Efficacy and safety of psychedelics for the treatment of mental disorders: A systematic review and meta-analysis.

We aim to systematically review and meta-analyze the effectiveness and safety of psychedelics [psilocybin, ayahuasca (active component DMT), LSD and MDMA] in treating symptoms of various mental disorders. Web of Science, Embase, EBSCO, and PubMed were searched up to February 2024 and 126 articles were finally included. Results showed that psilocybin has the largest number of articles on treating mood disorders (N = 28), followed by ayahuasca (N = 7) and LSD (N = 6). Overall, psychedelics have therapeutic effects on mental disorders such as depression and anxiety. Specifically, psilocybin (Hedges' g = -1.49, 95% CI [-1.67, -1.30]) showed the strongest therapeutic effect among four psychedelics, followed by ayahuasca (Hedges' g = -1.34, 95% CI [-1.86, -0.82]), MDMA (Hedges' g = -0.83, 95% CI [-1.33, -0.32]), and LSD (Hedges' g = -0.65, 95% CI [-1.03, -0.27]). A small amount of evidence also supports psychedelics improving tobacco addiction, eating disorders, sleep disorders, borderline personality disorder, obsessive-compulsive disorder, and body dysmorphic disorder. The most common adverse event with psychedelics was headache. Nearly a third of the articles reported that no participants reported lasting adverse effects. Our analyses suggest that psychedelics reduce negative mood, and have potential efficacy in other mental disorders, such as substance-use disorders and PTSD.

Patient-centered and integrated outreach care for chronic hepatitis C patients with serious mental illness in Taiwan.

Patients with serious mental illness have a higher risk of hepatitis C virus (HCV) infection but suboptimal HCV care. The current study aimed to facilitate HCV treatment uptake by implementing an integrated outreach care model. Multidisciplinary outreach screening followed by HCV reflex testing and onsite treatment for schizophrenia patients was accomplished through the coordination of nongovernmental organizations, remote specialists, and local care providers. The objective was microelimination effectiveness, defined as the multiplication of the rates of anti-HCV antibodies screening, accurate HCV RNA diagnosis, treatment allocation, treatment completion, and sustained virological response (SVR12; no detectable HCV RNA throughout 12 weeks in the post-treatment follow-up period). A total of 1478 of the 2300 (64.3%) psychiatric patients received HCV mass screening. Seventy-three (4.9%) individuals were seropositive for anti-HCV antibodies. Of the 73 anti-HCV seropositive patients, all (100%) received HCV reflex testing, and 29 (37.7%) patients had HCV viremia. Eight patients (34.8%) had advanced liver disease, including 3 with liver cirrhosis and 2 with newly diagnosed hepatocellular carcinoma. Twenty-three of the 24 (95.8%) patients who stayed in the healthcare system received and completed 8 weeks of glecaprevir/pibrentasvir treatment and post-treatment follow-up without significant DDIs or adverse events. The SVR12 rate was 100%. The microelimination effectiveness in the current study was 61.6%. Individuals with serious mental illness are underserved and suffer from diagnostic delays. This patient-centered and integrated outreach program facilitated HCV care in this marginalized population.

Drug-induced psychiatric disorders: A pharmacovigilance update.

The psychiatric risks associated with drugs are sometimes one of the few restrictions on the use of certain drug classes, such as corticosteroids in patients with a history of severe psychotic episodes associated with this drug class. In this non-exhaustive review, we propose to deal with the most recent issues concerning psychiatric disorders induced by drugs and encountered in doctors' clinical practice. Firstly, we look at depressive disorders and suicide risks, secondly at psychotic and manic disorders and thirdly at anxiety and sleep disorders. While lot of drugs are associated with psychiatric disorders, the confounding by indication represents an important methodological gap since information on the psychiatric profile of patients is not always available. This is particularly the case for serotonin reuptake inhibitors and esketamine used as antidepressants. Recent pharmacovigilance concerns of psychiatric disorders emerged with montelukast, orexin receptor antagonists or cystic fibrosis transmembrane regulator (CFTR) modulators.

Indicators of occupational pesticide exposure are associated with psychiatric symptoms.

In southeastern Spain, intensive and highly productive agriculture under plastic also poses a risk to human health, as evidenced by reports on acute pesticide poisoning and its effects on mental health. However, knowledge of chronic exposures and their relationship to psychiatric disorders is still limited. This study analyzed the relationship between occupational exposure to pesticides and psychiatric disorders in farmers from Almería. A cross-sectional study was conducted amongst a coastal population in Almería, where over 32,800 ha of land are dedicated to intensive agriculture in plastic greenhouses. A total of 409 people participated in the study: 203 farmers and 206 control subjects. The highest risk of psychiatric disorders was observed in farmers living in areas of high exposure to pesticides, working in greenhouses (intensive agriculture), without protective goggles and without wearing masks. This study supports previous evidence of an elevated risk of psychiatric disorders among farm workers exposed to pesticides.

Clinical pharmacokinetics of antipsychotics in pediatric populations: a scoping review focusing on dosing regimen.

INTRODUCTION: Achieving optimal clinical responses and minimizing side effects through precision dosing of antipsychotics in children and adolescents with psychiatric disorders remains a challenge. Identifying patient characteristics (covariates) that affect pharmacokinetics can inform more effective dosing strategies and ultimately improve patient outcomes. This review aims to provide greater insight into the impact of covariates on the clinical pharmacokinetics of antipsychotics in pediatric populations. AREAS COVERED: A comprehensive literature search was conducted, and the main findings regarding the effects of the covariates on the pharmacokinetics of antipsychotics in children and adolescents are presented. EXPERT OPINION: Our study highlights significant covariates, including age, sex, weight, CYP2D6 phenotype, co-medication, and smoking habits, which affect the pharmacokinetics of antipsychotics. However, the findings were generally limited by the small sample sizes of naturalistic, open-label, observational studies, and the homogeneous subgroups. Dosing based on weight and preemptive genotyping could prove beneficial for optimizing the dosing regimen in pediatric populations. Future research is needed to refine dosing recommendations and establish therapeutic reference ranges critical for precision dosing and Therapeutic Drug Monitoring (TDM). The integration of individual patient characteristics with TDM can further optimize the efficacy and safety of antipsychotics for each patient.

Understanding Stimulant Use and Use Disorders in a New Era.

Extending from the triple wave epidemic of opioid-related overdose deaths, a fourth wave of high mortality involving methamphetamine and cocaine use has been gathering force. This article provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments.

Mitochondria and Antibiotics: For Good or for Evil?

The discovery and application of antibiotics in the common clinical practice has undeniably been one of the major medical advances in our times. Their use meant a drastic drop in infectious diseases-related mortality and contributed to prolonging human life expectancy worldwide. Nevertheless, antibiotics are considered by many a double-edged sword. Their extensive use in the past few years has given rise to a global problem: antibiotic resistance. This factor and the increasing evidence that a wide range of antibiotics can damage mammalian mitochondria, have driven a significant sector of the medical and scientific communities to advise against the use of antibiotics for purposes other to treating severe infections. Notwithstanding, a notorious number of recent studies support the use of these drugs to treat very diverse conditions, ranging from cancer to neurodegenerative or mitochondrial diseases. In this context, there is great controversy on whether the risks associated to antibiotics outweigh their promising beneficial features. The aim of this review is to provide insight in the topic, purpose for which the most relevant findings regarding antibiotic therapies have been discussed.

Aspartame-True or False? Narrative Review of Safety Analysis of General Use in Products.

Aspartame is a sweetener introduced to replace the commonly used sucrose. It was discovered by James M. Schlatter in 1965. Being 180-200 times sweeter than sucrose, its intake was expected to reduce obesity rates in developing countries and help those struggling with diabetes. It is mainly used as a sweetener for soft drinks, confectionery, and medicines. Despite its widespread use, its safety remains controversial. This narrative review investigates the existing literature on the use of aspartame and its possible effects on the human body to refine current knowledge. Taking to account that aspartame is a widely used artificial sweetener, it seems appropriate to continue research on safety. Studies mentioned in this article have produced very interesting results overall, the current review highlights the social problem of providing visible and detailed information about the presence of aspartame in products. The studies involving the impact of aspartame on obesity, diabetes mellitus, children and fetus, autism, neurodegeneration, phenylketonuria, allergies and skin problems, its cancer properties and its genotoxicity were analyzed. Further research should be conducted to ensure clear information about the impact of aspartame on health.

Neuroprotective effect of hesperidin against emamectin benzoate-induced neurobehavioral toxicity in rats.

Emamectin Benzoate (EMB) is an avermectin insecticide widely used in agriculture and veterinary medicine. Hesperidin (HSP) is a flavanone glycoside predominantly found in citrus fruits and has various beneficial health effects. The current research was conducted to study the neurobehavioral toxic effects of EMB in rats and also to evaluate the protective effect of HSP against these toxic effects. Sixty Sprague-Dawley rats were randomly divided into 4 equal groups: control group, EMB group, HSP group, and EMB + HSP group. EMB (8.8. mg/kg) and/or HSP (100 mg/kg) were administered daily by gavage for 8 weeks. The behavioral assessment demonstrated the adverse effects of EMB on the behavioral, motor, and cognitive brain functions. Exposure to EMB also decreased the activity of antioxidants (catalase and reduced glutathione) and increased the malondialdehyde level in nervous tissue. Moreover, EMB increased the level of inflammatory cytokines (tumor necrosis factor-α and interleukin-1ß) and decreased brain-derived neurotrophic factor (BDNF) levels in rats' brains. On the other hand, concurrent administration of HSP ameliorated the toxic effects of EMB as indicated by improvements in neural functions and reduction of oxidative stress and inflammation. The study concluded that exposure to EMB induces toxic effects in the brain of rats and that HSP has a protective effect against these toxic effects.

Pharmacological treatment during CoViD-19 and mental health issues.

Infection outbreak has been prevalent since previous decades. The impact of infection outbreak not merely limited to physical suffering but grounded for massive mental health issues. The fear of getting contagion and persistent exposure to diverse medication and vaccination contribute enormously to develop mental health issues among people. During previous infection treatment with diverse vaccination and antiviral agent, the common mental health issues found to be a mood disorder, delirium, schizophrenia, and psychotic symptoms. Cumbersomely, it is almost impossible to treat mental health issues during the pandemic with the help of only pharmacological availability. Hence psychological intervention is also important to ameliorate better consequences. The current study highlights the impact of CoViD-19 related diverse medication and vaccination on the mental health of the people.

Evaluation of severe hypoglycemia and common mental disorders in patients receiving insulin analogues for treatment of type 1 diabetes

ABSTRACT This is a retrospective report of the frequency of severe hypoglycemia and the association between common mental disorders and type 1 diabetes mellitus treated with insulin analogues. Patients with severe hypoglycemia compared with those without this complication had a higher prevalence of positive screening for common mental disorders (88% vs.77%, respectively, p = 0.03).

Albumin-bilirubin score for predicting neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy.

WHAT IS KNOWN AND OBJECTIVE: Ifosfamide, an alkylating agent, is widely used in the treatment of malignant diseases. However, these treatments are often limited due to the incidence of neuropsychiatric symptoms such as delirium, seizures, hallucinations and agitation. In this study, we examined risk factors for neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy. METHODS: The study cases were patients with cancer receiving ifosfamide-based chemotherapy between April 2007 and March 2018. Risk analysis for ifosfamide-related neuropsychiatric symptoms was determined by time-dependent Cox proportional hazard regression analysis. RESULTS AND DISCUSSION: Of 183 eligible patients, 32 patients (17.5%) experienced ifosfamide-related neuropsychiatric symptoms. Time-dependent Cox proportional hazard model showed that the albumin-bilirubin (ALBI) score was significantly correlated with the incidence of ifosfamide-related neuropsychiatric symptoms (hazard ratio [HR] =1.45, 95% confidence interval [CI] = 1.05-2.01, p = 0.025). Additionally, there were correlations between the predicted risk of neuropsychiatric symptoms and ifosfamide-dose per cycle (HR =0.51, 95% CI = 0.27-0.94, p = 0.030) and creatinine clearance (Ccr) (HR = 0.53, 95% CI = 0.28-1.00, p = 0.050). In contrast, neither serum albumin nor total bilirubin was a significant risk factor for neuropsychiatric symptoms. WHAT IS NEW AND CONCLUSION: These findings indicate that ALBI score may be a useful biomarker for predicting neuropsychiatric symptoms in patients receiving ifosfamide-based chemotherapy.

Psychiatric Disorders and Hydroxychloroquine for Coronavirus Disease 2019 (COVID-19): A VigiBase Study.

INTRODUCTION: In the stressful context of the coronavirus disease 2019 (COVID-19) pandemic, some reports have raised concerns regarding psychiatric disorders with the use of hydroxychloroquine. In this study, we reviewed all psychiatric adverse effects with hydroxychloroquine in COVID-19 patients, as well as in other indications, reported in VigiBase, the World Health Organization's (WHO) global database of individual case safety reports. METHODS: First, we analyzed all psychiatric adverse effects, including suicide, of hydroxychloroquine in COVID-19 patients reported to 16 June 2020. We also performed disproportionality analysis to investigate the risk of reporting psychiatric disorders with hydroxychloroquine compared with remdesivir, tocilizumab, or lopinavir/ritonavir prescribed in COVID-19 patients. We used reporting odds ratios (RORs) and their 95% confidence intervals (CIs) to calculate disproportionality. Second, we sought to examine the psychiatric safety profile of hydroxychloroquine in other indications (before 2020). RESULTS: Among the 1754 reports with hydroxychloroquine in COVID-19 patients, we found 56 psychiatric adverse effects. Half of these adverse effects were serious, including four completed suicides, three cases of intentional self-injury, and 12 cases of psychotic disorders with hallucinations. Compared with remdesivir, tocilizumab, or lopinavir/ritonavir, the use of hydroxychloroquine was associated with an increased risk of reporting psychiatric disorders (ROR 6.27, 95% CI 2.74-14.35). Before 2020, suicide was the main cause of death among all adverse drug reactions reported with hydroxychloroquine, followed by cardiac adverse effects (cardiomyopathy) and respiratory failure. CONCLUSIONS: This pharmacovigilance analysis suggests that COVID-19 patients exposed to hydroxychloroquine experienced serious psychiatric disorders, and, among these patients, some committed suicide. Further real-world studies are needed to quantify the psychiatric risk associated with hydroxychloroquine during the COVID-19 pandemic.

Dopamine agonists and antipsychotics.

There can potentially be a number of clinical interactions that could adversely affect patient outcomes in a patient with a prolactinoma and psychiatric disease that might require antipsychotic and dopamine agonist treatment. Dopamine agonists stimulate the dopamine D2 receptor, resulting in a decrease in prolactin (PRL) levels and in prolactinoma size but action on dopamine receptors in the meso-limbic system may rarely cause psychosis and more commonly cause impulse control disorders. The psychiatric benefits of antipsychotic agents involve blocking the D2 and other dopamine receptors but this blockade often also causes hyperprolactinemia. In patients with macroprolactinomas and psychosis, observation, estrogen/progestin replacement, and surgery can be considered in addition to dopamine agonists. In those who require dopamine agonists for PRL and tumor size control, the introduction of antipsychotics may blunt this effect, so that higher doses of the dopamine agonists may be needed. Alternatively, antipsychotics that have less of a blocking effect at the D2 receptor, such as aripiprazole, can be tried, if appropriate. For patients already on antipsychotic drugs who are found to have a macroprolactinoma for which dopamine agonists are required, dopamine agonists can be initiated at low dose and the dose escalated slowly. However, such patients require careful monitoring of psychiatric status to avoid the rare complication of exacerbation of the underlying psychosis. Again, if appropriate, use of antipsychotics that have less of a blocking effect at the D2 receptor may allow lower doses of dopamine agonists to be used in this situation.

Post-finasteride syndrome

Abstract Finasteride is a 5α-reductase enzyme inhibitor that has been approved for the treatment of male androgenic alopecia since 1997. Over time, it has been considered a safe and well-tolerated drug with rare and reversible side effects. Recently there have been reports of adverse drug-related reactions that persisted for at least three months after discontinuation of this drug, and the term post-finasteride syndrome arose. It includes persistent sexual, neuropsychiatric, and physical symptoms. Studies to date cannot refute or confirm this syndrome as a nosological entity. If it actually exists, it seems to occur in susceptible people, even if exposed to small doses and for short periods, and symptoms may persist for long periods. Based on currently available data, the use of 5α-reductase inhibitors in patients with a history of depression, sexual dysfunction, or infertility should be carefully and individually assessed.

Long-Term Effects of Intrauterine Exposure to Antidepressants on Physical, Neurodevelopmental, and Psychiatric Outcomes: A Systematic Review.

OBJECTIVE: Reviews on child outcomes following in utero antidepressant exposure have focused on short-term outcomes. However, several recent individual studies reported on adverse physical, neurodevelopmental, and psychiatric outcomes beyond infancy and early childhood. The objective of this systematic review was to establish the long-term effects of prenatal antidepressant exposure on physical, neurodevelopmental, and psychiatric outcomes in individuals aged 4 years and older. DATA SOURCES: Embase, MEDLINE Ovid, Web of Science, Cochrane Central, and Google Scholar were systematically searched for all relevant articles, written in English and published prior to November 8, 2018, using terms describing antidepressants, pregnancy, and developmental outcomes. STUDY SELECTION: All original research articles on long-term outcomes of prenatal antidepressant exposure were eligible for inclusion. After screening and removal of duplicates, a total of 34 studies were identified. DATA EXTRACTION: Included articles were qualitatively analyzed to determine inconsistency, indirectness, imprecision, and study bias. RESULTS: The identified studies demonstrated statistically significant associations between prenatal antidepressant exposure and a range of physical, neurodevelopmental, and psychiatric outcomes. Yet, the risk of confounding by indication was high. When controlling for confounders, 5 studies investigating physical outcomes (asthma, cancer, body mass index [BMI], epilepsy) found no association except conflicting outcomes for BMI. Eighteen studies examining neurodevelopmental outcomes (cognition, behavior, IQ, motor development, speech, language, and scholastic outcomes) found no consistent associations with antidepressant exposure after taking confounders into account. Eleven studies investigated psychiatric outcomes. After adjusting for confounders, prenatal antidepressant exposure was associated with affective disorders but not with childhood psychiatric outcomes (eg, autism spectrum disorders, attention-deficit/hyperactivity disorder). CONCLUSIONS: Reported associations between in utero exposure to antidepressants and physical, neurodevelopmental, and psychiatric outcomes, in large part, seem to be driven by the underlying maternal disorder. When limiting confounding by indication, prenatal exposure to antidepressants was significantly associated only with offspring BMI and affective disorders.

Psychopharmacology of COVID-19.

Background: With the rapid, global spread of severe acute respiratory syndrome coronavirus 2, hospitals have become inundated with patients suffering from coronavirus disease 2019. Consultation-liaison psychiatrists are actively involved in managing these patients and should familiarize themselves with how the virus and its proposed treatments can affect psychotropic management. The only Food and Drug Administration-approved drug to treat COVID-19 is remdesivir, and other off-label medications used include chloroquine and hydroxychloroquine, tocilizumab, lopinavir/ritonavir, favipiravir, convalescent plasma therapy, azithromycin, vitamin C, corticosteroids, interferon, and colchicine. Objective: To provide an overview of the major safety considerations relevant to clinicians who prescribe psychotropics to patients with COVID-19, both related to the illness and its proposed treatments. Methods: In this targeted review, we performed structured literature searches in PubMed to identify articles describing the impacts of COVID-19 on different organ systems, the neuropsychiatric adverse effects of treatments, and any potential drug interactions with psychotropics. The articles most relevant to this one were included. Results: COVID-19 impacts multiple organ systems, including gastrointestinal, renal, cardiovascular, pulmonary, immunological, and hematological systems. This may lead to pharmacokinetic changes that impact psychotropic medications and increase sensitivity to psychotropic-related adverse effects. In addition, several proposed treatments for COVID-19 have neuropsychiatric effects and potential interactions with commonly used psychotropics. Conclusions: Clinicians should be aware of the need to adjust existing psychotropics or avoid using certain medications in some patients with COVID-19. They should also be familiar with neuropsychiatric effects of medications being used to treat this disease. Further research is needed to identify strategies to manage psychiatric issues in this population.

[Informations on psychotropics and their adaptations for patients suffering from mental disorders in France during the SARS-CoV-2 epidemic]. / Informations relatives aux psychotropes et à leurs adaptations éventuelles pour les patients souffrant de troubles psychiques en France pendant l'épidémie à SARS-CoV-2.

The 2019-20 coronavirus pandemic (SARS-CoV-2; severe acute respiratory syndrome coronavirus 2) has dramatic consequences on populations in terms of morbidity and mortality and in social terms, the general confinement of almost half of the world's population being a situation unprecedented in history, which is difficult today to measure the impact at the individual and collective levels. More specifically, it affects people with various risk factors, which are more frequent in patients suffering from psychiatric disorders. Psychiatrists need to know: (i) how to identify, the risks associated with the prescription of psychotropic drugs and which can prove to be counterproductive in their association with COVID-19 (coronavirus disease 2019), (ii) how to assess in terms of benefit/risk ratio, the implication of any hasty and brutal modification on psychotropic drugs that can induce confusion for a differential diagnosis with the evolution of COVID-19. We carried out a review of the literature aimed at assessing the specific benefit/risk ratio of psychotropic treatments in patients suffering from COVID-19. Clinically, symptoms suggestive of COVID-19 (fever, cough, dyspnea, digestive signs) can be caused by various psychotropic drugs and require vigilance to avoid false negatives and false positives. In infected patients, psychotropic drugs should be used with caution, especially in the elderly, considering the pulmonary risk. Lithium and Clozapine, which are the reference drugs in bipolar disorder and resistant schizophrenia, warrant specific attention. For these two treatments the possibility of a reduction in the dosage - in case of minimal infectious signs and in a situation, which does not allow rapid control - should ideally be considered taking into account the clinical response (even biological; plasma concentrations) observed in the face of previous dose reductions. Tobacco is well identified for its effects as an inducer of CYP1A2 enzyme. In a COVID+ patient, the consequences of an abrupt cessation of smoking, particularly related with the appearance of respiratory symptoms (cough, dyspnea), must therefore be anticipated for patients receiving psychotropics metabolized by CYP1A2. Plasma concentrations of these drugs are expected to decrease and can be related to an increase risk of relapse. The symptomatic treatments used in COVID-19 have frequent interactions with the most used psychotropics. If there is no curative treatment for infection to SARS-CoV-2, the interactions of the various molecules currently tested with several classes of psychotropic drugs (antidepressants, antipsychotics) are important to consider because of the risk of changes in cardiac conduction. Specific knowledge on COVID-19 remains poor today, but we must recommend rigor in this context in the use of psychotropic drugs, to avoid adding, in patients suffering from psychiatric disorders, potentially vulnerable in the epidemic context, an iatrogenic risk or loss of efficiency.

Imatinib in combination with phosphoinositol kinase inhibitor buparlisib in patients with gastrointestinal stromal tumour who failed prior therapy with imatinib and sunitinib: a Phase 1b, multicentre study.

BACKGROUND: The majority of patients with advanced gastrointestinal stromal tumours (GISTs) develop resistance to imatinib and sunitinib, the standard of care for these patients. This study evaluated the combination of buparlisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, with imatinib in patients with advanced GIST, who have failed prior therapy with imatinib and sunitinib. METHODS: This Phase 1b, multicentre, open-label study aimed to determine the maximum tolerated dose (MTD) and/or a recommended Phase 2 dose of buparlisib in combination with 400 mg of imatinib through a dose-escalation part and a dose-expansion part, and also evaluated the clinical profile of the combination. RESULTS: Sixty patients were enrolled, including 25 in the dose-escalation part and 35 in the dose-expansion part. In the combination, MTD of buparlisib was established as 80 mg. No partial or complete responses were observed. The estimated median progression-free survival was 3.5 months in the expansion phase. Overall, 98.3% of patients had treatment-related adverse events (AEs), including 45% with grade 3 or 4 AEs. CONCLUSIONS: Buparlisib in combination with imatinib provided no additional benefit compared with currently available therapies. Due to the lack of objective responses, further development of this combination was not pursued for third-line/fourth-line advanced/metastatic GIST. TRIAL REGISTRATION NUMBER: NCT01468688.

Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex-stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long-term problems with learning may be related to residual posttreatment brain differences.