They underwent their first medical examination at the same clinic during the same time frame as the study subjects. Clinical and psychosocial information on subjects and controls including life histories (educational, occupational, and criminal) and clinical information (history of psychoactive substance use, access to the mainly abused drug, and DSM-IV diagnoses of substance use disorder and comorbid psychiatric disorders) were collected from medical records. These variables were compared between the two groups. RESULTS: Analyses revealed differences in the life history and clinical characteristics between the subjects and controls. The subjects had a higher level of education, more work experience, and a less marked history of anti-social behavior other than illicit drug use and possession than the controls. However, a clinical history of psychiatric disorders, other than substance-related disorders, before drug abuse began was more frequently found in the subjects than in the controls. CONCLUSIONS: The present study demonstrates that patients with dappou herb use disorder may differ from those with methamphetamine use disorder in terms of their background, psychosocial factors, and clinical features. These findings suggest that the dappou herb may be creating a new type of drug abuser in Japan. Our study also indicates that some patients abusing this herb may have been "self-medicating" for symptoms of other psychiatric disorders such as depression or anxiety, given that they were more likely to have received psychiatric treatment before the start of drug abuse. This suggests that the legal regulation of this drug as well as early comprehensive intervention for adolescents with mental health problems may be required to prevent abuse of the dappou herb. Two limitations of this study should be noted. The definition of the dappou herb was vague because the ingredients are still unclear. In addition, the sample size of this study was very small. However, no studies using larger samples have been reported in Japan. Future studies that overcome these limitations are needed.

Pharmacological characterization of [(125)I]CHIBA-1006 binding, a new radioligand for α7 nicotinic acetylcholine receptors, to rat brain membranes.

The α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable small molecule radioligands for imaging α7 nAChRs in the brain. In this study, we synthesized the novel radioligand [(125)I]4-iodophenyl 1,4-diazaicyclo[3.2.2]nonane-4-carboxylate ([(125)I]CHIBA-1006), a iodine-derivative of the selective α7 nAChR agonist SSR180711, and studied the characterization of [(125)I]CHIBA-1006 binding to rat brain membranes. The assays of [(125)I]CHIBA-1006 binding to rat brain membranes were performed at 4°C. The presence of a single saturable high-affinity binding component for [(125)I]CHIBA-1006 in the rat brain was shown. Scatchard analysis revealed an apparent equilibrium dissociation constant (K(d)) of 88.2±21.4nM and a maximal number of binding sites (B(max)) of 65.4±6.8fmol/mg protein (mean±SEM, n=4). The specific binding of [(125)I]CHIBA-1006 was inhibited by a number of α7 nAChR-selective ligands (e.g., unlabeled CHIBA-1006, SSR180711, CHIBA-1001, MG624 and A844606), suggesting a similarity among α7 nAChR pharmacological profiles. In contrast, α-bungarotoxin, MLA, and nicotine showed very weak affinity for [(125)I]CHIBA-1006 binding. The regional distribution of [(125)I]CHIBA-1006 binding to crude membranes from dissected regions of the rat brain was different from that of [(125)I]α-bungarotoxin binding, suggesting that [(125)I]CHIBA-1006 binding sites may not be identical to [(125)I]α-bungarotoxin binding sites in the rat brain. The present findings suggest that [(125)I]CHIBA-1006 would be a useful new small molecule radioligand for α7 nAChRs in the brain.

A case of methamphetamine use disorder treated with the antibiotic drug minocycline.

Methamphetamine (METH) use is one of the major public health concerns worldwide. Long-term use of METH induces not only dependence but also psychosis which is associated with METH-induced brain damage, including neuroinflammation produced by activated microglia. We report the case of a female patient whose psychotic symptoms in METH use disorder were successfully improved by anti-inflammatory drug minocycline therapy. Although the precise mechanism(s) underlying the efficacy of minocycline in METH use disorder are currently unclear, minocycline appears to be a good candidate for future investigation clinical trials for medication development in METH using populations.

Characterization of [(3)H]CHIBA-1001 binding to alpha7 nicotinic acetylcholine receptors in the brain from rat, monkey, and human.

Accumulating evidence suggests that the alpha7 subtype of nicotinic acetylcholine receptors (nAChRs) plays a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer's disease. Currently, there are no suitable small molecule radioligands for alpha7 nAChRs in the brain, although [(125)I]alpha-bungarotoxin has been widely used as a radioligand for alpha7 nAChRs. In the present study, we characterized a new radioligand, 4-[(3)H]methylphenyl 2,5-diazabicyclo[3.2.2]nonane-2-carboxylate ([(3)H]CHIBA-1001), a derivative of the selective alpha7 nAChR agonist SSR180711, in brain membranes from rat, monkey, and human. Scatchard analysis revealed an apparent equilibrium dissociation constant (Kd) of 193.4nM in rat brain membranes at 4 degrees C, and the maximal number of binding sites (Bmax) was 346.2fmol/mg protein. The order of drugs for the inhibition of [(3)H]CHIBA-1001 binding to rat brain membranes is SSR180711>A-844606>MG624>epibatidine>DMAB>A-582941, suggesting a similarity of alpha7 nAChR pharmacological profiles. In contrast, alpha-bungarotoxin, MLA, and nicotine were found to be very weak. The distribution of [(3)H]CHIBA-1001 binding to crude membranes from dissected regions of rat, monkey, and human brain was different from that of [(125)I]alpha-bungarotoxin binding, suggesting that [(3)H]CHIBA-1001 binding sites may not be identical to [(125)I]alpha-bungarotoxin binding in the brain. In summary, [(3)H]CHIBA-1001 would be a useful radioligand for alpha7 nAChRs in the brains of rodents, non-human primates, and humans.

Effects of quetiapine on phencyclidine-induced cognitive deficits in mice: a possible role of alpha1-adrenoceptors.

Accumulating evidence suggests that alpha(1)-adrenoceptors may be involved in the mechanisms of action of some antipsychotic drugs. The present study was undertaken to examine the effects of quetiapine, an atypical antipsychotic drug with alpha(1)-adrenoceptor antagonism, on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). Subsequent subchronic (14 days) administration of quetiapine (1.0, 10, or 30 mg/kg, p.o.) attenuated PCP (10 mg/kg/day for 10 days)-induced cognitive deficits in mice, in a dose dependent manner. Furthermore, PCP (10 mg/kg)-induced cognitive deficits were also significantly ameliorated by subsequent subchronic (14 days) administration of the selective alpha(1)-adrenoceptor antagonist prazosin (1.0 mg/kg/day, p.o.). Moreover, Western blot analysis revealed that levels of two subtypes (alpha(1A) and alpha(1B)) of alpha(1)-adrenoceptors were significantly lower in the brains of PCP-treated mice than in those of saline-treated mice. These findings suggest that repeated PCP administration could decrease the density of alpha(1)-adrenoceptors in mouse brain, and that subsequent subchronic administration of quetiapine might ameliorate PCP-induced cognitive deficits via alpha(1)-adrenoceptors. Therefore, it is likely that antagonism at alpha(1)-adrenoceptors is involved in the mechanism underlying quetiapine's psychopharmacological action.

Phencyclidine-induced cognitive deficits in mice are ameliorated by subsequent subchronic administration of donepezil: role of sigma-1 receptors.

This study was undertaken to examine the effects of two acetylcholinesterase inhibitors (donepezil and physostigmine) on cognitive deficits in mice after repeated administration of the NMDA receptor antagonist phencyclidine (PCP). In the novel object recognition test, PCP (10 mg/kg/day for 10 days)-induced cognitive deficits were significantly improved by subsequent subchronic (14 days) administration of donepezil (1.0 mg/kg/day), but not donepezil (0.1 mg/kg/day). Furthermore, the effect of donepezil (1.0 mg/kg/day) on PCP-induced cognitive deficits was significantly antagonized by co-administration of the selective sigma-1 receptor antagonist NE-100 (1.0 mg/kg/day), suggesting the role of sigma-1 receptors in the active mechanisms of donepezil. In contrast, PCP-induced cognitive deficits were not improved by subsequent subchronic (14 days) administration of physostigmine (0.25 mg/kg/day). Moreover, repeated administration of PCP significantly caused the reduction of sigma-1 receptors in the hippocampus. The present study suggests that agonistic activity of donepezil at sigma-1 receptors plays a role in the active mechanisms of donepezil on PCP-induced cognitive deficits in mice. Therefore, it is likely that donepezil would be potential therapeutic drugs for the treatment of the cognitive deficits in schizophrenia.