The effects of ketamine and classic hallucinogens on neurotrophic and inflammatory markers in unipolar treatment-resistant depression: a systematic review of clinical trials.

Although results are still preliminary, ketamine and classical hallucinogens have shown promise in recent years as novel, fast-acting antidepressants, especially for the treatment of unipolar treatment-resistant depression (TRD). Depression also seems to be related to abnormal levels of peripheral inflammatory and neurotrophic biomarkers, which may one day help to diagnose of this disorder. In this context, this systematic review of clinical trials evaluated the current evidence that relates the antidepressant effects of ketamine and classical hallucinogens on TRD with changes in inflammatory and neurotrophic biomarkers. Twelve studies were found (n = 587), 2 with oral ayahuasca (1 mL/kg) and 10 with ketamine (mostly intravenous 0.5 mg/kg) administration. Results for all biomarkers assessed were contradictory and thus inconclusive. Randomized controlled trials with bigger samples and higher statistical power are warranted to clarify if peripheral biomarkers can confidently be used to indicate and measure ketamine's and classical hallucinogens' antidepressant effect. The PROSPERO ID for this study is CRD42021249089.

Cannabidiol reverses memory impairments and activates components of the Akt/GSK3ß pathway in an experimental model of estrogen depletion.

Clinical and preclinical evidence has indicated that estrogen depletion leads to memory impairments and increases the susceptibility to neural damage. Here, we have sought to investigate the effects of Cannabidiol (CBD) a non-psychotomimetic compound from Cannabis sativa, on memory deficits induced by estrogen depletion in rats, and its underlying mechanisms. Adult rats were subjected to bilateral ovariectomy, an established estrogen depletion model in rodents, or sham surgery and allowed to recover for three weeks. After that, they received daily injections of CBD (10 mg/kg) for fourteen days. Rats were tested in the inhibitory avoidance task, a type of emotionally-motivated memory. After behavioral testing they were euthanized, and their hippocampi were isolated for analysis of components of the Akt/GSK3ß survival pathway and the antiapoptotic protein Bcl2. Results revealed that ovariectomy impaired avoidance memory, and CBD was able to completely reverse estrogen depletion-induced memory impairment. Ovariectomy also reduced Akt/GSK3ß pathway's activation by decreasing the phosphorylation levels of Akt and GSK3ß and Bcl2 levels, which were ameliorated by CBD. The present results indicate that CBD leads to a functional recovery accompanied by the Akt/GSK3ß survival pathway's activation, supporting its potential as a treatment for estrogen decline-induced deterioration of neural functioning and maintenance.

Essential oil-based dispersive liquid-liquid microextraction for the determination of N,N-dimethyltryptamine and ß-carbolines in human plasma: A novel solvent-free alternative.

The present study describes the development of a novel solvent-free vortex-assisted dispersive liquid-liquid microextraction alternative based on a natural essential oil as extracting solvent (VA-EO-DLLME) for the determination of N,N-dimethyltryptamine (DMT), harmine (HRM), harmaline (HRL) and tetrahydroarmine (THH) (compounds found in the ayahuasca tea, a psychedelic plant preparation) in human plasma. After optimization through full factorial and Box-Behnken experimental designs, this VA-EO-DLLME followed by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) was completely validated and applied to authentic plasma specimens. Sample preparation consisted in the addition of 60 mg of NaCl, 100 µL of borate buffer and 100 µL of Eucalyptus globulus essential oil to a 200 µL aliquot of human plasma. After 30 s of vortex agitation followed by 5 min of centrifugation (10,000 rpm), 80 µL of the oil supernatant was dried and resuspended in mobile phase prior to injection into the UHPLC-MS/MS system. Once optimized, the validated method yielded LoDs ≤1.0 ng mL-1 for all analytes. LoQ was 1.0 ng mL-1 for DMT, HRL and HRM and 2.0 ng mL-1 for THH. The method has shown to be linear over the range of LoQ up to 150 ng mL-1 (r2 ≥ 0.9926). Intra/inter-day precision and accuracy met the acceptance criteria at three quality control (QC) levels. An additional intermediate precision study demonstrated that, except for THH and HRL at low and medium QCs, the overall method performance was similar for the three different oil sources. Matrix effect evaluation showed predominant ion suppression, ranging from 56% to 83%. Recovery varied from 33 up to 101% with an average of 50 ± 15.8%. Selectivity studies showed no interferences. Analysis of 13 authentic samples proved method feasibility. Finally, we believe that our novel VA-EO-DLLME approach offers a very simple, fast, cost-effective and eco-friendly alternative based on the use of an easily accessible and entirely green material as an extracting solvent. This may represent an incentive for researchers to investigate novel and creative alternatives, such as essential oils, as substitutes of organic solvents for microextraction methods in forensic and clinical contexts.

Polypharmacology or "Pharmacological Promiscuity" In Psychedelic Research: What Are We Missing?

Research with psychedelic drugs has mainly focused on isolated compounds. However, this approach is challenged by the "polypharmacology" paradigm. In this Viewpoint, we suggest that we may be missing something if we do not use the whole product in the case of ayahuasca or Psilocybe mushrooms. After describing how research on psychedelic drugs can be effectively combined with the polypharmacology paradigm, ethical issues are also briefly discussed.

Serotonergic hallucinogens/psychedelics could be promising treatments for depressive and anxiety disorders in end-stage cancer.

In a recent issue of the BMC Psychiatry, the evidence of effectiveness of treatments for psychiatric conditions in end-stage cancer patients was reviewed (Johnson, 2018). The review was comprehensive, and included traditional and non-traditional/alternative treatments, including herbal medicines and spirituality. However, evidence showing that classic or serotonergic hallucinogens/psychedelics such as psilocybin and lysergic acid diethylamide (LSD) could be effective treatments for depressive and anxiety disorders in end-stage cancer was not included. In this commentary, we expand the information available on the original article by briefly reviewing data from recent placebo-controlled, double-blind, cross-over clinical trials showing evidence that administration of single (or few) doses of LSD and psilocybin was associated with rapid and sustained reductions in depressive and anxiety symptoms in patients with end-stage cancer and other life-threatening diseases (e.g., Bechterew's disease, Parkinson's disease, Celiac disease). Since these substances seem to produce rapid and sustained therapeutic effects with single (or few) doses and well tolerated, large-scale, prospective, multi-site studies of end-stage cancer and classical/serotonergic hallucinogens/psychedelics should be performed to improve our understanding of the therapeutic potentials of these drugs and their use on clinical practice.

Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews.

INTRODUCTION: Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) have anxiolytic, antidepressive, and antiaddictive effects. Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included. Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open label, and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.

Long-term effects of ayahuasca in patients with recurrent depression: a 5-year qualitative follow-up

Background Ayahuasca is a botanical hallucinogenic preparation traditionally used by indigenous populations of Northwestern Amazonian countries for ritual and therapeutic purposes. It is rich in β-carboline alkaloids and N,N-dimethyltryptamine (DMT). Preclinical, observational, and experimental studies suggest that ayahuasca and its alkaloids have anxiolytic and antidepressive effects. We recently reported in an open-label trial that ayahuasca administration was associated with significant decreases in depression symptoms for 2-3 weeks after the experimental session in 17 patients with treatment-resistant major depressive disorder. Objectives To investigate if the experiment had any long-lasting effects on patients Methods Eight patients were interviewed 4 to 7 years after ayahuasca intake. Results Our results suggest that ayahuasca was well tolerated and that symptom reductions were limited to a few weeks. Importantly, most patients believed that the experience was among the most important of their lives, even 4-7 years later. Discussion To the best of our knowledge, this is the first long-term follow-up of a clinical sample that participated in an ayahuasca trial. Further studies with different and repeated dosing should be designed to further explore the antidepressive and anxiolytic effects of ayahuasca.

Effects of sodium nitroprusside in the prevention of schizophrenia-like symptoms induced by ketamine - A translational double-blind study

Abstract Background: Recent evidence has shown improvements in schizophrenia symptoms after the infusion of sodium nitroprusside (SNP), a nitric oxide (NO) donor. In the rat model of schizophrenia using ketamine injection, pretreatment with SNP seems to prevent behavioral changes associated with positive symptoms for up to one week. Objective: We investigated whether SNP would have preventative effects on psychogenic symptoms induced by ketamine in healthy subjects. Methods: Healthy subjects (N = 38) were assigned to distinct groups that received SNP in different doses (0.15, 0.25, and 0.5 mcg/kg/min). First, participants received an infusion of SNP or placebo over 75 minutes. After 10 minutes, they were injected for 1 minute with a bolus of 0.26 mg/kg of ketamine and a maintenance dose was started 5 minutes later, with 0.25 mg/kg/h of ketamine for 50 minutes. Results: Ketamine-induced psychopathological alterations induced were reduced by SNP, as assessed with the Brief Psychological Rating Scale. Scores in the objective subscale of the Clinician-Administered Dissociative States Scale were also lower in SNP sessions compared to placebo. SNP had protective effects against deterioration in facial emotion and identity recognition tasks induced by ketamine. Discussion: Our findings support the view that SNP has preventative properties against psychotic manifestations.

Arterial spin labeling in patients with schizophrenia: a systematic review

Abstract Background: Neuroimaging studies are an invaluable source of information about the physiopathology of schizophrenia. Arterial spin labeling (ASL) is a new magnetic resonance technique (MRI) that is able to effectively evaluate brain function without the use of radiation. Objective: To make a systematic review of studies using ASL to compare resting-state regional cerebral blood flow (rCBF) patterns in patients with schizophrenia and healthy controls. Methods: Original articles were searched for on PubMed, Scopus, Web of Science and PsycINFO electronic databases. The search terms used were 'arterial', 'spin', 'labeling', and 'schizophrenia'. Only studies comparing resting-state rCBF were included, a qualitative synthesis was then performed. Results: Ten articles were included in the review among a total of 22. Decreased rCBF in schizophrenia patients was described in the anterior cingulate, cuneus, fusiform gyrus, frontal lobe, left middle frontal gyrus, inferior frontal gyrus, lingual gyrus, middle occipital gyrus, and parietal lobe. The putamen was the only region with increased rCBF in schizophrenia. Discussion: The evidence of the studies reviewed lends support to the concept of hipofrontality in schizophrenia. rCBF alterations were found in regions classically associated with schizophrenia. ASL seems to be valid, and reliable tool to assess schizophrenia.

Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol.

Animal studies and preliminary clinical trials have shown that cannabidiol (CBD)-enriched extracts may have beneficial effects for children with treatment-resistant epilepsy. However, these compounds are not yet registered as medicines by regulatory agencies. We describe the cases of two children with treatment-resistant epilepsy (Case A with left frontal dysplasia and Case B with Dravet Syndrome) with initial symptom improvement after the introduction of CBD extracts followed by seizure worsening after a short time. The children presented typical signs of intoxication by Δ9-THC (inappropriate laughter, ataxia, reduced attention, and eye redness) after using a CBD-enriched extract. The extract was replaced by the same dose of purified CBD with no Δ9-THC in both cases, which led to improvement in intoxication signs and seizure remission. These cases support pre-clinical and preliminary clinical evidence suggesting that CBD may be effective for some patients with epilepsy. Moreover, the cases highlight the need for randomized clinical trials using high-quality and reliable substances to ascertain the safety and efficacy of cannabinoids as medicines.

Role of Methylene Blue in Trauma Neuroprotection and Neuropsychiatric Diseases.

The prevalence of central nervous system trauma, neurodegenerative and psychiatric diseases has significantly increased in recent years. Most of these diseases show multifactorial causes and several progression mechanisms. The search for a medication which positively interferes in these mechanisms and thereby changes the course of these diseases is of great scientific interest. The aim of the present review is to assess current literature on the possible role of methylene blue (MB) in the central nervous system due to the increasing number of citations in spite of the few articles available on the subject which suggest growing interest in the protective effects of MB on the central nervous system. Searches were performed on PubMed and Thomson Reuters Web of Knowledge. Therefore, we provide an overview of existing articles concerning: 1) MB actions; 2) MB neuroprotection and cardiac arrest; 3) MB neuroprotection and degenerative brain diseases; 4) MB neuroprotection and psychiatric diseases. PubMed was chosen because it holds the highest number of articles on the subject, Thomson Reuters was chosen due to its functionality which evaluates citations through analytic graphs. We conclude that MB has a beneficial effect and acts through many mechanisms and pathways of the central nervous system, being a potential alternative for the treatment of many neurodegenerative and psychiatric diseases.

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years.

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.

Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies

Objective: To conduct a systematic literature review of animal and human studies reporting anxiolytic or antidepressive effects of ayahuasca or some of its isolated alkaloids (dimethyltryptamine, harmine, tetrahydroharmine, and harmaline). Methods: Papers published until 3 April 2015 were retrieved from the PubMed, LILACS and SciELO databases following a comprehensive search strategy and using a predetermined set of criteria for article selection. Results: Five hundred and fourteen studies were identified, of which 21 met the established criteria. Studies in animals have shown anxiolytic and antidepressive effects of ayahuasca, harmine, and harmaline, and experimental studies in humans and mental health assessments of experienced ayahuasca consumers also suggest that ayahuasca is associated with reductions in anxiety and depressive symptoms. A pilot study reported rapid antidepressive effects of a single ayahuasca dose in six patients with recurrent depression. Conclusion: Considering the need for new drugs that produce fewer adverse effects and are more effective in reducing anxiety and depression symptomatology, the described effects of ayahuasca and its alkaloids should be further investigated.

Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia.

Increasing evidence suggests that the tetracycline antibiotic minocycline has neuroprotective effects and is a potential treatment for schizophrenia. However, the mechanisms of action of minocycline in the CNS remain elusive. The aim of this study was to investigate the effects of minocycline on brain morphology and cerebral perfusion in patients with recent-onset schizophrenia after 12months of a randomized double-blind, placebo-controlled clinical trial of minocycline add-on treatment. This study included 24 outpatients with recent-onset schizophrenia randomized for 12months of adjuvant treatment with minocycline (200mg/d) or placebo. MRI (1.5T) and [(99m)Tc]-ECD SPECT brain scans were performed at the end of the 12-month of trial. Between-condition comparisons of SPECT and MRI brain images were performed using statistical parametric mapping and analyzed by voxel-based morphometry (VBM). Minocycline adjuvant treatment significantly reduced positive and negative symptoms when compared with placebo. The VBM analysis of MRI scans showed that the patients in the placebo group had significant lower gray matter volumes in the midposterior cingulate cortex and in the precentral gyrus in comparison with the patients in the minocycline group. In addition, a decreased ECD uptake in the minocycline condition was observed in fronto-temporal areas. These results suggest that minocycline may protect against gray matter loss and modulate fronto-temporal areas involved in the pathophysiology of schizophrenia. Furthermore, minocycline add-on treatment may be a potential treatment in the early stages of schizophrenia and may ameliorate clinical deterioration and brain alterations observed in this period.

Acute and chronic administration of cannabidiol increases mitochondrial complex and creatine kinase activity in the rat brain

Objective: To investigate the effects of cannabidiol (CBD) on mitochondrial complex and creatine kinase (CK) activity in the rat brain using spectrophotometry. Method: Male adult Wistar rats were given intraperitoneal injections of vehicle or CBD (15, 30, or 60 mg/kg) in an acute (single dose) or chronic (once daily for 14 consecutive days) regimen. The activities of mitochondrial complexes and CK were measured in the hippocampus, striatum, and prefrontal cortex. Results: Both acute and chronic injection of CBD increased the activity of the mitochondrial complexes (I, II, II-III, and IV) and CK in the rat brain. Conclusions: Considering that metabolism impairment is certainly involved in the pathophysiology of mood disorders, the modulation of energy metabolism (e.g., by increased mitochondrial complex and CK activity) by CBD could be an important mechanism implicated in the action of CBD. .

Quality of life in patients with Charcot-Marie-Tooth disease type 1A / Análise da qualidade de vida de pacientes com a doença de Charcot-Marie-Tooth tipo 1A

We assessed the functional impairment in Charcot-Marie-Tooth resulting from 17p11.2-p12 duplication (CMT1A) patients using the Short-Form Health Survey (SF-36), which is a quality of life questionnaire. Twenty-five patients of both genders aged ≥10 years with a positive molecular diagnosis of CMT1A were selected. Age- and gender-matched Control Group (without family history of neuropathy), and the sociodemographic and professional conditions similar to the patients' group were selected to compare the SF-36 results between them. The results showed that the majority quality of life impairments in CMT1A patients occurred in the social and emotional domains. Functional capacity also tended to be significantly affected; other indicators of physical impairment were preserved. In conclusion, social and emotional aspects are mostly neglected in the assistance provided to CMT1A Brazilian patients, and they should be better understood in order to offer global health assistance with adequate quality of life as a result.

Avaliou-se o comprometimento funcional de pacientes com Charcot-Marie-Tooth provenientes da duplicação 17p11.2-p12 (CMT1A), utilizando o SF-36, que é um questionário para medir a qualidade de vida. Vinte e cinco pacientes de ambos os sexos com idades ≥10 anos e diagnóstico molecular de CMT1A foram selecionados. Idade, sexo, condições sociodemográficas e profissionais foram pareados com o Grupo Controle (sem histórico familiar de neuropatia). Os resultados mostraram que o maior impacto da CMT1A na qualidade de vida ocorreu nos domínios social e emocional dos pacientes avaliados. A capacidade funcional também tende a ser significativamente afetada, enquanto outros indicadores de deficiência física foram preservados. Por fim, os aspectos sociais e emocionais dos pacientes acometidos por CMT1A costumam ser negligenciados na assistência médica prestada aos pacientes brasileiros, e devem ser melhor compreendidos a fim de oferecer uma assistência global à saúde, resultando em adequada qualidade de vida.