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Irish Journal of Psychological Medicine Jun 2021The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across...
The medium- to long-term consequences of COVID-19 are not yet known, though an increase in mental health problems are predicted. Multidisciplinary strategies across socio-economic and psychological levels may be needed to mitigate the mental health burden of COVID-19. Preliminary evidence from the rapidly progressing field of psychedelic science shows that psilocybin therapy offers a promising transdiagnostic treatment strategy for a range of disorders with restricted and maladaptive habitual patterns of cognition and behaviour, notably depression, addiction and obsessive compulsive disorder. The COMPASS Pathways (COMPASS) phase 2b double-blind trial of psilocybin therapy in antidepressant-free, treatment-resistant depression (TRD) is underway to determine the safety, efficacy and optimal dose of psilocybin. Results from the Imperial College London Psilodep-RCT comparing the efficacy and mechanisms of action of psilocybin therapy to the selective serotonin reuptake inhibitor (SSRI) escitalopram will soon be published. However, the efficacy and safety of psilocybin therapy in conjunction with SSRIs in TRD is not yet known. An additional COMPASS study, with a centre in Dublin, will begin to address this question, with potential implications for the future delivery of psilocybin therapy. While at a relatively early stage of clinical development, and notwithstanding the immense challenges of COVID-19, psilocybin therapy has the potential to play an important therapeutic role for various psychiatric disorders in post-COVID-19 clinical psychiatry.
Topics: COVID-19; Hallucinogens; Humans; Psilocybin; Psychiatry; SARS-CoV-2
PubMed: 32811575
DOI: 10.1017/ipm.2020.94 -
International Journal of Molecular... Dec 2023The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these...
The pathophysiology of depression is related to the reduced volume of the hippocampus and amygdala and hypertrophy of the nucleus accumbens. The mechanism of these changes is not well understood; however, clinical studies have shown that the administration of the fast-acting antidepressant ketamine reversed the decrease in hippocampus and amygdala volume in depressed patients, and the magnitude of this effect correlated with the reduction in depressive symptoms. In the present study, we attempted to find out whether the psychedelic substance psilocybin affects neurotransmission in the limbic system in comparison to ketamine. Psilocybin and ketamine increased the release of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of naive rats as demonstrated using microdialysis. Both drugs influenced glutamate and GABA release in the nucleus accumbens, hippocampus and amygdala and increased ACh levels in the hippocampus. The changes in D2, 5-HT1A and 5-HT2A receptor density in the nucleus accumbens and hippocampus were observed as a long-lasting effect. A marked anxiolytic effect of psilocybin in the acute phase and 24 h post-treatment was shown in the open field test. These data provide the neurobiological background for psilocybin's effect on stress, anxiety and structural changes in the limbic system and translate into the antidepressant effect of psilocybin in depressed patients.
Topics: Humans; Animals; Rats; Psilocybin; Ketamine; Limbic System; Glutamic Acid; Antidepressive Agents
PubMed: 38203271
DOI: 10.3390/ijms25010100 -
Frontiers in Psychology 2022Psilocybin-assisted psychotherapy, i.e., psilocybin treatment with psychological support, has demonstrated the efficacy of psilocybin to reduce depressive symptoms....
Psilocybin-assisted psychotherapy, i.e., psilocybin treatment with psychological support, has demonstrated the efficacy of psilocybin to reduce depressive symptoms. However, in clinical trials, the structure of psilocybin-assisted psychotherapy is primarily based on preparation, navigation (support during dosing sessions), and integration. For psychotherapeutic guidance, the application of this structure is favored over the usage of theoretical models. The applied psychotherapeutic models may be of critical importance if the effects are augmented due to the psychologically insightful experiences during the navigation and integration sessions. One of the important next steps is to provide therapists with guidance on how to provide psilocybin-assisted psychotherapy. We present an integrated protocol for psilocybin-assisted psychotherapy for depression based on the theoretical model and psychotherapeutic framework of Compassion Focused Therapy (CFT). We hypothesize that CFT can provide the theoretical model and compassion practices that will reinforce the experiences during the navigation and follow-up therapy sessions. In this paper, we describe the rationale for selecting CFT, the compatibility of CFT and psilocybin-therapy, an overview of the psilocybin-assisted CFT protocol, the study protocol, and limitations to this approach.
PubMed: 35401294
DOI: 10.3389/fpsyg.2022.812930 -
Communicative & Integrative Biology 2022Psilocybin fungi, aka "magic" mushrooms, are well known for inducing colorful and visionary states of mind. Such psychoactive properties and the ease of cultivating...
Psilocybin fungi, aka "magic" mushrooms, are well known for inducing colorful and visionary states of mind. Such psychoactive properties and the ease of cultivating their basidiocarps within low-tech setups make psilocybin fungi promising pharmacological tools for mental health applications. Understanding of the intrinsic electrical patterns occurring during the mycelial growth can be utilized for better monitoring the physiological states and needs of these species. In this study we aimed to shed light on this matter by characterizing the extra-cellular electrical potential of two popular species of psilocybin fungi: Psilocybe and . As in previous experiments with other common edible mushrooms, the undisturbed fungi have shown to generate electric potential spikes and trains of spiking activity. This short analysis provides a proof of intrinsic electrical communication in psilocybin fungi, and further establishes these fungi as a valuable tool for studying fungal electro-physiology.
PubMed: 36311546
DOI: 10.1080/19420889.2022.2136118 -
Pharmaceuticals (Basel, Switzerland) Sep 2021There has recently been a renewal of interest in psychedelic research on the use of psilocybin in psychiatric treatment and, in particular, for the treatment of major... (Review)
Review
There has recently been a renewal of interest in psychedelic research on the use of psilocybin in psychiatric treatment and, in particular, for the treatment of major depressive disorder (MDD). Several state-of-the-art studies have provided new insight into the mechanisms of action of psilocybin and its therapeutic potential. Nevertheless, many questions remain unanswered. With this review, we provide an overview of the current state of research on the potential mechanisms of psilocybin, its antidepressant potential, and the associated risks and adverse effects, to provide an update on a controversial topic discussed in psychopharmacology. A database search was conducted in Medline including articles on psilocybin over the period of the last 20 years. Despite the promising progress in understanding the mechanisms of psilocybin, the exact antidepressive mechanism and the role of the psychedelic experience remain elusive. The studies included in this review found high treatment effect sizes for psilocybin as an antidepressant. However, the results must be regarded as preliminary due to several limitations. Although the current studies observed no severe adverse events, several questions regarding safety and utility remain and must be subject of future research.
PubMed: 34681209
DOI: 10.3390/ph14100985 -
Neuropsychopharmacology : Official... Jun 2023Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the...
Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2 A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybin's pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.
Topics: Male; Female; Animals; Rats; Psilocybin; Ketanserin; Hallucinogens; Anxiety; Serotonin 5-HT2 Receptor Antagonists; Serotonin; Cognition
PubMed: 36807609
DOI: 10.1038/s41386-023-01545-z -
BJPsych Open Jul 2023Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression...
BACKGROUND
Randomised controlled trials (RCTs) of psilocybin have reported large antidepressant effects in adults with major depressive disorder and treatment-resistant depression (TRD). Given psilocybin's psychedelic effects, all published studies have included psychological support. These effects depend on serotonin 2A (5-HT2A) receptor activation, which can be blocked by 5-HT2A receptor antagonists like ketanserin or risperidone. In an animal model of depression, ketanserin followed by psilocybin had similar symptomatic effects as psilocybin alone.
AIMS
To conduct a proof-of-concept RCT to (a) establish feasibility and tolerability of combining psilocybin and risperidone in adults with TRD, (b) show that this combination blocks the psychedelic effects of psilocybin and (c) provide pilot data on the antidepressant effect of this combination (compared with psilocybin alone).
METHOD
In a 4-week, three-arm, 'double dummy' trial, 60 adults with TRD will be randomised to psilocybin 25 mg plus risperidone 1 mg, psilocybin 25 mg plus placebo, or placebo plus risperidone 1 mg. All participants will receive 12 h of manualised psychotherapy. Measures of feasibility will include recruitment and retention rates; tolerability and safety will be assessed by rates of drop-out attributed to adverse events and rates of serious adverse events. The 5-Dimensional Altered States of Consciousness Rating Scale will be a secondary outcome measure.
RESULTS
This trial will advance the understanding of psilocybin's mechanism of antidepressant action.
CONCLUSIONS
This line of research could increase acceptability and access to psilocybin as a novel treatment for TRD without the need for a psychedelic experience and continuous monitoring.
PubMed: 37489299
DOI: 10.1192/bjo.2023.535 -
Frontiers in Psychology 2021Our hominin ancestors inevitably encountered and likely ingested psychedelic mushrooms throughout their evolutionary history. This assertion is supported by current...
Our hominin ancestors inevitably encountered and likely ingested psychedelic mushrooms throughout their evolutionary history. This assertion is supported by current understanding of: early hominins' paleodiet and paleoecology; primate phylogeny of mycophagical and self-medicative behaviors; and the biogeography of psilocybin-containing fungi. These lines of evidence indicate mushrooms (including bioactive species) have been a relevant resource since the Pliocene, when hominins intensified exploitation of forest floor foods. Psilocybin and similar psychedelics that primarily target the serotonin 2A receptor subtype stimulate an active coping strategy response that may provide an enhanced capacity for adaptive changes through a flexible and associative mode of cognition. Such psychedelics also alter emotional processing, self-regulation, and social behavior, often having enduring effects on individual and group well-being and sociality. A homeostatic and drug instrumentalization perspective suggests that incidental inclusion of psychedelics in the diet of hominins, and their eventual addition to rituals and institutions of early humans could have conferred selective advantages. Hominin evolution occurred in an ever-changing, and at times quickly changing, environmental landscape and entailed advancement into a socio-cognitive niche, i.e., the development of a socially interdependent lifeway based on reasoning, cooperative communication, and social learning. In this context, psychedelics' effects in enhancing sociality, imagination, eloquence, and suggestibility may have increased adaptability and fitness. We present interdisciplinary evidence for a model of psychedelic instrumentalization focused on four interrelated instrumentalization goals: management of psychological distress and treatment of health problems; enhanced social interaction and interpersonal relations; facilitation of collective ritual and religious activities; and enhanced group decision-making. The socio-cognitive niche was simultaneously a selection pressure and an adaptive response, and was partially constructed by hominins through their activities and their choices. Therefore, the evolutionary scenario put forward suggests that integration of psilocybin into ancient diet, communal practice, and proto-religious activity may have enhanced hominin response to the socio-cognitive niche, while also aiding in its creation. In particular, the interpersonal and prosocial effects of psilocybin may have mediated the expansion of social bonding mechanisms such as laughter, music, storytelling, and religion, imposing a systematic bias on the selective environment that favored selection for prosociality in our lineage.
PubMed: 34659037
DOI: 10.3389/fpsyg.2021.729425 -
Frontiers in Neuroscience 2023Psilocybin, a naturally occurring hallucinogenic component of magic mushrooms, has significant psychoactive effects in both humans and rodents. But the underlying...
Psilocybin, a naturally occurring hallucinogenic component of magic mushrooms, has significant psychoactive effects in both humans and rodents. But the underlying mechanisms are not fully understood. Blood-oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) is a useful tool in many preclinical and clinical trials to investigate psilocybin-induced changes of brain activity and functional connectivity (FC) due to its noninvasive nature and widespread availability. However, fMRI effects of psilocybin on rats have not been carefully investigated. This study aimed to explore how psilocybin affects resting-state brain activity and FC, through a combination of BOLD fMRI and immunofluorescence (IF) of EGR1, an immediate early gene (IEG) closely related to depressive symptoms. Ten minutes after psilocybin hydrochloride injection (2.0 mg/kg, i.p.), positive brain activities were observed in the frontal, temporal, and parietal cortex (including the cingulate cortex and retrosplenial cortex), hippocampus, and striatum. And a region-of-interest (ROI) -wise FC analysis matrix suggested increased interconnectivity of several regions, such as the cingulate cortex, dorsal striatum, prelimbic, and limbic regions. Further seed-based analyses revealed increased FC of cingulate cortex within the cortical and striatal areas. Consistently, acute psilocybin increased the EGR1 level throughout the brain, indicating a consistent activation thought the cortical and striatal areas. In conclusion, the psilocybin-induced hyperactive state of rats is congruent to that of humans, and may be responsible for its pharmacological effects.
PubMed: 37287797
DOI: 10.3389/fnins.2023.1168911