OPEN Foundation

Mushrooms / Psilocybin

Classic psychedelics: the special role of the visual system

Abstract

Here, we briefly overview the various aspects of classic serotonergic hallucinogens reported by a number of studies. One of the key hypotheses of our paper is that the visual effects of psychedelics might play a key role in resetting fears. Namely, we especially focus on visual processes because they are among the most prominent features of hallucinogen-induced hallucinations. We hypothesize that our brain has an ancient visual-based (preverbal) intrinsic cognitive process that, during the transient inhibition of top-down convergent and abstract thinking (mediated by the prefrontal cortex) by psychedelics, can neutralize emotional fears of unconscious and conscious life experiences from the past. In these processes, the decreased functional integrity of the self-referencing processes of the default mode network, the modified multisensory integration (linked to bodily self-consciousness and self-awareness), and the modified amygdala activity may also play key roles. Moreover, the emotional reset (elimination of stress-related emotions) by psychedelics may induce psychological changes and overwrite the stress-related neuroepigenetic information of past unconscious and conscious emotional fears.

Császár-Nagy, N., Kapócs, G., & Bókkon, I. (2019). Classic psychedelics: the special role of the visual system. Reviews in the neurosciences.,  10.1515/revneuro-2018-0092
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Beyond LSD: A Broader Psychedelic Zeitgeist during the Early to Mid-20 th Century

Abstract

During the 1950s and 1960s, there was a tremendous surge in research into the effects of psychedelic drugs. When discussing this period of research, the discovery of the psychoactive properties of LSD in 1943 is often presented as the main, and sometimes only, driving force of the boom in research. This “Great Person,” or “Great Chemical,” historiographical lens fails to acknowledge other factors that were fundamental in setting the stage for the research. In particular, other psychedelic drugs, such as mescaline, were already being probed for their uses in psychotherapy and as models for psychosis before the effects of LSD had been discovered. Psilocybin and other classical psychedelics had also been discovered by Western researchers around the same time as the synthesis of LSD. Additionally, many of the dominant zeitgeists (e.g., pharmacological, psychoanalytic, and humanistic) in psychology during this period were congruent with psychedelic research. This article argues that while the discovery of LSD may have been a catalyst for psychedelic research in the 1950s and ’60s, there was a broader psychedelic zeitgeist that deserves acknowledgement for setting the stage.
Aday, J. S., Bloesch, E. K., & Davoli, C. C. (2019). Beyond LSD: A broader psychedelic zeitgeist during the early to mid-20th century. Journal of psychoactive drugs51(3), 210-217., https://doi.org/10.1080/02791072.2019.1581961
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Sub-Acute Effects of Psilocybin on Empathy, Creative Thinking, and Subjective Well-Being

Abstract

Creative thinking and empathy are crucial for everyday interactions and subjective well-being. This is emphasized by studies showing a reduction in these skills in populations where social interaction and subjective well-being are significantly compromised (e.g., depression). Anecdotal reports and recent studies suggest that a single administration of psilocybin can enhance such processes and could therefore be a potential treatment. However, it has yet to be assessed whether effects outlast acute intoxication. The present study aimed to assess the sub-acute effects of psilocybin on creative thinking, empathy, and well-being. Participants attending a psilocybin retreat completed tests of creative (convergent and divergent) thinking and empathy, and the satisfaction with life scale on three occasions: before ingesting psilocybin (N = 55), the morning after (N = 50), and seven days after (N = 22). Results indicated that psilocybin enhanced divergent thinking and emotional empathy the morning after use. Enhancements in convergent thinking, valence-specific emotional empathy, and well-being persisted seven days after use. Sub-acute changes in empathy correlated with changes in well-being. The study demonstrates that a single administration of psilocybin in a social setting may be associated with sub-acute enhancement of creative thinking, empathy, and subjective well-being. Future research should test whether these effects contribute to the therapeutic effects in clinical populations.

Mason, N. L., Mischler, E., Uthaug, M. V., & Kuypers, K. P. (2019). Sub-Acute Effects of Psilocybin on Empathy, Creative Thinking, and Subjective Well-Being. Journal of psychoactive drugs, 1-12., 10.1080/02791072.2019.1580804
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Psychedelic medicine: The biology underlying the persisting psychedelic effects.

Abstract

Psychedelic substances have regained interest as therapeutic agents in the treatment of stress-related disorders. The effects seem to be of persisting nature even after a single dose. Also in lower than ‘regular’ recreational doses, so-called micro-doses, without the typical effects on consciousness, users report beneficial effects on cognitive processes and well-being. The exact neurobiological mechanism underlying these persisting effects is not clear. While previous research has mainly focused on the central nervous system including the immune system and the neuroendocrine system, I propose a central role for sleep and the microbiome in the effects of regular and low doses of psychedelics respectively. It will be explained why this is hypothesized and studies to test this idea proposed. It is concluded that while these studies are needed to understand the biology underlying psychedelic medicine, it is also important to approach it in a holistic way, including all the above mentioned biological processes psychedelics are known to affect, and explore the role of other substance-related factors like route of administration and form, and factors like diet and lifestyle which are part of the psychedelic experience.

Kuypers, K. P. C. (2019). Psychedelic medicine: The biology underlying the persisting psychedelic effects. Medical hypotheses125, 21-24., https://doi.org/10.1016/j.mehy.2019.02.029
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A systematic study of microdosing psychedelics

Abstract

The phenomenon of ‘microdosing’, that is, regular ingestion of very small quantities of psychedelic substances, has seen a rapid explosion of popularity in recent years. Individuals who microdose report minimal acute effects from these substances yet claim a range of long-term general health and wellbeing benefits. There have been no published empirical studies of microdosing and the current legal and bureaucratic climate makes direct empirical investigation of the effects of psychedelics difficult. In Study One we conducted a systematic, observational investigation of individuals who microdose. We tracked the experiences of 98 microdosing participants, who provided daily ratings of psychological functioning over a six week period. 63 of these additionally completed a battery of psychometric measures tapping mood, attention, wellbeing, mystical experiences, personality, creativity, and sense of agency, at baseline and at completion of the study. Analyses of daily ratings revealed a general increase in reported psychological functioning across all measures on dosing days but limited evidence of residual effects on following days. Analyses of pre and post study measures revealed reductions in reported levels of depression and stress; lower levels of distractibility; increased absorption; and increased neuroticism. To better understand these findings, in Study Two we investigated pre-existing beliefs and expectations about the effects of microdosing in a sample of 263 naïve and experienced microdosers, so as to gauge expectancy bias. All participants believed that microdosing would have large and wide-ranging benefits in contrast to the limited outcomes reported by actual microdosers. Notably, the effects believed most likely to change were unrelated to the observed pattern of reported outcomes. The current results suggest that dose controlled empirical research on the impacts of microdosing on mental health and attentional capabilities are needed.

Polito, V., & Stevenson, R. J. (2019). A systematic study of microdosing psychedelics. PloS one14(2), e0211023., 10.1371/journal.pone.0211023.
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Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels.

Abstract

The main psychedelic component of magic mushrooms is psilocybin, which shows promise as a treatment for depression and other mental disorders. Psychedelic effects are believed to emerge through stimulation of serotonin 2A receptors (5-HT2ARs) by psilocybin’s active metabolite, psilocin. We here report for the first time the relationship between intensity of psychedelic effects, cerebral 5-HT2AR occupancy and plasma levels of psilocin in humans. Eight healthy volunteers underwent positron emission tomography (PET) scans with the 5-HT2AR agonist radioligand [11C]Cimbi-36: one at baseline and one or two additional scans on the same day after a single oral intake of psilocybin (3-30 mg). 5-HT2AR occupancy was calculated as the percent change in cerebral 5-HT2AR binding relative to baseline. Subjective psychedelic intensity and plasma psilocin levels were measured during the scans. Relations between subjective intensity, 5-HT2AR occupancy, and plasma psilocin levels were modeled using non-linear regression. Psilocybin intake resulted in dose-related 5-HT2AR occupancies up to 72%; plasma psilocin levels and 5-HT2AR occupancy conformed to a single-site binding model. Subjective intensity was correlated with both 5-HT2AR occupancy and psilocin levels as well as questionnaire scores. We report for the first time that intake of psilocybin leads to significant 5-HT2AR occupancy in the human brain, and that both psilocin plasma levels and 5-HT2AR occupancy are closely associated with subjective intensity ratings, strongly supporting that stimulation of 5-HT2AR is a key determinant for the psychedelic experience. Important for clinical studies, psilocin time-concentration curves varied but psilocin levels were closely associated with psychedelic experience.
Madsen, M. K., Fisher, P. M., Burmester, D., Dyssegaard, A., Stenbæk, D. S., Kristiansen, S., … & Erritzoe, D. (2019). Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology, 1., 10.1038/s41386-019-0324-9
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Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study.

Abstract

Recent research found lasting increases in personality trait Openness in healthy individuals and patients after administration of the serotonin 2A receptor (5-HT2A R) agonist psilocybin. However, no studies have investigated whether 5-HT2A R availability as imaged using positron emission tomography (PET) is associated with this trait. In 159 healthy individuals (53 females), the association between 5-HT2A R binding in neocortex imaged with [18 F]altanserin or [11 C]Cimbi-36 PET and personality trait Openness was investigated using linear regression models. In these models the influence of sex on the association was also investigated. Trait Openness was assessed with the NEO Personality Inventory-Revised. No significant associations between neocortical 5-HT2A R binding and trait Openness were found for [18F]altanserin (p = 0.5) or [11 C]Cimbi-36 (p = 0.8). Pooling the data in a combined model did not substantially change our results (p = 0.4). No significant interactions with sex were found (p > 0.35). Our results indicate that differences in 5-HT2A R availability are not related to variations in trait Openness in healthy individuals. Although stimulation of the 5-HT2A R with compounds such as psilocybin may contribute to long-term changes in trait Openness, there is no evidence in favor of an association between 5-HT2A R and trait Openness.
Stenbæk, D. S., Kristiansen, S., Burmester, D., Madsen, M. K., Frokjaer, V. G., Knudsen, G. M., & Fisher, P. M. (2019). Trait Openness and serotonin 2A receptors in healthy volunteers: A positron emission tomography study. Human brain mapping., 10.1002/hbm.24511
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Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats

Abstract

The prototype 5-HT2A receptor agonist hallucinogens LSD, mescaline, and psilocybin are classified as Schedule 1 drugs of abuse by the U.S. Drug Enforcement Administration. Accumulating clinical evidence has also suggested that acute or repeated “microdosing” with these drugs may have utility for treatment of some mental health disorders, including drug abuse and depression. The goal of the present study was to evaluate LSD, mescaline, and psilocybin effects on intracranial self-stimulation (ICSS), a procedure that has been used to evaluate abuse-related effects of other classes of abused drugs. Effects of repeated LSD were also examined to evaluate potential changes in its own effects on ICSS or changes in effects produced by the abused psychostimulant methamphetamine or the prodepressant kappa opioid receptor (KOR) agonist U69,593. Male Sprague-Dawley rats were implanted with microelectrodes targeting the medial forebrain bundle and trained to respond under a “frequency-rate” ICSS procedure, in which many drugs of abuse increase (or “facilitate”) ICSS. In acute dose-effect and time-course studies, evidence for abuse-related ICSS facilitation was weak and inconsistent; the predominant effect of all 3 drugs was dose- and time-dependent ICSS depression. Repeated LSD treatment failed to alter either its own ICSS depressant effects or the abuse-related effects of methamphetamine; however, repeated LSD did attenuate ICSS depression by U69,593. These results extend those of previous preclinical studies to suggest weak expression of abuse-related effects by 5-HT2A agonist hallucinogens and provide supportive evidence for therapeutic effects of repeated LSD dosing to attenuate KOR-mediated depressant effects but not abuse potential of psychostimulants.

Sakloth, F., Leggett, E., Moerke, M. J., Townsend, E. A., Banks, M. L., & Negus, S. S. (2019). Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self-stimulation in rats. Experimental and clinical psychopharmacology., 10.1037/pha0000253.
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Microdosing psychedelics: personality, mental health, and creativity differences in microdosers

Abstract

RATIONALE:

Microdosing psychedelics-the regular consumption of small amounts of psychedelic substances such as LSD or psilocybin-is a growing trend in popular culture. Recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. While full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses.

OBJECTIVES:

This pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity.

METHODS:

In this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. Respondents also performed the Unusual Uses Task to assess their creativity.

RESULTS:

Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = – 0.92) and negative emotionality (p = 0.009, r = – 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls.

CONCLUSIONS:

These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. As microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.

Anderson, T., Petranker, R., Rosenbaum, D., Weissman, C. R., Dinh-Williams, L. A., Hui, K., … & Farb, N. A. (2018). Microdosing Psychedelics: Personality, mental health, and creativity differences in microdosers. Psychopharmacology, 1-10., 10.1007/s00213-018-5106-2
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Microdosing psychedelics: personality, mental health, and creativity differences in microdosers.

Abstract

RATIONALE:
Microdosing psychedelics-the regular consumption of small amounts of psychedelic substances such as LSD or psilocybin-is a growing trend in popular culture. Recent studies on full-dose psychedelic psychotherapy reveal promising benefits for mental well-being, especially for depression and end-of-life anxiety. While full-dose therapies include perception-distorting properties, microdosing mayprovide complementary clinical benefits using lower-risk, non-hallucinogenic doses.
OBJECTIVES:
This pre-registered study aimed to investigate whether microdosing psychedelics is related to differences in personality, mental health, and creativity.
METHODS:
In this observational study, respondents recruited from online forums self-reported their microdosing behaviors and completed questionnaires concerning dysfunctional attitudes, wisdom, negative emotionality, open-mindedness, and mood. Respondents also performed the Unusual Uses Task to assess their creativity.
RESULTS:
Current and former microdosers scored lower on measures of dysfunctional attitudes (p < 0.001, r = – 0.92) and negative emotionality (p = 0.009, r = – 0.85) and higher on wisdom (p < 0.001, r = 0.88), openmindedness(p = 0.027, r = 0.67), and creativity (p < 0.001, r = 0.15) when compared to non-microdosing controls.
CONCLUSIONS:
These findings provide promising initial evidence that warrants controlled experimental research to directly test safety and clinical efficacy. As microdoses are easier to administer than full-doses, this new paradigm has the exciting potential to shape future psychedelic research.

Anderson, T., Petranker, R., Rosenbaum, D., Weissman, C. R., Dinh-Williams, L. A., Hui, K., … & Farb, N. A. (2019). Microdosing Psychedelics: Personality, mental health, and creativity differences in microdosers. Psychopharmacology236(2), 731-740., https://doi.org/10.1007/s00213-018-5106-2
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