Psychedelics may not be ready to be accepted by the FDA (more research needs to be done). The use of psilocybin has positive effects one month later, but repeated and high-dose usage is correlated with more negative outcomes. And microdosing may have a positive effect on mental disorders as reported by users.

Structure Based Drug Design towards Exploring Potential Anti-Psychotic and Anti-Depressant Activity of Possible Stiff Base of Psilocybin

Author: Krishna K. Varshney

Published: 2 Feb 2020

One sentence summary: The stiff base of psilocybin could aid in efficient anti-psychotic and anti-depressants in drug design.

“One among four people in the world are affected by mental or neurological illness at some point of their lives. An estimated number of 450 million people suffers from neurological disorders of one or the other type making mental disorders as the leading cause for disability across the globe. Under psychosis and depression maintenance therapy drug acting on Dopamine (D2) and 5-Hydroxytryptamine receptor (5HT2R) respectively are used in clinical practices. Our study is to design several series of novel chemical entity based on scaffold of psychedelic prodrug i.e. psilocybin. As protein-ligand interactions play a key role in structure based drug design, by using molecular docking, we screened 9 hypothetical inhibitors and investigated their binding affinity against D2 and 5HT2R. We have performed homology modelling to predict 3D structure and build a templet using FASTA sequence of amino acid D2 and 5-HT2 receptor using UniProt database (accession number: P14416 & P28223) and swiss-modeller. In this investigation we performed molecular docking and molecular dynamic study using AutoDock software on their respective grid pocket. Several physicochemical description, pharmacokinetic properties, toxicity, and drug-likeness score with respective 9 hypothetical inhibitors were access using QikProp software, molispiration and OSIRIS property explorer web server. The docking results were evaluated based on free energies of binding (ΔG, kcal/mol) and the results suggested that all the 9 hypothetical chemical entity to be potent inhibitor of D2 and 5HT2R. All the hypothetical inhibitors respect the Lipinski’s rule of five. Based on these observations, we firmly believe that the stiff base of psilocybin could aid in efficient anti-psychotic and anti-depressants in drug design.”

Perceived outcomes of psychedelic microdosing as self-managed therapies for mental and substance use disorders

Authors: Toby Lea, Nicole Amada, Henrik Jungaberle, Henrike Schecke, Norbert Scherbaum & Michael Klein

Published: 11 Feb 2020

One-sentence summary: A survey (n=1102) looked at self-reported therapeutic or enhancement of microdosing and found that 79% indicated a beneficial effect on mental health.

“Results Twenty-one percent of respondents reported primarily microdosing as a therapy for depression, 7% for anxiety, 9% for other mental disorders and 2% for substance use cessation or reduction. Forty-four percent of respondents perceived that their mental health was “much better” as a consequence of microdosing. In a multivariate analysis, perceived improvements in mental health from microdosing were associated with a range of variables including gender, education, microdosing duration and motivations, and recent use of larger psychedelic doses. Conclusions Given the promising findings of clinical trials of standard psychedelic doses as mental health therapies, clinical microdosing research is needed to determine its potential role in psychiatric treatment, and ongoing social research to better understand the use of microdosing as self-managed mental health and substance use therapies. “

Emotions and brain function are altered up to one month after a single high dose of psilocybin

Authors: Frederick S. Barrett, Manoj K. Doss, Nathan D. Sepeda, James J. Pekar & Roland R. Griffiths

Published: 12 Feb 2020

One-sentence summary: One high-dose of psilocybin can alter brain function (positive affect +, trait anxiety -, resting-function connections +) up to one month later.

“Psilocybin is a classic psychedelic compound that may have efficacy for the treatment of mood and substance use disorders. Acute psilocybin effects include reduced negative mood, increased positive mood, and reduced amygdala response to negative affective stimuli. However, no study has investigated the long-term, enduring impact of psilocybin on negative affect and associated brain function. Twelve healthy volunteers (7F/5M) completed an open-label pilot study including assessments 1-day before, 1-week after, and 1-month after receiving a 25 mg/70 kg dose of psilocybin to test the hypothesis that psilocybin administration leads to enduring changes in affect and neural correlates of affect. One-week post-psilocybin, negative affect and amygdala response to facial affect stimuli were reduced, whereas positive affect and dorsal lateral prefrontal and medial orbitofrontal cortex responses to emotionally-conflicting stimuli were increased. One-month post-psilocybin, negative affective and amygdala response to facial affect stimuli returned to baseline levels while positive affect remained elevated, and trait anxiety was reduced. Finally, the number of significant resting-state functional connections across the brain increased from baseline to 1-week and 1-month post-psilocybin. These preliminary findings suggest that psilocybin may increase emotional and brain plasticity, and the reported findings support the hypothesis that negative affect may be a therapeutic target for psilocybin.”

Psychedelics and Psychedelic-Assisted Psychotherapy: Clinical Implications

Authors: Collin M. Reiff, Elon E. Richman, Charles B. Nemeroff, Linda L. Carpenter, Alik S. Widge, Carolyn I. Rodriguez, Ned H. Kalin & William M. McDonald

Published: 12 Feb 2020

One-sentence summary: An extensive literature review concludes that more research needs to be done for FDA approval and psychedelic-assisted psychotherapy.

“Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on“psilocybin,” “lysergic acid diethylamide,” “LSD,” “ayahuasca,” “3,4-methylenedioxymethamphetamine,” and “MDMA,” in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms “clinical trial,” “therapy,” or “imaging” in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4- methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care. … Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.”

Dissolving the self: Active inference, psychedelics, and ego-dissolution

Author: George Deane

Published: 12 Feb 2020

One-sentence summary: This theory-building paper presents a framework underpinning ego-dissolution during a peak/mystical experience. It is presented as the result of lowered precision on high-level priors (top-down), due to a collapse in ‘temporal thickness’.

“Psychedelic drugs such as psilocybin, LSD and DMT are known to induce powerful alterations in phenomenology. Perhaps of most philosophical and scientific interest is their capacity to disrupt and even “dissolve” one of the most primary features of normal experience: that of being a self. Such “peak” or “mystical” experiences are of increasing interest for their potentially transformative therapeutic value. While empirical research is underway, a theoretical conception of the mechanisms underpinning these experiences remains elusive. In the following paper, psychedelic-induced ego-dissolution is accounted for within an active inference framework, as a collapse in the “temporal thickness” of an agent’s deep temporal model, as a result of lowered precision on high-level priors. The argument here is composed of three moves: first, a view of the self-model is proposed as arising within a temporally deep generative model of an embodied organism navigating an affordance landscape in the service of allostasis. Next, a view of the action of psychedelics as lowering the precision of high-level priors within the generative model is unpacked in terms of a high Bayesian learning rate. Finally, the relaxation of high-level priors is argued to cause a “collapse” in the temporal thickness of the generative model, resulting in a collapse in the self-model and a loss of the ordinary sense of being a self. This account has implications for our understanding of ordinary self-consciousness and disruptions in self-consciousness present in psychosis, autism, depression, and dissociative disorders. The philosophical, theoretical and therapeutic implications of this account are touched upon.”

Rostral Anterior Cingulate Thickness Predicts the Emotional Psilocybin Experience

Authors: Candace R. Lewis, Katrin H. Preller, B. Blair Braden, Cory Riecken & Franz X. Vollenweider

Published: 18 Feb 2020

One-sentence summary: In an MRI study (n=55), the size of the rostral anterior cingulate (but not the caudal and posterior) predicted the size of the subjective psilocybin experience.

“Psilocybin is the psychoactive compound of mushrooms in the psilocybe species. Psilocybin directly affects a number of serotonin receptors, with highest affinity for the serotonin 2A receptor (5HT-2Ar). Generally, the effects of psilocybin, and its active metabolite psilocin, are well established and include a range of cognitive, emotional, and perceptual perturbations. Despite the generality of these effects, there is a high degree of inter-individual variability in subjective psilocybin experiences that are not well understood. Others have shown brain morphology metrics derived from magnetic resonance imaging (MRI) can predict individual drug response. Due to high expression of serotonin 2A receptors (5HT-2Ar) in the cingulate cortex, and its prior associations with psilocybin, we investigate if cortical thickness of this structure predicts the psilocybin experience in healthy adults. We hypothesized that greater cingulate thickness would predict higher subjective ratings in sub-scales of the Five-Dimensional Altered State of Consciousness (5D-ASC) with high emotionality in healthy participants (n = 55) who received oral psilocybin (either low dose: 0.160 mg/kg or high dose: 0.215 mg/kg). After controlling for sex, age, and using false discovery rate (FDR) correction, we found the rostral anterior cingulate predicted all four emotional sub-scales, whereas the caudal and posterior cingulate did not. How classic psychedelic compounds induce such large inter-individual variability in subjective states has been a long-standing question in serotonergic research. These results extend the traditional set and setting hypothesis of the psychedelic experience to include brain structure metrics.”

Self-reported negative outcomes of psilocybin users: A quantitative textual analysis

Authors: Bheatrix Bienemann, Nina Stamato Ruschel, Maria Luiza Campos, Marco Aure´lio Negreiros & Daniel C. MograbiI

Published: 21 Feb 2020

One-sentence summary: An analysis of 346 self-reports of psilocybin validates that both high-dose and repeated-dose use of it is associated with more bad trips.

“Psilocybin, a substance mainly found in mushrooms of the genus psilocybe, has been historically used for ritualistic, recreational and, more recently, medicinal purposes. The scientific literature suggests low toxicity, low risk of addiction, overdose, or other causes of injury commonly caused by substances of abuse, with growing interest in the use of this substance for conditions such as treatment-resistant depression. However, the presence of negative outcomes linked to psilocybin use is not clear yet. The objective of this study is to investigate the negative effects of psilocybin consumption, according to the users’ own perception through self-reports extracted from an online platform. 346 reports were analyzed with the assistance of the IRAMUTEQ textual analysis software, adopting the procedures of Descending Hierarchical Classification, Correspondence Factor Analysis and Specificities Analysis. The text segments were grouped in 4 main clusters, describing thinking distortions, emergencies, perceptual alterations and the administration of the substance. Bad trips were more frequent in female users, being associated with thinking distortions. The use of multiple doses of psilocybin in the same session or its combination with other substances was linked to the occurrence of long-term negative outcomes, while the use of mushrooms in single high doses was linked to medical emergencies. These results can be useful for a better understanding of the effects of psilocybin use, guiding harm-reduction initiatives.”

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