Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed

Novel Treatment Approaches for Substance Use Disorders: Therapeutic Use of Psychedelics and the Role of Psychotherapy

Purpose of Review: The use of psychedelics in a therapeutical setting has been reported for the treatment of various diagnoses in recent years. However, as psychedelic substances are still commonly known for their ( illicit) recreational use, it may seem counterintuitive to use psychedelic therapy to treat substance use disorders. This review aims to discuss how psychedelics can promote and intensify psychotherapeutic key processes, in different approaches like psychodynamic and cognitive behavioral therapy, with a spotlight on the treatment of substance use disorders (SUD). Recent Findings: There is promising evidence of feasibility, safety, and efficacy of psychedelic therapy in SUD. In the whole process of former and current psychedelic therapy regimes that have shown to be safe and efficacious, various psychotherapeutic elements, both psychodynamic and behavioral as well as other approaches, can be identified, while a substantial part of the assumed mechanism of action, the individual psychedelic experience, cannot be distinctly classified to just one approach. Summary: Psychedelic therapy consists of a complex interaction of pharmacological and psychological processes. When administered in well-defined conditions, psychedelics can serve as augmentation of different psychotherapy interventions in the treatment of SUD and other mental disorders, regardless of their theoretical origin

The Altered States Database: Psychometric data from a systematic literature review

In this paper, we present the development of the Altered States Database (ASDB), an open-science project based on a systematic literature review. The ASDB contains psychometric questionnaire data on subjective experiences of altered states of consciousness (ASC) induced by pharmacological and non-pharmacological methods. The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Scientific journal articles were identified through PubMed and Web of Science. We included studies that examined ASC using the following validated questionnaires: Altered States of Consciousness Rating Scale (APZ, 5D-ASC, 11-ASC), Phenomenology of Consciousness Inventory (PCI), Hallucinogen Rating Scale (HRS), or Mystical Experience Questionnaire (MEQ30). The systematic review resulted in the inclusion of a total of 165 journal articles, whereof questionnaire data was extracted and is now available on the Open Science Framework (OSF) website (https://osf.io/8mbru) and on the ASDB website (http://alteredstatesdb.org), where questionnaire data can be easily retrieved and visualized. This data allows the calculation of comparable psychometric values of ASC experiences and of dose-response relationships of substances inducing ASC

Vertebral arteries do not experience tensile force during manual cervical spine manipulation applied to human cadavers

Background: The vertebral artery (VA) may be stretched and subsequently damaged during manual cervical spine manipulation. The objective of this study was to measure VA length changes that occur during cervical spine manipulation and to compare these to the VA failure length. Methods: Piezoelectric ultrasound crystals were implanted along the length of the VA (C1 to C7) and were used to measure length changes during cervical spine manipulation of seven un-embalmed, post-rigor human cadavers. Arteries were then excised, and elongation from arbitrary in-situ head/neck positions to first force (0.1 N) was measured. Following this, VA were stretched (8.33 mm/s) to mechanical failure. Failure was defined as the instance when VA elongation resulted in a decrease in force. Results: From arbitrary in-situ head/neck positions, the greatest average VA length change during spinal manipulation was [mean (range)] 5.1% (1.1 to 15.1%). From arbitrary in-situ head/neck positions, arteries were elongated on average 33.5% (4.6 to 84.6%) prior to first force occurrence and 51.3% (16.3 to 105.1%) to failure. Average failure forces were 3.4 N (1.4 to 9.7 N). Conclusions: Measured in arbitrary in-situ head/neck positions, VA were slack. It appears that this slack must be taken up prior to VA experiencing tensile force. During cervical spine manipulations (using cervical spine extension and rotation), arterial length changes remained below that slack length, suggesting that VA elongated but were not stretched during the manipulation. However, in order to answer the question if cervical spine manipulation is safe from a mechanical perspective, the testing performed here needs to be repeated using a defined in-situ head/neck position and take into consideration other structures (e.g. carotid arteries). Keywords: Spinal biomechanics; cerebrovascular accidents; spinal manipulation; stroke; vertebral artery dissection

Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development

Mental disorders are rising while development of novel psychiatric medications is declining. This stall in innovation has also been linked with intense debates on the current diagnostics and explanations for mental disorders, together constituting a paradigmatic crisis. A radical innovation is psychedelic-assisted psychotherapy (PAP): professionally supervised use of ketamine, MDMA, psilocybin, LSD and ibogaine as part of elaborated psychotherapy programs. Clinical results so far have shown safety and efficacy, even for “treatment resistant” conditions, and thus deserve increasing attention from medical, psychological and psychiatric professionals. But more than novel treatments, the PAP model also has important consequences for the diagnostics and explanation axis of the psychiatric crisis, challenging the discrete nosological entities and advancing novel explanations for mental disorders and their treatment, in a model considerate of social and cultural factors, including adversities, trauma, and the therapeutic potential of some non-ordinary states of consciousness

The Effects of Psilocybin on Cognitive and Emotional Processing in Healthy Adults and Adults with Depression: A Systematic Literature Review

Aim. Psilocybin, a naturally occurring serotonergic agonist in some mushroom species, has shown promise as a novel, fast-acting pharmacotherapy seeking to overcome the limitations of conventional first-line antidepressants. Studying psilocybin effects on cognition and emotional processing may help to clarify the mechanisms underlying the therapeutic potential of psilocybin and may also support studies with people suffering from depression. Thus, this review aims to synthesize and integrate the literature regarding the effects of psilocybin on these two key areas in both healthy and depressed populations. Method. A systematic search was performed on PubMed, EBSCOhost, Web of Science and SCOPUS databases, restricting to publications from 2000 to 15th July 2022. After duplicates removal, study selection was conducted considering pre-specified criteria. Data extraction was then performed. The quality assessment was evaluated using the Cochrane Collaboration tools for randomized (RoB 2.0) and non-randomized (ROBINS-I) controlled trials. Results. Eighteen papers were included, with sixteen targeting healthy adults and two adults with depression. Impairments within the attentional and inhibitory processes, and improvements within the creativity and social cognition domains were seen in healthy individuals. Only cognitive flexibility and emotional recognition were found to be affected in depressed subjects. Comparison of outcomes from both populations proved limited. Conclusions. Psilocybin acutely alters several cognitive domains, with a localized rather than global focus, in a time-dependent manner. However, the remarkable methodological heterogeneity calls for further research, in the context of mental illness and with standardized plans, with longitudinal studies also imperative

Molecular and Functional Imaging Studies of Psychedelic Drug Action in Animals and Humans

Hallucinogens are a loosely defined group of compounds including LSD, N,N-dimethyltryptamines, mescaline, psilocybin/psilocin, and 2,5-dimethoxy-4-methamphetamine (DOM), which can evoke intense visual and emotional experiences. We are witnessing a renaissance of research interest in hallucinogens, driven by increasing awareness of their psychotherapeutic potential. As such, we now present a narrative review of the literature on hallucinogen binding in vitro and ex vivo, and the various molecular imaging studies with positron emission tomography (PET) or single photon emission computer tomography (SPECT). In general, molecular imaging can depict the uptake and binding distribution of labelled hallucinogenic compounds or their congeners in the brain, as was shown in an early PET study with N1-([11C]-methyl)-2-bromo-LSD ([11C]-MBL); displacement with the non-radioactive competitor ketanserin confirmed that the majority of [11C]-MBL specific binding was to serotonin 5-HT2A receptors. However, interactions at serotonin 5HT1A and other classes of receptors and pleotropic effects on second messenger pathways may contribute to the particular experiential phenomenologies of LSD and other hallucinogenic compounds. Other salient aspects of hallucinogen action include permeability to the blood–brain barrier, the rates of metabolism and elimination, and the formation of active metabolites. Despite the maturation of radiochemistry and molecular imaging in recent years, there has been only a handful of PET or SPECT studies of radiolabeled hallucinogens, most recently using the 5-HT2A/2C agonist N-(2[11CH3O]-methoxybenzyl)-2,5-dimethoxy- 4-bromophenethylamine ([11C]Cimbi-36). In addition to PET studies of target engagement at neuroreceptors and transporters, there is a small number of studies on the effects of hallucinogenic compounds on cerebral perfusion ([15O]-water) or metabolism ([18F]-fluorodeoxyglucose/FDG). There remains considerable scope for basic imaging research on the sites of interaction of hallucinogens and their cerebrometabolic effects; we expect that hybrid imaging with PET in conjunction with functional magnetic resonance imaging (fMRI) should provide especially useful for the next phase of this research

Classic Psychedelic Drugs: Update on Biological Mechanisms

Renewed interest in the effects of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances. During the past two decades, state-of-the-art studies of animals and humans have yielded new important insights into the molecular, cellular, and systems-level actions of psychedelic drugs. These efforts have revealed that psychedelics affect primarily serotonergic receptor subtypes located in cortico-thalamic and cortico-cortical feedback circuits of information processing. Psychedelic drugs modulate excitatory-inhibitory balance in these circuits and can participate in neuroplasticity within brain structures critical for the integration of information relevant to sensation, cognition, emotions, and the narrative of self. Neuroimaging studies showed that characteristic dimensions of the psychedelic experience obtained through subjective questionnaires as well as alterations in self-referential processing and emotion regulation obtained through neuropsychological tasks are associated with distinct changes in brain activity and connectivity patterns at multiple-system levels. These recent results suggest that changes in self-experience, emotional processing, and social cognition may contribute to the potential therapeutic effects of psychedelics

An Evidence-Based Critical Review of The Mind-Brain Identity Theory

In the philosophy of mind, the causal relationship between phenomenal consciousness, mentation and brain states has always been a matter of debate. On the one hand, material monism posits consciousness and mind as pure brain-epiphenomena. One of its most stringent lines of reasoning relies on the premise that because a cerebral impairment, or its anatomical and biochemical modification, leads to a cognitive impairment and/or altered states of consciousness, there is no reason to doubt the mind-brain identity. On the other hand, dualism or idealism (in one form or another) regard consciousness and mind as something other than the sole product of cerebral activity pointing at the ineffable and undefinable seemingly unphysical nature of our subjective qualitative experience and its related mental dimension. Here, we argue that the premise of material monism is based on a logical correlation-causation fallacy and will review some neuroscientific and biological findings that question the idea that posits phenomenal experience as an emergent property of brain activity. While these (mostly ignored) findings, if considered separately from each other, could, in principle, be recast into a physicalist paradigm, once viewed from an integral perspective, they substantiate equally well, if not even more effectively, an ontology that posits mind and consciousness as a primal phenomenon