Psilocybin history, action and reaction: A narrative clinical review.

Hallucinogenic mushrooms have been used in religious and cultural ceremonies for centuries. Of late, psilocybin, the psychoactive compound in hallucinogenic mushrooms, has received increased public interest as a novel drug for treating mood and substance use disorders (SUDs). In addition, in recent years, some states in the United States have legalized psilocybin for medical and recreational use. Given this, clinicians need to understand the potential benefits and risks related to using psilocybin for therapeutic purposes so that they can accurately advise patients. This expert narrative review summarizes the scientific basis and clinical evidence on the safety and efficacy of psilocybin-assisted therapy for treating psychiatric disorders and SUDs. The results of this review are structured as a more extensive discussion about psilocybin's history, putative mechanisms of action, and recent legislative changes to its legal status. There is modest evidence of psilocybin-assisted therapy for treating depression and anxiety disorders. In addition, early data suggest that psilocybin-assisted therapy may effectively reduce harmful drinking in patients with alcohol use disorders. The evidence further suggests psilocybin, when administered under supervision (psilocybin-assisted therapy), the side effects experienced are mild and transient. The occurrence of severe adverse events following psilocybin administration is uncommon. Still, a recent clinical trial found that individuals in the psilocybin arm had increased suicidal ideations and non-suicidal self-injurious behaviors. Given this, further investigation into the safety and efficacy of psilocybin-assisted therapy is warranted to determine which patient subgroups are most likely to benefit and which are most likely to experience adverse outcomes related to its use.

Clustering and Switching in Verbal Fluency Across Varying Degrees of Cognitive Control Demands: Evidence From Healthy Bilinguals and Bilingual Patients With Aphasia.

Different linguistic contexts place varying amounts of cognitive control on lexical retrieval in bilingual speakers, an issue that is complicated in bilingual patients with aphasia (BPWA) due to subsequent language and cognitive deficits. Verbal fluency tasks may offer insight into the interaction between executive and language control in healthy bilinguals and BPWA, by examining conditions with varying cognitive control demands. The present study examined switching and clustering in verbal fluency tasks in BPWA and healthy bilinguals across single- and dual-language conditions. We also examined the influence of language processing and language proficiency on switching and clustering performance across the dual-language conditions. Thirty-five Spanish-English BPWA and twenty-two Spanish-English healthy bilinguals completed a language use questionnaire, tests of language processing, and two verbal fluency tasks. The semantic category generation task included four conditions: two single-language conditions (No-Switch L1 and No-Switch L2) that required word production in each language separately; one dual-language condition that allowed switching between languages as desired (Self-Switch); and one dual-language condition that required switching between languages after each response (Forced-Switch). The letter fluency task required word production in single-language contexts. Overall, healthy bilinguals outperformed BPWA across all measures. Results indicate that switching is more sensitive to increased control demands than clustering, with this effect being more pronounced in BPWA, underscoring the interaction between semantic executive processes and language control in this group. Additionally, for BPWA switching performance relies on a combination of language abilities and language experience metrics.

Telerehabilitation for Word Retrieval Deficits in Bilinguals With Aphasia: Effectiveness and Reliability as Compared to In-person Language Therapy.

Background: Bilinguals with post-stroke aphasia (BWA) require treatment options that are sensitive to their particular bilingual background and deficits across languages. However, they may experience limited access to bilingual clinical resources due to reduced availability of bilingual practitioners, geographical constraints, and other difficulties. Telerehabilitation can improve access to bilingual clinical services for BWA and facilitate the delivery of specific language treatments at distance, but more evidence on its effectiveness and reliability is needed. This study aimed to determine the equivalence of effectiveness and reliability of a semantic treatment for word retrieval deficits in BWA delivered via telerehabilitation relative to in-person therapy. Methods: We examined the retrospective data of 16 BWA who received 20 sessions of therapy based on semantic feature analysis for word retrieval deficits in person (n = 8) or via telerehabilitation (n = 8). The two groups were comparable on age, years of education, time of post-stroke onset, aphasia severity, and naming ability in both languages. Treatment effectiveness (i.e., effect sizes in the treated and the untreated language, and change on secondary outcome measures) and reliability (i.e., clinician adherence to treatment protocol) were computed for each delivery modality and compared across groups. Results: Significant improvements were observed in most patients, with no significant differences in treatment effect sizes or secondary outcomes in the treated and the untreated language between the teletherapy group and the in-person therapy group. Also, the average percentage of correctly delivered treatment steps by clinicians was high for both therapy delivery methods with no significant differences between the telerehabilitation vs. the in-person modality. Discussion: This study provides evidence of the equivalence of treatment gains between teletherapy and in-person therapy in BWA and the high reliability with which treatment for word retrieval deficits can be delivered via telerehabilitation, suggesting that the essential treatment components of the intervention can be conducted in a comparable manner in both delivery modalities. We further discuss the benefits and potential challenges of the implementation of telerehabilitation for BWA. In the future, telerehabilitation may increase access to therapy for BWA with varying linguistic and cultural backgrounds, thus, offering a more inclusive treatment approach to this population.

Verbal fluency as a measure of lexical access and cognitive control in bilingual persons with aphasia.

BACKGROUND: Lexical access in bilinguals can be influenced by the demands that different interactional contexts pose on cognitive control processes (Green & Abutalebi, 2013: Adaptive Control Hypothesis; Green, 1998: Inhibitory Control Model). However, how varying cognitive control demands impact lexical access in bilingual persons with aphasia (BPWA) remains unclear. Verbal fluency tasks may provide valuable insights into the interplay between cognitive control and lexical access in BPWA by addressing word generation abilities in language contexts that exert varying degrees of cognitive control effort. AIMS: The present study aimed to examine the performance of BPWA on a semantic category generation task that required word retrieval in single and dual-language contexts under varying cognitive control demands and a traditional letter fluency task conducted in single-language contexts. We also examined the associations between verbal fluency performance and (i) bilingual language history, and (ii) performance on standardized language assessments in both BPWA and healthy bilinguals. METHODS AND PROCEDURES: Thirteen Spanish-English BPWA and twenty-two Spanish-English healthy bilinguals completed a language use questionnaire, verbal fluency testing and standardized language assessments in each language. The semantic category generation task included four conditions: two conditions examined word retrieval in the first-acquired (L1) and second-acquired language (L2) in single language contexts (No Switch-L1 and No Switch-L2) and two conditions elicited word retrieval in dual-language contexts (Self-Switch and Forced-Switch) with low and high cognitive control demands by allowing or restricting switching across languages. The letter fluency task was administered in single language contexts only (F, A, S for English and P, M, R for Spanish). Verbal fluency performance was compared across conditions and groups using multivariate analyses. Further, correlational analyses were used to examine associations between verbal fluency tasks and bilingual language history, language assessments, and cognitive function. OUTCOMES AND RESULTS: Overall, the healthy bilinguals produced a higher proportion of accurate words in both verbal fluency tasks relative to the BPWA. Results indicate that BPWA were more sensitive to the effects of increased cognitive control on lexical access relative to healthy bilinguals. BPWA and healthy bilinguals' performance on both verbal fluency tasks was associated with metrics of bilingual language history and standardized language assessments. Additionally, for BPWA, L2 letter fluency performance was associated with cognitive function. CONCLUSIONS: Our findings suggest that verbal fluency tasks can help characterize the impact of cognitive control on lexical access in BPWA in single and mixed language contexts with important clinical implications.

Predicting treatment outcomes for bilinguals with aphasia using computational modeling: Study protocol for the PROCoM randomised controlled trial.

INTRODUCTION: Bilinguals with aphasia (BWA) present varying degrees of lexical access impairment and recovery across their two languages. Because both languages may benefit from therapy, identifying the optimal target language for treatment is a current challenge for research and clinical practice. Prior research has demonstrated that the BiLex computational model can accurately simulate lexical access in healthy bilinguals, and language impairment and treatment response in bilingual aphasia. Here, we aim to determine whether BiLex can predict treatment outcomes in BWA in the treated and the untreated language and compare these outcome predictions to determine the optimal language for rehabilitation. METHODS AND ANALYSIS: The study involves a prospective parallel-group, double-blind, randomised controlled trial. Forty-eight Spanish-English BWA will receive 20 sessions of semantic treatment for lexical retrieval deficits in one of their languages and will complete assessments in both languages prior and after treatment. Participants will be randomly assigned to an experimental group receiving treatment in the optimal language determined by the model or a control group receiving treatment in the language opposite to the model's recommendation. Primary treatment outcomes include naming probes while secondary treatment outcomes include tests tapping additional language domains. Treatment outcomes will be compared across the two groups using 2×2 mixed effect models for repeated measures Analysis of variance (ANOVA) on metrics of treatment effects commonly employed in rehabilitation studies (ie, effect size and percentage change). ETHICS AND DISSEMINATION: All procedures included in this protocol (protocol number 29, issue date: 19 March 2019) were approved by the Boston University Charles River Campus Institutional Review Board at Boston, Massachusetts (reference number: 4492E). The results of this study will be published in peer-reviewed scientific journals and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02916524.

CYP2D6 genotype in relation to perphenazine concentration and pituitary pharmacodynamic tissue sensitivity in Asians: CYP2D6-serotonin-dopamine crosstalk revisited.

OBJECTIVES: Hyperprolactinemia is a common side effect of first-generation antipsychotics mediated by antagonism of dopaminergic neurotransmission in the pituitary. Most first-generation antipsychotics are metabolized by CYP2D6 in the liver. Further, CYP2D6 is expressed in the human brain as a 5-methoxyindolethylamine O-demethylase potentially contributing to regeneration of serotonin from 5-methoxytryptamine. As dopaminergic neurotransmission is subject to regulation by serotonin, CYP2D6 may exert a nuanced (serotonergic) influence on dopaminergic tone in the pituitary. CYP2D6*10 is an allele associated with reduced enzyme function and occurs in high frequency (about 50%) in Asians. We prospectively evaluated significance of CYP2D6 genetic variation for prolactin response to perphenazine (a model first-generation antipsychotic) in Asians. METHODS: A single oral dose of perphenazine (0.1 mg/kg) or placebo was administered to 22 medication-free nonsmoker healthy male Chinese-Canadian volunteers, following a double-blind within-subject randomized design. Blood samples were drawn at baseline and 2, 3, 4, 5 and 6 h after drug administration. RESULTS: In volunteers with CYP2D6*10/CYP2D6*10 genotype, the mean area under curve (AUC0-6) for perphenazine concentration was 2.9-fold higher than those who carry the CYP2D6*1 allele (P<0.01). Notably, volunteers homozygous for CYP2D6*10 exhibited a significant reduction (66%) in mean pharmacodynamic tissue sensitivity as measured by the (prolactin-AUC0-6/perphenazine-AUC0-6) ratio (P=0.02). CONCLUSIONS: CYP2D6 genotype is a significant contributor to perphenazine concentration in Chinese-Canadians. Importantly, prolactin response, when normalized per unit perphenazine concentration, appears to be blunted in volunteers homozygous for CYP2D6*10. We suggest that CYP2D6 genetic variation may potentially influence pharmacodynamic tissue sensitivity in the pituitary, presumably through disposition of an endogenous substrate (e.g. 5-methoxytryptamine).