Previous attempts to identify a unified theory of brain serotonin function have largely failed to achieve consensus. In this present synthesis, we integrate previous perspectives with new and older ...data to create a novel bipartite model centred on the view that serotonin neurotransmission enhances two distinct adaptive responses to adversity, mediated in large part by its two most prevalent and researched brain receptors: the 5-HT1A and 5-HT2A receptors. We propose that passive coping (i.e. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (i.e. actively addressing a source of stress) is mediated by 5-HT2AR signalling and characterised by enhanced plasticity (defined as capacity for change). We propose that 5-HT1AR-mediated stress moderation may be the brain’s default response to adversity but that an improved ability to change one’s situation and/or relationship to it via 5-HT2AR-mediated plasticity may also be important – and increasingly so as the level of adversity reaches a critical point. We propose that the 5-HT1AR pathway is enhanced by conventional 5-HT reuptake blocking antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), whereas the 5-HT2AR pathway is enhanced by 5-HT2AR-agonist psychedelics. This bipartite model purports to explain how different drugs (SSRIs and psychedelics) that modulate the serotonergic system in different ways, can achieve complementary adaptive and potentially therapeutic outcomes.
Psychedelic Psychiatry Nutt, D.
European psychiatry,
06/2022, Letnik:
65, Številka:
S1
Journal Article
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Odprti dostop
The last decade has seen a remarkable resurgence of interest in psychedelic drugs such as psilocybin (from magic mushrooms) LSD and DMT (dimethyl tryptamine – the active ingredient of ayahuasca). ...This has been driven by the discovery that these psychedelics all act agonists of
5-HT2A receptors. Human imaging studies have revealed this action leads to profound alterations in brain measures of activity particularly in terms of increased entropy of EEG MEG and fMRI signals and reduced within-network, but increased between-network, connectivity. In addition they all can increase synaptic growth and brain plasticity. These findings not only explain the subjective nature of the psychedelic experience but also have implications for the treatment of internalising disorders such as depression addiction anorexia and OCD that are characterised by increased within network connectivity especially of the default mode network. Subsequent trials, particularly of psilocybin, in these disorders has revealed significant clinical benefits from even just a single administration. A number of companies have now been set up to extend these discoveries with regulatory-level trials that could result in market authorisations within a few years. My talk will explore these brain mechanisms and clinical data and discuss the potential place of psychedelic medicine in the future of psychiatry.
Disclosure
I am an advisor to Compass pathways and Beckley Psytec two companies that are developing psychedelics for depression and other psychiatric indications. Several members of my research group receive support from these companies and also from Small Pharma.
The British Association for Psychopharmacology guidelines for the treatment of substance abuse, harmful use, addiction and comorbidity with psychiatric disorders primarily focus on their ...pharmacological management. They are based explicitly on the available evidence and presented as recommendations to aid clinical decision making for practitioners alongside a detailed review of the evidence. A consensus meeting, involving experts in the treatment of these disorders, reviewed key areas and considered the strength of the evidence and clinical implications. The guidelines were drawn up after feedback from participants. The guidelines primarily cover the pharmacological management of withdrawal, short- and long-term substitution, maintenance of abstinence and prevention of complications, where appropriate, for substance abuse or harmful use or addiction as well management in pregnancy, comorbidity with psychiatric disorders and in younger and older people.
Networks, as efficient representations of complex systems, have appealed to scientists for a long time and now permeate many areas of science, including neuroimaging (Bullmore and Sporns 2009 Nat. ...Rev. Neurosci. 10, 186–198. (doi:10.1038/nrn2618)). Traditionally, the structure of complex networks has been studied through their statistical properties and metrics concerned with node and link properties, e.g. degree-distribution, node centrality and modularity. Here, we study the characteristics of functional brain networks at the mesoscopic level from a novel perspective that highlights the role of inhomogeneities in the fabric of functional connections. This can be done by focusing on the features of a set of topological objects—homological cycles—associated with the weighted functional network. We leverage the detected topological information to define the homological scaffolds, a new set of objects designed to represent compactly the homological features of the correlation network and simultaneously make their homological properties amenable to networks theoretical methods. As a proof of principle, we apply these tools to compare resting-state functional brain activity in 15 healthy volunteers after intravenous infusion of placebo and psilocybin—the main psychoactive component of magic mushrooms. The results show that the homological structure of the brain's functional patterns undergoes a dramatic change post-psilocybin, characterized by the appearance of many transient structures of low stability and of a small number of persistent ones that are not observed in the case of placebo.
Sleep disorders are common in the general population and even more so in clinical practice, yet are relatively poorly understood by doctors and other health care practitioners. These British ...Association for Psychopharmacology guidelines are designed to address this problem by providing an accessible up-to-date and evidence-based outline of the major issues, especially those relating to reliable diagnosis and appropriate treatment. A consensus meeting was held in London in May 2009. Those invited to attend included BAP members, representative clinicians with a strong interest in sleep disorders and recognized experts and advocates in the field, including a representative from mainland Europe and the USA. Presenters were asked to provide a review of the literature and identification of the standard of evidence in their area, with an emphasis on meta-analyses, systematic reviews and randomized controlled trials where available, plus updates on current clinical practice. Each presentation was followed by discussion, aimed to reach consensus where the evidence and/or clinical experience was considered adequate or otherwise to flag the area as a direction for future research. A draft of the proceedings was then circulated to all participants for comment. Key subsequent publications were added by the writer and speakers at draft stage. All comments were incorporated as far as possible in the final document, which represents the views of all participants although the authors take final responsibility for the document.
The therapeutic potential of medical cannabis to treat a variety of conditions is becoming increasingly recognised. Globally, a large number of countries have now legalised cannabis for medical uses ...and a substantial number of patients are able to access their medications. Yet in the UK, where medical cannabis was legalised in November 2018, only a handful of NHS prescriptions have been written, meaning that most patients are unable to access the medicine. Reasons for this are manyfold and include the perceived lack of clinical evidence due to the challenges of studying medical cannabis through randomised controlled trials. In order to develop the current evidence base, the importance of incorporating real-world data (RWD) to assess the effectiveness and efficacy of medical cannabis has gradually become recognised. The current paper provides a detailed outline of Project Twenty21 (T21), the UK’s first medical cannabis registry, launched in August 2020. We provide the rationale for T21 and describe the methodology before reporting the characteristics of the ‘first patients’ enrolled in the registry. We describe the health status of all patients enrolled into the project during its first 7 months of operation and the sociodemographic characteristics and primary presenting conditions for these patients, as well as details of the medical cannabis prescribed to these individuals. By 12th March 2021, 678 people had been enrolled into T21; the majority (64%) were male and their average age was 38.7 years (range = 18–80). The most commonly reported primary conditions were chronic pain (55.6%) and anxiety disorders (32.0%) and they reported high levels of multi-morbidity, including high rates of insomnia and depression. We also present preliminary evidence from 75 patients followed up after 3 months indicating that receipt of legal, prescribed cannabis was associated with a significant increase in self-reported health, assessed using the visual analogue scale of the EQ-5D-5L (Cohen’s
d
= .77, 95% CI = .51–1.03). Our initial findings complement reports from other large-scale databases globally, indicating that the current RWD is building up a pattern of evidence. With many clinicians demanding better and faster evidence to inform their decisions around prescribing medical cannabis, the current and future results of T21 will expand the existing evidence base on the effectiveness of cannabis-based medical products (CBMPs).
The EEG/MEG signal is generated primarily by the summation of the post-synaptic potentials of cortical principal cells. At a microcircuit level, these glutamatergic principal cells are reciprocally ...connected to GABAergic interneurons and cortical oscillations are thought to be dependent on the balance of excitation and inhibition between these cell types. To investigate the dependence of movement-related cortical oscillations on excitation–inhibition balance, we pharmacologically manipulated the GABA system using tiagabine, which blocks GABA Transporter 1(GAT-1), the GABA uptake transporter and increases endogenous GABA activity. In a blinded, placebo-controlled, crossover design, in 15 healthy participants we administered either 15mg of tiagabine or a placebo. We recorded whole-head magnetoencephalograms, while the participants performed a movement task, prior to, one hour post, three hour post and five hour post tiagabine ingestion. Using time-frequency analysis of beamformer source reconstructions, we quantified the baseline level of beta activity (15–30Hz), the post-movement beta rebound (PMBR), beta event-related desynchronisation (beta-ERD) and movement-related gamma synchronisation (MRGS) (60–90Hz). Our results demonstrated that tiagabine, and hence elevated endogenous GABA levels causes, an elevation of baseline beta power, enhanced beta-ERD and reduced PMBR, but no modulation of MRGS. Comparing our results to recent literature (Hall et al., 2011) we suggest that beta-ERD may be a GABAA receptor mediated process while PMBR may be GABAB receptor mediated.
► Recorded MEG during a movement task before and after tiagabine or placebo ► Tiagabine elevates the activity of endogenous GABA. ► Results showed increased beta-ERD, decreased PMBR and no change in MRGS. ► It is suggested that beta-ERD depends on GABAA while PMBR depends on GABAB.
Rationale
Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.
Objectives
Here, we report on safety and efficacy outcomes ...for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.
Methods
Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.
Results
Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s
d
= 2.2 at week 1 and 2.3 at week 5, both
p
< 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s
d
= 1.5 and 1.4, respectively, both
p
< 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.
Conclusions
Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
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