Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.

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.

Addressing global mental health is a major 21st-century challenge. Current treatments have recognized limitations; in this context, new ones that are prophylactic and effective across diagnostic boundaries would represent a major advance. The view that there exists a core of transdiagnostic overlap between psychiatric disorders has re-emerged in recent years, and evidence that psychedelic therapy holds promise for a range of psychiatric disorders supports the position that it may be transdiagnostically effective. Here, we propose that psychedelic therapy's core, transdiagnostically relevant action lies in its ability to increase neuronal and mental plasticity, thus enhancing the potential for change, which we consider to be a key to its therapeutic benefits. Moreover, we suggest that enhanced plasticity via psychedelics, combined with a psychotherapeutic approach, can aid healthy adaptability and resilience, which are protective factors for long-term well-being. We present candidate neurological and psychological markers of this plasticity and link them with a predictive processing model of the action of psychedelics. We propose that a model of psychedelic-induced plasticity combined with an adequate therapeutic context has prophylactic and transdiagnostic potential, implying that it could have a broad, positive impact on public health.

The human prefrontal cortex is a structurally and functionally heterogenous brain region, including multiple subregions that have been linked to different large-scale brain networks. It contributes to a broad range of mental phenomena, from goal-directed thought and executive functions to mind-wandering and psychedelic experience. Here we review what is known about the functions of different prefrontal subregions and their affiliations with large-scale brain networks to examine how they may differentially contribute to the diversity of mental phenomena associated with prefrontal function. An important dimension that distinguishes across different kinds of conscious experience is the stability or variability of mental states across time. This dimension is a central feature of two recently introduced theoretical frameworks-the dynamic framework of thought (DFT) and the relaxed beliefs under psychedelics (REBUS) model-that treat neurocognitive dynamics as central to understanding and distinguishing between different mental phenomena. Here, we bring these two frameworks together to provide a synthesis of how prefrontal subregions may differentially contribute to the stability and variability of thought and conscious experience. We close by considering future directions for this work.

Rationale

Previous research suggests that classical psychedelic compounds can induce lasting changes in personality traits, attitudes and beliefs in both healthy subjects and patient populations.

Aim

Here we sought to investigate the effects of psilocybin on nature relatedness and libertarian-authoritarian political perspective in patients with treatment-resistant depression (TRD).

Methods

This open-label pilot study with a mixed-model design studied the effects of psilocybin on measures of nature relatedness and libertarian-authoritarian political perspective in patients with moderate to severe TRD ( n=7) versus age-matched non-treated healthy control subjects ( n=7). Psilocybin was administered in two oral dosing sessions (10 mg and 25 mg) 1 week apart. Main outcome measures were collected 1 week and 7-12 months after the second dosing session. Nature relatedness and libertarian-authoritarian political perspective were assessed using the Nature Relatedness Scale (NR-6) and Political Perspective Questionnaire (PPQ-5), respectively.

Results

Nature relatedness significantly increased ( t(6)=-4.242, p=0.003) and authoritarianism significantly decreased ( t(6)=2.120, p=0.039) for the patients 1 week after the dosing sessions. At 7-12 months post-dosing, nature relatedness remained significantly increased ( t(5)=-2.707, p=0.021) and authoritarianism remained decreased at trend level ( t(5)=-1.811, p=0.065). No differences were found on either measure for the non-treated healthy control subjects.

Conclusions

This pilot study suggests that psilocybin with psychological support might produce lasting changes in attitudes and beliefs. Although it would be premature to infer causality from this small study, the possibility of drug-induced changes in belief systems seems sufficiently intriguing and timely to deserve further investigation.

Background: Evidence suggests that classical psychedelics can promote enduring changes in personality, attitudes and optimism, as well as improvements in mental health outcomes. Aim: To investigate the effects of a composite intervention, involving psilocybin, on pessimism biases in patients with treatment-resistant depression (TRD). Methods: Patients with TRD (n = 15) and matched, untreated non-depressed controls (n = 15) performed the Prediction Of Future Life Events (POFLE) task. The POFLE task requires participants to predict the likelihood of certain life events occurring within a 30-day period, after which the actual rate of event occurrence is reported; this gives an index of potential pessimism versus optimism bias. Psilocybin was administered in two oral dosing sessions (10 and 25 mg) one week apart. Main outcome measures were collected at baseline and one week after the second dosing session. Results: Patients showed a significant pessimism bias at baseline [t(14) = -3.260, p = 0.006; 95% CI (-0.16, -0.03), g = 1.1] which was related to the severity of their depressive symptoms (r_s = -0.55, p = 0.017). One week after psilocybin treatment, this bias was significantly decreased [t(14) = -2.714, p = 0.017; 95% CI (-0.21, -0.02), g = 0.7] and depressive symptoms were greatly improved [t(14) = 7.900, p < 0.001; 95% CI (16.17, 28.23), g = 1.9]; moreover, the magnitude of change in both variables was significantly correlated (r = -0.57, p = 0.014). Importantly, post treatment, patients became significantly more accurate at predicting the occurrence of future life events [t(14) = 1.857, p = 0.042; 95% CI (-0.01, 0.12), g = 0.6] whereas no such change was observed in the control subjects. Conclusion: These findings suggest that psilocybin with psychological support might correct pessimism biases in TRD, enabling a more positive and accurate outlook.

Based on its ability to increase brain complexity, a seemingly reliable index of conscious level, we propose testing the capacity of the classic psychedelic, psilocybin, to increase conscious awareness in patients with disorders of consciousness. We also confront the considerable ethical and practical challenges this proposal must address, if this hypothesis is to be directly assessed.

It is a paradox that psychotomimetic drugs can relieve symptoms that increase risk of and cooccur with psychosis, such as attention and motivational deficits (e.g., amphetamines), pain (e.g., cannabis) and symptoms of depression (e.g., psychedelics, dissociatives). We introduce the ideas of psychotomimetic compensation and psychotomimetic sensitization to explain this paradox. Psychotomimetic compensation refers to a short-term stressor or drug-induced compensation against stress that is facilitated by engagement of neurotransmitter/modulator systems (endocannabinoid, serotonergic, glutamatergic and dopaminergic) that mediate the effects of common psychotomimetic drugs. Psychotomimetic sensitization occurs after repeated exposure to stress and/or drugs and is evidenced by the gradual intensification and increase of psychotic-like experiences over time. Theoretical and practical implications of this model are discussed.

Mystical-like states of consciousness may arise through means such as psychedelic substances, but may also occur unexpectedly during near-death experiences (NDEs). So far, research studies comparing experiences induced by serotonergic psychedelics and NDEs, along with their enduring effects, have employed between-subject designs, limiting direct comparisons. We present results from an online survey exploring the phenomenology, attribution of reality, psychological insights, and enduring effects of NDEs and psychedelic experiences (PEs) in individuals who have experienced both at some point during their lifetime. We used frequentist and Bayesian analyses to determine significant differences and overlaps (evidence for null hypotheses) between the two. Thirty-one adults reported having experienced both an NDE (i.e. NDE-C scale total score ≥27/80) and a PE (intake of lysergic acid diethylamide, psilocybin/mushrooms, ayahuasca, N,N-dimethyltryptamine, or mescaline). Results revealed areas of overlap between both experiences for phenomenology, attribution of reality, psychological insights, and enduring effects. A finer-grained analysis of the phenomenology revealed a significant overlap in mystical-like effects, while low-level phenomena (sensory effects) were significantly different, with NDEs displaying higher scores of disembodiment and PEs higher scores of visual imagery. This suggests psychedelics as a useful model for studying mystical-like effects induced by NDEs, while highlighting distinctions in sensory experiences.

Understanding the phenomenology and content of the inhaled N, N, dimethyltryptamine (N, N-DMT) experience is critical to facilitate and support ongoing research and therapeutic models targeting mental health conditions and central nervous system pathology. A qualitative analysis was conducted of all N, N-DMT experiences posted to the r/DMT Reddit community over a 10-year period from 2009 to 2018. A total of 3778 experiences from 3305 posts were included in this study. A median dose of N, N-DMT of 40.0 mg [interquartile range (IQR), 27.5 to 50.0] and a median experience duration of 10 min (IQR, 5.0 to 15.0) were identified. The most common somatic effects were somaesthesias (n = 1415, 37.5%) and an auditory ringing (n = 583, 15.4%). Visualizations predominantly consisted of fractals, shapes, patterns (n = 1231, 32.6%) and vivid colours (n = 953, 25.2%). Entity encounters were reported in 45.5% (n = 1719) of the experiences and involved predominantly a feminine phenotype (n = 416, 24.2%); deities (n = 293, 17.0%); aliens (n = 281, 16.3%); creature-based entities (n = 158, 9.2%, including reptilian and insectoid beings); mythological beings (n = 144, 8.4%, including machine elves); and jesters (n = 112, 6.5%). Entity interactions were predominantly positive (n = 600, 34.9% of encounters) involving benevolent, comforting, protecting, or outwardly caring interactions. A companion-type, pedagogical, or guide-type interaction was identified 32.4% of encounters (n = 557). Common typology, architecture, and structural features of the "DMT world" included descriptions of alternate or higher dimensions (n = 952, 25.2%); rooms [n = 582, 15.4%, including the "waiting room" (n = 105, 2.8%)], and a tunnel (n = 390, 10.3%). Features of mystical and ego-dissolution experiences were common. Additional rewarding aspects were identified, including a sense of familiarity and the acceptance/removal of the fear of death. Challenging and difficult responses were less frequent but also documented. Statements of profundity were identified in 232 experiences (6.1%), including pronouncing the experience or an aspect of the experience as the most "beautiful" or feeling the most "beautiful" of their life (n = 47, 1.2%). This study identified common phenomenological themes and content of naturalistic inhaled N, N-DMT experiences. Major thematic domains included (1) physical and somatic experiences; (2) visualizations and imagery; (3) entity encounters including entity phenotype, descriptors, attributes, disposition, and characteristics of the interaction; (4) typology, architectural features, structural characteristics, and scenery of the "DMT world"; (5) alerations in consciousness (including mystical experiences, out-of-body experiences, and ego-dissolution); (6) emotional responses (including positive, rewarding, difficult, and challenging); and (7) statements of profundity.