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.
Psychedelics and connectedness Carhart-Harris, R. L.; Erritzoe, D.; Haijen, E. ...
Psychopharmacology,
02/2018, Letnik:
235, Številka:
2
Journal Article
Recenzirano
Psychedelic drugs are creating ripples in psychiatry as evidence accumulates of their therapeutic potential. An important question remains unresolved however:
how
are psychedelics effective? We ...propose that a sense of
connectedness
is key, provide some preliminary evidence to support this, and suggest a roadmap for testing it further.
Objective
To explore whether psilocybin with psychological support modulates personality parameters in patients suffering from treatment‐resistant depression (TRD).
Method
Twenty patients with ...moderate or severe, unipolar, TRD received oral psilocybin (10 and 25 mg, one week apart) in a supportive setting. Personality was assessed at baseline and at 3‐month follow‐up using the Revised NEO Personality Inventory (NEO‐PI‐R), the subjective psilocybin experience with Altered State of Consciousness (ASC) scale, and depressive symptoms with QIDS‐SR16.
Results
Neuroticism scores significantly decreased while Extraversion increased following psilocybin therapy. These changes were in the direction of the normative NEO‐PI‐R data and were both predicted, in an exploratory analysis, by the degree of insightfulness experienced during the psilocybin session. Openness scores also significantly increased following psilocybin, whereas Conscientiousness showed trend‐level increases, and Agreeableness did not change.
Conclusion
Our observation of changes in personality measures after psilocybin therapy was mostly consistent with reports of personality change in relation to conventional antidepressant treatment, although the pronounced increases in Extraversion and Openness might constitute an effect more specific to psychedelic therapy. This needs further exploration in future controlled studies, as do the brain mechanisms of postpsychedelic personality change.
The benefits of aerobic exercise (AE) training on blood pressure (BP) and arterial stiffness are well established, but the effects of resistance training are less well delineated. The purpose of this ...study was to determine the impact of resistance vs aerobic training on haemodynamics and arterial stiffness. Thirty pre- or stage-1 essential hypertensives (20 men and 10 women), not on any medications, were recruited (age: 48.2 +/- 1.3 years) and randomly assigned to 4 weeks of either resistance (RE) or AE training. Before and after training, BP, arterial stiffness (pulse wave velocity (PWV)) and vasodilatory capacity (VC) were measured. Resting systolic BP (SBP) decreased following both training modes (SBP: RE, pre 136 +/- 2.9 vs. post 132 +/- 3.4; AE, pre 141 +/- 3.8 vs. post 136 +/- 3.4 mm Hg, P = 0.005; diastolic BP: RE, pre 78 +/- 1.3 vs post 74 +/- 1.6; AE, pre 80 +/- 1.6 vs. post 77 +/- 1.7 mm Hg, P = 0.001). Central PWV increased (P = 0.0001) following RE (11 +/- 0.9-12.7 +/- 0.9 ms(-1)) but decreased after AE (12.1 +/- 0.8-11.1 +/- 0.8 m s(-1). Peripheral PWV also increased (P = 0.013) following RE (RE, pre 11.5 +/- 0.8 vs. post 12.5 +/- 0.7 ms(-1)) and decreased after AE (AE, pre 12.6 +/- 0.8 vs post 11.6 +/- 0.7 m s(-1)). The VC area under the curve (VC(AUC)) increased more with RE than that with AE (RE, pre 76 +/- 8.0 vs. post 131.1 +/- 11.6; AE, pre 82.7 +/- 8.0 vs. post 110.1 +/- 11.6 ml per min per s per 100 ml, P = 0.001). Further, peak VC (VCpeak) increased more following resistance training compared to aerobic training (RE, pre 17 +/- 1.9 vs. post 25.8 +/- 2.1; AE, pre 19.2 +/- 8.4 vs post 22.9 +/- 8.4 ml per min per s per 100 ml, P = 0.005). Although both RE and AE training decreased BP, the change in pressure may be due to different mechanisms.
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.
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.
Psychedelic microdosing describes the ingestion of near-threshold perceptible doses of classic psychedelic substances. Anecdotal reports and observational studies suggest that microdosing may promote ...positive mood and well-being, but recent placebo-controlled studies failed to find compelling evidence for this. The present study collected web-based mental health and related data using a prospective (before, during and after) design. Individuals planning a weekly microdosing regimen completed surveys at strategic timepoints, spanning a core four-week test period. Eighty-one participants completed the primary study endpoint. Results revealed increased self-reported psychological well-being, emotional stability and reductions in state anxiety and depressive symptoms at the four-week primary endpoint, plus increases in psychological resilience, social connectedness, agreeableness, nature relatedness and aspects of psychological flexibility. However, positive expectancy scores at baseline predicted subsequent improvements in well-being, suggestive of a significant placebo response. This study highlights a role for positive expectancy in predicting positive outcomes following psychedelic microdosing and cautions against zealous inferences on its putative therapeutic value.
This article explores the notion that Freudian constructs may have neurobiological substrates. Specifically, we propose that Freud’s descriptions of the primary and secondary processes are consistent ...with self-organized activity in hierarchical cortical systems and that his descriptions of the ego are consistent with the functions of the default-mode and its reciprocal exchanges with subordinate brain systems. This neurobiological account rests on a view of the brain as a hierarchical inference or Helmholtz machine. In this view, large-scale intrinsic networks occupy supraordinate levels of hierarchical brain systems that try to optimize their representation of the sensorium. This optimization has been formulated as minimizing a free-energy; a process that is formally similar to the treatment of energy in Freudian formulations. We substantiate this synthesis by showing that Freud’s descriptions of the primary process are consistent with the phenomenology and neurophysiology of rapid eye movement sleep, the early and acute psychotic state, the aura of temporal lobe epilepsy and hallucinogenic drug states.
Recent years have seen a resurgence of research on the potential of psychedelic substances to treat addictive and mood disorders. Historically and contemporarily, psychedelic studies have emphasized ...the importance of contextual elements ('set and setting') in modulating acute drug effects, and ultimately, influencing long-term outcomes. Nevertheless, current small-scale clinical and laboratory studies have tended to bypass a ubiquitous contextual feature of naturalistic psychedelic use: its social dimension. This study introduces and psychometrically validates an adapted
assessing acute relational experiences of perceived togetherness and shared humanity, in order to investigate psychosocial mechanisms pertinent to psychedelic ceremonies and retreats.
In this observational, web-based survey study, participants (
= 886) were measured across five successive time-points: 2 weeks before, hours before, and the day after a psychedelic ceremony; as well as the day after, and 4 weeks after leaving the ceremony location. Demographics, psychological traits and state variables were assessed pre-ceremony, in addition to changes in psychological wellbeing and social connectedness from before to after the retreat, as primary outcomes. Using correlational and multiple regression (path) analyses, predictive relationships between psychosocial 'set and setting' variables, communitas, and long-term outcomes were explored.
The adapted Communitas Scale demonstrated substantial internal consistency (Cronbach's alpha = 0.92) and construct validity in comparison with validated measures of intra-subjective (visual, mystical, challenging experiences questionnaires) and inter-subjective (perceived emotional synchrony, identity fusion) experiences. Furthermore, communitas during ceremony was significantly correlated with increases in psychological wellbeing (
= 0.22), social connectedness (
= 0.25), and other salient mental health outcomes. Path analyses revealed that the effect of ceremony-communitas on long-term outcomes was fully mediated by communitas experienced in reference to the retreat overall, and that the extent of personal sharing or 'self-disclosure' contributed to this process. A positive relationship between participants and facilitators, and the perceived impact of emotional support, facilitated the emergence of communitas.
Highlighting the importance of intersubjective experience, rapport, and emotional support for long-term outcomes of psychedelic use, this first quantitative examination of psychosocial factors in guided psychedelic settings is a significant step toward evidence-based benefit-maximization guidelines for collective psychedelic use.
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