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Rationale: In recent years, psychedelic substances with serotonergic mechanisms have accumulated substantial evidence that they may provide therapeutic benefits for people suffering with psychiatric symptoms. Psychiatric disorders targeted by these psychedelic-assisted therapies are managed with serotonergic drugs like selective serotonin reuptake inhibitors (SSRIs) as the current standard of care, so it is important to evaluate the potential risks of drug-drug interactions and serotonin toxicity (ST) between these agents., Objectives: A critical evaluation of the scientific literature is necessary to delineate the risks of ST when combining psychedelics with available serotonergic pharmacotherapy options. This review article describes signs and symptoms of ST, characterizes mechanisms of ST risk, summarizes what is known about serotonergic psychedelic drug interactions, and outlines potential management strategies., Results: True ST typically occurs with a serotonergic drug overdose or in combinations in which a drug that can increase intrasynaptic serotonin is combined with a monoamine oxidase inhibitor (MAOI). Serotonergic psychotropics that do not contain MAOIs are low risk in combination with psychedelics that also do not contain MAOIs. Signs and symptoms warranting immediate medical attention include myoclonus, extreme and fluctuating vital signs, agitation or comatose mental state, muscle rigidity, pronounced hyperthermia (fever), and/or seizure activity., Conclusions: Serotonin-related adverse reactions exist along a spectrum with serotonin syndrome being the most severe manifestations of ST. Due to varying serotonergic mechanisms of psychedelics and psychotropics, with varying propensities to increase intrasynaptic serotonin, some combinations may present a significant risk for serotonin toxicity (ST) while others are likely benign., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance., Objective: To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance., Methods: In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks-road-tracking, car-following, and harsh-braking-using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone., Results: The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71-5.79) and 4.07 cm (90% CI: 2.02-6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94-6.69) and 24.6 ms (90% CI: 12.7-36.4), respectively., Conclusions: The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Prospective memory (PM) impairment in recreational drug users has been documented in recent years. However, most studies on the effects of drugs on PM contain several methodological challenges, such as small sample size (< 100 participants), unrepresentative sample type (e.g., student or patient), short abstinence period (< 7 days), and lack of control of potential confounds (e.g., sleep and IQ). The present study investigated the possible consequences of recreational drug use on prospective memory, using self-report and lab-based prospective memory measures while overcoming the methodological challenges. The sample was composed of 47 non-users (27 females, age range from 18 to 50 +) and 53 drug users (21 females, age range from 18 to 50 +). Recreational drug users reported significantly more deficits in the long-term episodic, short-term habitual, and internally cued PM failures subscales of the Prospective Memory Questionnaire. However, these deficits were eliminated after controlling for covariates (e.g., age, sleep quality, general health, alcohol usage). Recreational drug users also performed worse than non-users in the short-term, long-term, event-based, and time-based PM subscales of the Royal Prince Alfred Prospective Memory Test. These results remained significant after controlling for the covariates. Drug users demonstrated greater impairments on time-based and long-term PM tasks thought to be linked with executive functioning. Taken together, the present study provides further support for recreational drug-related deficits in PM and highlights a dissociation between self-report and lab-based PM measures., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Rationale: Investigation of associated risk factors of valproic acid (VPA)-induced tremor helped in increasing tolerance and optimizing treatment scheme individually., Objectives: To determine the risk factors of VPA-induced tremor, with particular attention on identifying tremor-susceptible gene mutations., Methods: Epileptic patients taking VPA were divided into a tremor and a non-tremor groups. A mutation of rs9652490 in the leucine-rich repeat and immunoglobulin domain-containing Nogo-receptor-interacting protein 1 (LINGO-1) gene was determined by Sanger sequencing. Cerebellar atrophy was assessed, and various cerebellar dimensions were measured on magnetic resonance imaging (MRI) scans., Results: One hundred and eighty-one of 200 subjects were included. Multivariate regression analysis indicated several VPA-induced tremor-related factors: females (OR = 2.718, p = 0.014), family history of tremor (OR = 7.595, p = 0.003), treatment duration (> 24 months; OR = 3.294, p = 0.002), and daily dosage (> 1,000 mg/d; OR = 19.801, p = 0.008) of VPA. Chi-square tests revealed that treatment with VPA magnesium-ER (p = 0.030) and carbamazepine combination (p = 0.040) reduced the incidence of tremor. One hundred and seventy-six gene sequencing and 86 MRI results excluded any significant difference between the two groups in the mutation of rs9652490 within LINGO-1, the ratio of cerebellar atrophy or the cerebellar-dimension values (p > 0.05). However, mutation of rs9652490 within LINGO-1 was correlated with increased cerebellar atrophy (p = 0.001), reduced cerebellar hemisphere thickness (p = 0.025), and right cerebellar hemisphere longitudinal diameter (p = 0.047)., Conclusions: Our cohort indicated risk (female, positive family history of tremor, daily dosage > 1000 mg and treatment duration > 24 months of VPA) and protective factors (VPA magnesium-ER and combination with CBZ) of VPA-induced tremor. Mutation of rs9652490 within LINGO-1 correlated with cerebellar atrophy, neither was correlated with VPA-induced tremor., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The importance of integrative biobehavioral responses to complex challenges cannot be overlooked. In this study, the synergetic effects of icariin (a flavonoid present in the plant Epimedium brevicornum), natural enrichment (NaEn), and play behavior were investigated. Rats (n = 60) were assigned to standard housing or NaEn; these two groups were subsequently divided into controls, rats receiving icariin treatments, and rats receiving icariin and allowed to play with an individual from another cage. All rats were exposed to unpredictable mild stressors for 4 weeks. At the end of the treatment, a Forced Swim Task (FST) was conducted to assess emotional regulation during an inescapable acute challenge. Biological samples were collected weekly and before and after the FST to monitor endocrine changes. Corticosterone (CORT), dehydroepiandrosterone (DHEA), and testosterone (T) were assayed. We found that icariin had a significant effect on DHEA/CORT ratios and T levels. NaEn also had a significant effect on both CORT and DHEA, but not on T levels. Play did not appear to be significantly related to the endocrine changes. The strongest positive effects on emotional resilience were observed in NaEn rats that also received icariin. Our results confirmed that using multiple channels to stimulate adaptive responses can be effective in increasing the ability of an organism to face uncertainty. Considering how quickly our life can change due to unpredictable events, our data is instrumental to a better comprehension of the many aspects of integrative biobehavioral responses., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The use of sedatives or hypnotics and the recurrence of depression have not been adequately explored. This study investigated the roles of sedative-hypnotics in patients with major depressive disorder (MDD). Various characteristics of sedative-hypnotic use were tested as risk factors for recurrence., Methods: Clinical records of 15,510 patients with major depressive disorder who prescribed selective serotonin reuptake inhibitors (SSR) during 1997-2009 were collected from the National Health Insurance Research Database (NHIRD). Cox proportional hazard regression models were used to analyze factors related to depression recurrence., Results: The risk of MDD recurrence was lower for patients using SED/HYP with an indication of both anxiolytics and hypnotics (AHR = 0.66; 95% CI = 0.59-0.72) than for those using SED/HYP with an indication of anxiolytics only. AHR was slightly greater in current users than in recent users (AHR = 0.77; 95% CI = 0.72-0.83) and past users (AHR = 0.70; 95% CI = 0.67-0.74). There was a higher AHR of MDD recurrence in patients who used SED/HYP over 1 DDD in 1 month than those who used SED/HYP less than 1 DDD in 1 month, with the highest-dose users having the highest risk of MDD recurrence (AHR = 7.91; 95% CI = 6.86-9.11)., Conclusions: Patterns and characteristics of sedative-hypnotic use may affect depression recurrence. These findings should be considered by clinicians when combining sedative-hypnotics with antidepressant treatment.