Showing papers in "Journal of Psychopharmacology in 2021"
TL;DR: Underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling are considered.
Abstract: The discovery of the rapid antidepressant effects of the dissociative anaesthetic ketamine, an uncompetitive N-Methyl-D-Aspartate receptor antagonist, is arguably the most important breakthrough in depression research in the last 50 years. Ketamine remains an off-label treatment for treatment-resistant depression with factors that limit widespread use including its dissociative effects and abuse potential. Ketamine is a racemic mixture, composed of equal amounts of (S)-ketamine and (R)-ketamine. An (S)-ketamine nasal spray has been developed and approved for use in treatment-resistant depression in the United States and Europe; however, some concerns regarding efficacy and side effects remain. Although (R)-ketamine is a less potent N-Methyl-D-Aspartate receptor antagonist than (S)-ketamine, increasing preclinical evidence suggests (R)-ketamine may have more potent and longer lasting antidepressant effects than (S)-ketamine, alongside fewer side effects. Furthermore, a recent pilot trial of (R)-ketamine has demonstrated rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research is ongoing to determine the specific cellular and molecular mechanisms underlying the antidepressant actions of ketamine and its component enantiomers in an effort to develop future rapid-acting antidepressants that lack undesirable effects. Here, we briefly review findings regarding the antidepressant effects of ketamine and its enantiomers before considering underlying mechanisms including N-Methyl-D-Aspartate receptor antagonism, γ-aminobutyric acid-ergic interneuron inhibition, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptor activation, brain-derived neurotrophic factor and tropomyosin kinase B signalling, mammalian target of rapamycin complex 1 and extracellular signal-regulated kinase signalling, inhibition of glycogen synthase kinase-3 and inhibition of lateral habenula bursting, alongside potential roles of the monoaminergic and opioid receptor systems.
78 citations
TL;DR: It is argued that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this, and that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed.
Abstract: This paper introduces a new construct, the 'pivotal mental state', which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.
63 citations
TL;DR: Several measures have been developed to examine acute psychedelic effects (e.g. mystical-type and challenging experiences), but no measure assesses acute psychologically insightful exper... as discussed by the authors. But none of these measures assesses the effect of hallucinogenic drugs.
Abstract: Background:Several measures have been developed to examine acute psychedelic effects (e.g. mystical-type and challenging experiences), but no measure assesses acute psychologically insightful exper...
41 citations
TL;DR: In this paper, treatment-resistant depression (TRD) is identified as a problem in the treatment of MDD, and steps to address TRD include increasing an increasing an...
Abstract: Background:Successful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing an...
38 citations
TL;DR: It is demonstrated that psilocybin rapidly induces gene expression related to neuroplasticity, biased towards the prefrontal cortex, compared to the hippocampus, which provides further evidence for the rapid plasticity-promoting effects of p silocybin.
Abstract: Background:Psilocybin is a serotonergic psychedelic found in “magic mushrooms” with a putative therapeutic potential for treatment-resistant depression, anxiety, obsessive-compulsive disorder, and ...
37 citations
TL;DR: The findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience and examine whether individual brain levels of 5- HT2AR have an impact on therapeutic outcomes in clinical studies.
Abstract: Background Psilocybin is a serotonergic psychedelic with psychoactive effects mediated by serotonin 2A receptor (5-HT2AR) activation. It produces an acute psychedelic altered state of consciousness with a unique phenomenology that can be temporally characterized by three intensity phases: onset of psychoactive effect, a peak plateau and return to normal consciousness. Aims We evaluated whether pre-drug brain 5-HT2AR binding predicted the three phases of psilocybin subjective drug intensity (SDI) and retrospective self-report of mystical type experiences in healthy individuals. Method Sixteen participants completed a pre-drug [11C]Cimbi-36 positron emission tomography scan to assess 5-HT2AR binding. On a separate day, participants completed a single psilocybin session (oral dose range 0.2-0.3 mg/kg), during which SDI was assessed every 20 min. The Mystical Experience Questionnaire (MEQ) was completed at the end of the session. The three SDI phases were modelled using segmented linear regressions. We evaluated the associations between neocortex 5-HT2AR binding and SDI/MEQ outcomes using linear regression models. Results Neocortex 5-HT2AR was statistically significantly negatively associated with peak plateau duration and positively with time to return to normal waking consciousness. It was also statistically significantly negatively associated with MEQ total score. Conclusion This is the first study to investigate how individual brain 5-HT2AR binding predicts subjective effects of a single dose of psilocybin. Our findings reinforce the role of cerebral 5-HT2AR in shaping the temporal and mystical features of the psychedelic experience. Future studies should examine whether individual brain levels of 5-HT2AR have an impact on therapeutic outcomes in clinical studies.
36 citations
TL;DR: Ketamine is a novel rapid-acting antidepressant with high efficacy in treatment-resistant patients as discussed by the authors, however, its exact therapeutic mechanisms of action are unclear; however, in recent years its a...
Abstract: Background:Ketamine is a novel rapid-acting antidepressant with high efficacy in treatment-resistant patients. Its exact therapeutic mechanisms of action are unclear; however, in recent years its a...
34 citations
TL;DR: Recently, growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as a drug.
Abstract: Background:Growing evidence suggests psilocybin, a naturally occurring psychedelic, is a safe and promising pharmacotherapy for treatment of mood and substance use disorders when administered as pa...
34 citations
TL;DR: In this article, 3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study.
Abstract: Background:3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study. We...
34 citations
TL;DR: In recent years, there has been significant research on the mental health effects of classic psychedelic use, but there is very little evidence on how classic psychedelics might influence mental health as mentioned in this paper.
Abstract: Background:In recent years, there has been significant research on the mental health effects of classic psychedelic use, but there is very little evidence on how classic psychedelics might influenc...
34 citations
TL;DR: LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects.
Abstract: Background:Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s–1980s, and are currently being re-investigated as treatments for sev...
TL;DR: Ketamine leads to significantly greater mystical-type effects and dissociation and the Hood Mysticism Scale, but not Clinician Administered Dissociative States Scale score, was found to mediate the effect of ketamine on drinking behavior.
Abstract: Background:Sub-anesthetic ketamine administration may be helpful for substance use disorders. Converging evidence suggests that the efficacy of ketamine for certain conditions may implicate a subse...
TL;DR: Evidence is provided of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience, and at dose levels which are not expected to produce profound mind-altering effects.
Abstract: Background:Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that has been implicated in the management of persistent pain. Clinical studies in the 1960s ...
TL;DR: In this article, the effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5HT2A receptor.
Abstract: Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.
TL;DR: Mescaline is a naturally occurring psychoactive phenethylamine found in several cacti and historically used ceremonially by Indigenous and Latin American populations as discussed by the authors, and it has been recognized as a hallucinogenic drug.
Abstract: Background:Mescaline is a naturally occurring psychoactive phenethylamine found in several cacti and historically used ceremonially by Indigenous and Latin American populations. Broader recognition...
TL;DR: In this article, the authors explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health, such as maintaining a balanced diet, being physically active and refraining from smoking.
Abstract: Healthful behaviours such as maintaining a balanced diet, being physically active and refraining from smoking have major impacts on the risk of developing cancer, diabetes, cardiovascular diseases and other serious conditions. The burden of the so-called 'lifestyle diseases'-in personal suffering, premature mortality and public health costs-is considerable. Consequently, interventions designed to promote healthy behaviours are increasingly being studied, e.g., using psychobiological models of behavioural regulation and change. In this article, we explore the notion that psychedelic substances such as psilocybin could be used to assist in promoting positive lifestyle change conducive to good overall health. Psilocybin has a low toxicity, is non-addictive and has been shown to predict favourable changes in patients with depression, anxiety and other conditions marked by rigid behavioural patterns, including substance (mis)use. While it is still early days for modern psychedelic science, research is advancing fast and results are promising. Here we describe psychedelics' proposed mechanisms of action and research findings pertinent to health behaviour change science, hoping to generate discussion and new research hypotheses linking the two areas. Therapeutic models including psychedelic experiences and common behaviour change methods (e.g., Cognitive Behaviour Therapy, Motivational Interviewing) are already being tested for addiction and eating disorders. We believe this research may soon be extended to help promote improved diet, exercise, nature exposure and also mindfulness or stress reduction practices, all of which can contribute to physical and psychological health and well-being.
TL;DR: In this article, the quality of the psilocybin-induced experience might mediate beneficial health outcategories: Psilocybe mushrooms, magic mushrooms, hallucinogenic drugs, psychoactive components in magic mushrooms.
Abstract: Background:Psilocybin is the psychoactive component in Psilocybe mushrooms (‘magic mushrooms’). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outc...
TL;DR: A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes, and a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation.
Abstract: Dystonia is by far the most intrusive and invalidating extrapyramidal side effect of potent classical antipsychotic drugs. Antipsychotic drug-induced dystonia is classified in both acute and tardive forms. The incidence of drug-induced dystonia is associated with the affinity to inhibitory dopamine D2 receptors. Particularly acute dystonia can be treated with anticholinergic drugs, but the tardive form may also respond to such antimuscarinic treatment, which contrasts their effects in tardive dyskinesia. Combining knowledge of the pathophysiology of primary focal dystonia with the anatomical and pharmacological organization of the extrapyramidal system may shed some light on the mechanism of antipsychotic drug-induced dystonia. A suitable hypothesis is derived from the understanding that focal dystonia may be due to a faulty processing of somatosensory input, so leading to inappropriate execution of well-trained motor programmes. Neuroplastic alterations of the sensitivity of extrapyramidal medium-sized spiny projection neurons to stimulation, which are induced by the training of specific complex movements, lead to the sophisticated execution of these motor plans. The sudden and non-selective disinhibition of indirect pathway medium-sized spiny projection neurons by blocking dopamine D2 receptors may distort this process. Shutting down the widespread influence of tonically active giant cholinergic interneurons on all medium-sized spiny projection neurons by blocking muscarinic receptors may result in a reduction of the influence of extrapyramidal cortical-striatal-thalamic-cortical regulation. Furthermore, striatal cholinergic interneurons have an important role to play in integrating cerebellar input with the output of cerebral cortex, and are also targeted by dopaminergic nigrostriatal fibres affecting dopamine D2 receptors.
TL;DR: In this paper, the acute impairing effects of oral and vaporized cannabis consumption were characterized for both oral and inhaled forms of the drug, and no established methods for detecting cannabis impairment were established.
Abstract: Background:Cannabis legalization is expanding, but there are no established methods for detecting cannabis impairment.Aim:Characterize the acute impairing effects of oral and vaporized cannabis usi...
TL;DR: In this article, the authors suggest supplementing traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters.
Abstract: Favourable regulatory assessments, liberal policy changes, new research centres and substantial commercial investment signal that psychedelic therapy is making a major comeback. Positive findings from modern trials are catalysing developments, but it is questionable whether current confirmatory trials are sufficient for advancing our understanding of safety and best practice. Here we suggest supplementing traditional confirmatory trials with pragmatic trials, real-world data initiatives and digital health solutions to better support the discovery of optimal and personalised treatment protocols and parameters. These recommendations are intended to help support the development of safe, effective and cost-efficient psychedelic therapy, which, given its history, is vulnerable to excesses of hype and regulation.
TL;DR: Ketamine is central to one of the most rapidly growing areas of neuroscientific research into novel treatments for depression as discussed by the authors, and limited research has indicated that the psychedelic propert...
Abstract: Background:Ketamine is central to one of the most rapidly growing areas of neuroscientific research into novel treatments for depression. Limited research has indicated that the psychedelic propert...
TL;DR: In this article, the authors describe the use of clozapine and its use in the monitoring of plasma concentrations and white blood cell parameters and the delay between sending blood samples for analysis and receiving.
Abstract: Background:The use of clozapine demands regular monitoring of clozapine plasma concentrations and of white blood cell parameters The delay between sending blood samples for analysis and receiving
TL;DR: In this article, the authors provide a review of the current research to determine if, how and to what extent, concerns about problems of dependence in recreational cannabis users apply to prescribed medical users.
Abstract: Cannabis has been legalised for medical use in an ever-increasing number of countries. A growing body of scientific evidence supports the use of medical cannabis for a range of therapeutic indications. In parallel with these developments, concerns have been expressed by many prescribers that increased use will lead to patients developing cannabis use disorder. Cannabis use disorder has been widely studied in recreational users, and these findings have often been projected onto patients using medical cannabis. However, studies exploring medical cannabis dependence are scarce and the appropriate methodology to measure this construct is uncertain. This article provides a narrative review of the current research to discern if, how and to what extent, concerns about problems of dependence in recreational cannabis users apply to prescribed medical users. We focus on the main issues related to medical cannabis and dependence, including the importance of dose, potency, cannabinoid content, pharmacokinetics and route of administration, frequency of use, as well as set and setting. Medical and recreational cannabis use differs in significant ways, highlighting the challenges of extrapolating findings from the recreational cannabis literature. There are many questions about the potential for medical cannabis use to lead to dependence. It is therefore imperative to address these questions in order to be able to minimise harms of medical cannabis use. We draw out seven recommendations for increasing the safety of medical cannabis prescribing. We hope that the present review contributes to answering some of the key questions surrounding medical cannabis dependence.
TL;DR: The N-methyl-D-aspartate glutamate receptor is involved in the putative pathology of schizophrenia, and there is growing interest in the potential of N-MDS-ASpartate.
Abstract: Background:Dysfunction of the N-methyl-D-aspartate glutamate receptor is involved in the putative pathology of schizophrenia. There is growing interest in the potential of N-methyl-D-aspartate rece...
TL;DR: This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives to MDMA, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action andEntactogenic commonalities with MDMA.
Abstract: The last two decades have seen a revival of interest in the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA) as an adjunct to psychotherapy, particularly for the treatment of post-traumatic stress disorder. While clinical results are highly promising, and MDMA is expected to be approved as a treatment in the near future, it is currently the only compound in its class of action that is being actively investigated as a medicine. This lack of alternatives to MDMA may prove detrimental to patients who do not respond well to the particular mechanism of action of MDMA or whose treatment calls for a modification of MDMA's effects. For instance, patients with existing cardiovascular conditions or with a prolonged history of stimulant drug use may not fit into the current model of MDMA-assisted psychotherapy, and could benefit from alternative drugs. This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives in the future, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action and entactogenic commonalities with MDMA. The substances examined derive from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole and amphetamine classes. Several compounds from these classes are identified as potential alternatives to MDMA.
TL;DR: In this paper, a study aimed to use peripheral plasma d-glutamate levels to detect cognitive ageing. But the results showed that dglutamic levels were not associated with cognitive ageing, which may be attributed to N-methyl-d-aspartate receptor modulation.
Abstract: Background:d-glutamate, which is involved in N-methyl-d-aspartate receptor modulation, may be associated with cognitive ageing.Aims:This study aimed to use peripheral plasma d-glutamate levels to d...
TL;DR: In this article, emerging evidence supports the antipsychotic effect of cannabidiol, a non-intoxicating component of cannabis, in people with psychosis, and preclinical findings suggest that this antipsychot...
Abstract: Background:Emerging evidence supports the antipsychotic effect of cannabidiol, a non-intoxicating component of cannabis, in people with psychosis. Preclinical findings suggest that this antipsychot...
TL;DR: In this article, the factors influencing inter-and intra-individual differences in the inter and intra individual effects of 3,4-methylenedioxymethamphetamine (MDMA) were investigated.
Abstract: Background:3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) is used both recreationally and therapeutically. Little is known about the factors influencing inter- and intra-individual differences...
TL;DR: In this paper, N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals and few studies to date have addressed the neural and psychological effects of n,N.
Abstract: Background:N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals Few studies to date have addressed the neural and psychological effects of N,N
TL;DR: Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants.
Abstract: Background:Promethazine is a medicinal product, available on its own or in combination with other ingredients including dextromethorphan, paracetamol and/or expectorants. Anecdotal reports have how...