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“Trips and Neurotransmitters: Discovering Principled Patterns across 6,850 Hallucinogenic Experiences”, Ballentine et al 2022

“Trips and neurotransmitters: Discovering principled patterns across 6,850 hallucinogenic experiences”⁠, Galen Ballentine, Samuel Freesun Friedman, Danilo Bzdok (2022-03-16; ; similar):

Psychedelics probably alter states of consciousness by disrupting how the higher association cortex governs bottom-up sensory signals. Individual hallucinogenic drugs are usually studied in participants in controlled laboratory settings.

Here, we have explored word usage in 6,850 free-form testimonials [from Erowid] about 27 drugs through the prism of 40 neurotransmitter receptor subtypes, which were then mapped to 3-dimensional coordinates in the brain via their gene transcription levels from invasive tissue probes.

Despite high interindividual variability, our pattern-learning approach delineated how drug-induced changes of conscious awareness are linked to cortex-wide anatomical distributions of receptor density proxies. Each discovered receptor-experience factor spanned between a higher-level association pole and a sensory input pole, which may relate to the previously reported collapse of hierarchical order among large-scale networks.

Co-analyzing many psychoactive molecules and thousands of natural language descriptions of drug experiences, our analytical framework finds the underlying semantic structure and maps it directly to the brain.

“Efficacy and Safety of Psilocybin-assisted Treatment for Major Depressive Disorder: Prospective 12-month Follow-up”, Gukasyan et al 2022

“Efficacy and safety of psilocybin-assisted treatment for major depressive disorder: Prospective 12-month follow-up”⁠, Natalie Gukasyan, Alan K. Davis, Frederick S. Barrett, Mary P. Cosimano, Nathan D. Sepeda, Matthew W. Johnson et al (2022-02-15; ; similar):

Background: Preliminary data suggest that psilocybin-assisted treatment produces substantial and rapid antidepressant effects in patients with major depressive disorder (MDD), but little is known about long-term outcomes.

Aims: This study sought to examine the efficacy and safety of psilocybin through 12 months in participants with moderate to severe MDD who received psilocybin.

Methods: This randomized, waiting-list controlled study enrolled 27 patients aged 21–75 with moderate to severe unipolar depression (GRID-Hamilton Depression Rating Scale (GRID-HAMD) ⩾ 17). Participants were randomized to an immediate or delayed (8 weeks) treatment condition in which they received 2 doses of psilocybin with supportive psychotherapy. 24 participants completed both psilocybin sessions and were followed through 12 months following their second dose.

Results: All 24 participants attended all follow-up visits through the 12-month timepoint. Large decreases from baseline in GRID-HAMD scores were observed at 1-month, 3-month, 6-month, and 12-month follow-up (Cohen d = 2.3, 2.0, 2.6, and 2.4, respectively). Treatment response (⩾50% reduction in GRID-HAMD score from baseline) and remission were 75% and 58%, respectively, at 12 months. There were no serious adverse events judged to be related to psilocybin in the long-term follow-up period, and no participants reported psilocybin use outside the context of the study. Participant ratings of personal meaning, spiritual experience, and mystical experience after sessions predicted increased well-being at 12 months, but did not predict improvement in depression.

Conclusions: These findings demonstrate that the substantial antidepressant effects of psilocybin-assisted therapy may be durable at least through 12 months following acute intervention in some patients.

[Keywords: insight, long-term effects, major depressive disorder, mystical experience, psilocybin]

“Repeated Low Doses of LSD in Healthy Adults: A Placebo-controlled, Dose-response Study”, Wit et al 2022

2022-dewit.pdf: “Repeated low doses of LSD in healthy adults: A placebo-controlled, dose-response study”⁠, Harriet de Wit, Hanna M. Molla, Anya Bershad, Michael Bremmer, Royce Lee (2022-02-01; backlinks; similar):

The resurgence of interest in using psychedelic drugs, including lysergic acid diethylamide (LSD), in psychiatry has drawn attention to the medically unsupervised practice of ‘microdosing’⁠. Thousands of users claim that very low doses of LSD, taken at 3–4-day intervals, improve mood and cognitive function., However, few controlled studies have described the effects of the drug when taken in this way.

Here, in a double-blind controlled study, we studied the effects of 4 repeated doses of LSD tartrate (13 or 26 μg) or placebo, administered to healthy adults at 3–4 day intervals, on mood, cognitive performance and responses to emotional tasks. Participants were randomly assigned to one of 3 drug conditions: placebo (n = 18), 13 μg LSD (n = 19), or 26 μg LSD (n = 19). They attended 4 5-hour drug-administration sessions separated by 3–4 days, followed by a drug-free follow-up session 3–4 days after the last session.

[Measures: Depression, Anxiety and Stress Scale / Positive and Negative Affect Scale / Addiction Research Center Inventory, Drug Effects Questionnaire, Profile of Mood States (POMS); heart rate / blood pressure; Digital Symbol Substitution Test (DSST) / n-back⁠; Cyberball Emotional Images Task / Emotional Faces Task; 5D-ASC]

LSD (26 μg) produced modest subjective effects including increased ratings of ‘feeling a drug effect’ and both stimulant-like and LSD-like effects, but the drug did not improve mood or affect performance on psychomotor or most emotional tasks. No residual effects were detected on mood or task performance on the drug-free follow-up session.

We conclude that within the context of a controlled setting and a limited number of administrations, repeated low doses of LSD are safe, but produce negligible changes in mood or cognition in healthy volunteers.

[Keywords: behavior, cognition, LSD microdosing⁠, mood, psychopharmacology]

…3.7.3 Cognitive performance: The LSD (13 or 26 μg) groups did not differ from placebo on the n-back or DSST tasks on session 5 (Figure 9). Interestingly, when subjects were asked to rate (on a 7-point scale) how well they thought they performed on the task, subjects in the high-microdose LSD group self-reported performing statistically-significantly above average relative to other participants (one-way ANOVA: drug, F2,49 = 3.86, p = 0.028, 26 μg vs. placebo, p < 0.050) and statistically-significantly better compared with the first time they completed the task (one-way ANOVA: drug, F2,49 = 4.77, p = 0.013, 26 μg vs. placebo, p < 0.050).

Discussion: During the 4 drug administration sessions, LSD (26 μg) produced modest, dose-related increases in stimulant-like (ARCI A and POMS Vigor) and LSD-like effects (ARCI) and ratings of ‘feeling a drug effect’ during the sessions. These effects appeared to be stronger on the earlier sessions. The drug had no effect on most cognitive or emotional tasks or on cardiovascular measures, except for a small decrease in false alarm rates for recognizing fearful emotions, a decrease in feelings of rejection on the social rejection task and a non-statistically-significant trend for improved performance on the DSST. Most subjects did not correctly identify the drug as a hallucinogen/​psychedelic at either dose. There were no lasting effects of the drug on mood or cognitive or emotional performance on the follow-up session…We note that self-reported anxiety and depression ratings, as measured by the DASS, declined substantially from the initial screening to the first study session and then to the follow-up up session, regardless of what drug the participants received.

“Digital Localization in an Illicit Market Space: Interactional Creation of a Psychedelic Assemblage in a Darknet Community of Exchange”, Sawicka et al 2022

“Digital localization in an illicit market space: interactional creation of a psychedelic assemblage in a darknet community of exchange”⁠, Maja Sawicka, Irene Rafanell, Angus Bancroft (2022-02; ; similar):

Sociology of drugs and digital sociology—albeit for different reasons—need the analysis of interactions, an approach underdeveloped in current scholarship. We address this gap by providing a specific analytical framework for the analysis of digital interactions which enables an ethnomethodological account of micro-interactional dynamics within a cryptomarket: an anonymous darknet market of illicit drugs.

As a case study we chose the ‘PsychForumMarket’ which is unusual in that it operates as a forum based market space and explicitly rejects centralised technical market solutions such as escrow and encryption systems. Instead, it emphasises personal relationships between buyers and vendors as the basis of trust. Hence it forms a community of exchange, both material and cultural.

The data were collected through a process of manual scraping from the forum from 2017 to 2020. The data was purposefully sampled to construct a ‘thick data’ set, and analysed thematically to examine the micro interactional turn taking, sanctioning and norming processes by which the market culture is normalized and embedded.

This market is a laboratory to investigate the constitutive nature of digital group interactions. Due to the very nature of this market the disciplining process cannot lie with external authorities. Interactions between community members are permeated with mutual monitoring and policing. We find that in and through digital communication a particular culture emerges to which individuals who wish to join this community have to ascribe. We refer to this particular culture as a ‘psychedelic assemblage,’ i.e., a local constellation of cultural constructs which frames the experience of drug using and trading. Our investigation reveals the constitutive methods which enable the norming of members’ practices and underpin the emergence of a shared lifeworld which in turn ensures the operability of this cryptomarket.

[Keywords: cryptomarket, psychedelic drugs⁠, digital interactions, digital ethnography⁠, emotions, socio-technical assemblage]

“Structure-based Discovery of Non-hallucinogenic Psychedelic Analogs”, Cao et al 2022

2022-cao.pdf: “Structure-based discovery of non-hallucinogenic psychedelic analogs”⁠, Dongmei Cao, Jing Yu, Huan Wang, Zhipu Luo, Xinyu Liu, Licong He, Jianzhong Qi, Luyu Fan, Lingjie Tang et al (2022-01-28; ; similar):

Non-hallucinogenic psychedelic analogs: Psychedelic drugs such as lysergic acid diethylamide (LSD) and mushroom-derived psilocybin exert their effects by binding the serotonin 2A receptor (5-HT2AR). These drugs also have antidepressant effects, but the hallucinations they cause complicate their use as therapeutics. Cao et al 2022 present structures of 5-HT2AR bound to psychedelic drugs, the endogenous ligand serotonin⁠, and the non-hallucinogenic drug lisuride⁠. The structures reveal ligand-receptor interactions that cause a bias toward arrestin recruitment. Based on these insights, the authors designed arrestin-biased ligands that displayed antidepressant-like activity in mice without hallucination effects. Arrestin recruitment alone is insufficient for antidepressant effects, but the low G-protein signaling of the arrestin-biased ligands appears to allow antidepressant effects without causing hallucination.


Drugs that target the human serotonin 2A receptor (5-HT2AR) are used to treat neuropsychiatric diseases; however, many have hallucinogenic effects, hampering their use.

Here, we present structures of 5-HT2AR complexed with the psychedelic drugs psilocin (the active metabolite of psilocybin) & D-lysergic acid diethylamide (LSD), as well as the endogenous neurotransmitter serotonin and the non-hallucinogenic psychedelic analog lisuride.

Serotonin and psilocin display a second binding mode in addition to the canonical mode, which enabled the design of the psychedelic IHCH-7113 (a substructure of antipsychotic lumateperone) and several 5-HT2AR β-arrestin-biased agonists that displayed antidepressant-like activity in mice but without hallucinogenic effects.

The 5-HT2AR complex structures presented herein and the resulting insights provide a solid foundation for the structure-based design of safe and effective non-hallucinogenic psychedelic analogs with therapeutic effects.

…Additionally, although 2 recent studies have reported non-hallucinogenic psychedelic analogs with antidepressant-like behavior (15⁠, 16), it remains unclear how to rationally design such compounds…and it is unclear whether the hallucinogenic effects of psychedelics are necessary for therapeutic effects (2⁠, 7⁠, 8⁠, 9⁠, 10).

[Like the research on dissociating ketamine’s psychedelic effects from its anti-depressant effects⁠, work on “trip-free psychedelics” raise the question of how much of the therapeutic benefit comes from the trip and how much from low-level neurological changes. If the latter, and they can be separated, then the weird beliefs & personality changes of heavy-using psychedelicists may be unnecessary: perhaps those simply reflect the enhanced neuroplasticity during the trip while weird experiences happen to extreme disruption of normal cognition like object recognition or concept of self, and are irrelevant to the benefits (rather than themselves producing the benefits as most psychedelicists strongly believe).]

“Flashback Phenomena After Administration of LSD and Psilocybin in Controlled Studies With Healthy Participants”, Müller et al 2022

“Flashback phenomena after administration of LSD and psilocybin in controlled studies with healthy participants”⁠, Felix Müller, Elias Kraus, Friederike Holze, Anna Becker, Laura Ley, Yasmin Schmid, Patrick Vizeli, Matthias E. Liechti et al (2022-01-25; ; similar):

Background: LSD and psilocybin are increasingly used in phase I trials and evaluated as therapeutic agents for mental disorders. The phenomenon of reoccurring drug-like experiences after the acute substance effects have worn off was described for both substances and especially attributed to LSD. According to the DSM-V⁠, the persisting and distressing manifestation of these experiences is called hallucinogen-persisting perception disorder (HPPD). Data on both conditions is very limited.

Objective: This study aims to provide descriptive data on reoccurring drug-like experiences after the administration of LSD and psilocybin in controlled studies with healthy participants.

Methods & Materials: Data from 142 healthy subjects enrolled in 6 double-blinded, placebo-controlled, randomized cross-over studies were analyzed. In total, 60 subjects received LSD; 27 subjects received LSD, MDMA⁠, and d-amphetamine⁠; 31 subjects received LSD and psilocybin; and 25 subjects received psilocybin and escitalopram⁠. At the end-of-study visit (mean 39.8 days after last study session, SD 37.2), subjects were asked for any reoccurring drug effects since the initial substance effects had worn off. Those reporting reoccurring perception changes more than 24 h after administration were contacted for follow-up (mean follow-up duration: 31.2 months, SD 28.6).

Results: 13 out of 142 subjects reported reoccurring drug-like experiences (LSD: 7, psilocybin: 2, both: 4). The reported phenomena were predominantly mild and perceived as neutral to pleasant. Flashbacks were mostly of visual nature, lasted for seconds to minutes, and occurred within a week after the last drug administration. 2 subjects reported distressing experiences that subsided spontaneously. One subject reported brief and pleasant visual perception changes which reoccurred for 7 months. None of the subjects reported impairment in their daily lives. None of the cases met DSM-V criteria for HPPD.

Conclusion: Reoccurring drug-like experiences after the administration of LSD and psilocybin are a common phenomenon occurring in up to 9.2% of healthy subjects (7.8% for LSD, 8.3% for psilocybin and 14.3% if both substances are administered). Additionally, our work suggests that flashback phenomena are not a clinically relevant problem in controlled studies with healthy participants.

“Evenings With Molly: Adult Couples’ Use of MDMA for Relationship Enhancement”, Colbert & Hughes 2022

2022-colbert.pdf: “Evenings with Molly: Adult Couples’ Use of MDMA for Relationship Enhancement”⁠, Robert Colbert, Shannon Hughes (2022-01-15; similar):

Within the modern resurgence of psychedelics as medicinal agents for a range of conditions, the story of MDMA (Ecstasy, Molly) has been re-narrated from a dangerous street drug to a breakthrough mental health therapy. Even still, the story of MDMA remains incomplete within a binary discourse of deviant recreational use versus psychotherapeutic-medical use.

The present research aimed to uncover an emerging model of MDMA use grounded in the experiences of adult couples using MDMA privately and in the context of their committed relationships. 8 adult couples who self-reported active MDMA use were recruited for confidential in-depth interviews exploring questions related to drug, set, and setting as a general framework for understanding their private experiences with MDMA.

A general inductive coding process was used to arrive at 4 overarching themes: Conscious Use, A Tool for Exploring, Planned Recovery, and Difficult Experiences. Couples reported making purposeful decisions about MDMA use, collaborating together on becoming physically and emotionally “set” for their drug experience. Couples described positive effects on communication, intimate bonding, and providing a relationship “tune up”, among other durable changes to the relationship.

An emerging cognitive-relational model of “evenings with Molly” contrasts with existing models of use by suggesting the possibility of informed, non-problematic adult use of the drug for cognitive and relational enhancement. With a small, homogenous sample reporting generally positive experiences with MDMA self-administration, findings from this study cannot be generalized. It remains unknown what proportion of the total MDMA user population might align with the non-problematic adult use of MDMA explored in this study. Additional focused investigations might examine the prevalence and varieties of non-clinical use among adults in order to arrive at rational, science-based regulatory frameworks.

“The Effects of Psilocybin on Cognitive and Emotional Functions in Healthy Participants: Results from a Phase 1, Randomised, Placebo-controlled Trial Involving Simultaneous Psilocybin Administration and Preparation”, Rucker et al 2022

“The effects of psilocybin on cognitive and emotional functions in healthy participants: Results from a phase 1, randomised, placebo-controlled trial involving simultaneous psilocybin administration and preparation”⁠, James J. Rucker, Lindsey Marwood, Riikka-Liisa J. Ajantaival, Catherine Bird, Hans Eriksson, John Harrison et al (2022-01-04; ; similar):

Background: Psilocybin⁠, a psychoactive serotonin receptor partial agonist, has been reported to acutely reduce clinical symptoms of depressive disorders. Psilocybin’s effects on cognitive function have not been widely or systematically studied.

Aim: The aim of this study was to explore the safety of simultaneous administration of psilocybin to healthy participants in the largest randomised controlled trial of psilocybin to date. Primary and secondary endpoints assessed the short-term and longer-term change in cognitive functioning, as assessed by a Cambridge Neuropsychological Test Automated Battery (CANTAB) Panel, and emotional processing scales. Safety was assessed via endpoints which included cognitive function, assessed by CANTAB global composite score, and treatment-emergent adverse event (TEAE) monitoring.

Methods: In this phase 1, randomised, double-blind, placebo-controlled study, healthy participants (n = 89; mean age 36.1 years; 41 females, 48 males) were randomised to receive a single oral dose of 10 or 25 mg psilocybin, or placebo, administered simultaneously to up to 6 participants, with one-to-one psychological support—each participant having an assigned, dedicated therapist available throughout the session.

Results: In total, 511 TEAEs were reported, with a median duration of 1.0 day; 67% of all TEAEs started and resolved on the day of administration. There were no serious TEAEs, and none led to study withdrawal. There were no clinically relevant between-group differences in CANTAB global composite score, CANTAB cognitive domain scores, or emotional processing scale scores.

Conclusions: These results indicate that 10 mg and 25 mg doses of psilocybin were generally well tolerated when given to up to 6 participants simultaneously and did not have any detrimental short-term or long-term effects on cognitive functioning or emotional processing.

Clinical Trial Registration: EudraCT (https:/​/​www.clinicaltrialsregister.eu/​) number: 2018-000978-30.

[Keywords: Psilocybin, cognition, emotional processing, placebo-controlled, randomised clinical trial]

“United States National Institutes of Health Grant Funding for Psychedelic-assisted Therapy Clinical Trials from 2006–2020”, Barnett et al 2022

2022-barnett.pdf: “United States National Institutes of Health grant funding for psychedelic-assisted therapy clinical trials from 2006–2020”⁠, Brian S. Barnett, Sloane E. Parker, Jeremey Weleff (2022; ; similar):

Background: Medicine is currently experiencing a “psychedelic renaissance”, said by many to have commenced in 2006. Since then, clinical trials have consistently demonstrated promising findings for psychedelic-assisted therapies in the treatment of various mental health conditions and addictions. While most of this work has been privately funded, governmental biomedical research funding bodies in countries such as Australia, Canada, Israel, New Zealand, and the United Kingdom have begun supporting it. Given that the United States National Institutes of Health (NIH) is the largest public funder of biomedical research in the world, it is important to understand the degree to which the organization is supporting clinical trials of psychedelic-assisted therapies. We are unaware of existing literature quantifying direct NIH grant support for psychedelic-assisted therapy clinical trials, so we sought to answer this important question by searching all NIH grants awarded since the beginning of the psychedelic renaissance.

Methods: We queried NIH RePORTER, NIH’s grant database, for grants awarded from 2006–2020 mentioning the psychedelics 3,4-Methylenedioxymethamphetamine (MDMA), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), ayahuasca⁠, dimethyltryptamine (DMT), ibogaine⁠, lysergic acid (LSD), mescaline⁠, peyote⁠, and psilocybin⁠. We manually reviewed resulting grants to determine whether they directly funded psychedelic-assisted therapy clinical trials.

Results: We identified 0 NIH grants directly funding psychedelic-assisted therapy clinical trials during the study period.

Conclusion: While governmental biomedical research funding bodies in other countries have begun funding clinical trials of psychedelic-assisted therapies during the psychedelic renaissance, NIH has yet to directly fund a single psychedelic-assisted therapy clinical trial. Concerns about risks related to psychedelics, a federal law preventing promotion of legalization of Schedule 1 drugs, and prioritization of grants for other types of studies on psychedelics may explain the dearth of NIH funding for psychedelic-assisted therapy clinical trials.

[Keywords: psychedelics, psychedelic-assisted therapy, hallucinogens, research funding, National Institutes of Health, psilocybin, MDMA, ibogaine, ayahuasca, LSD, dimethyltryptamine]

“Psychedelics Alter Metaphysical Beliefs”, Timmermann et al 2021

“Psychedelics alter metaphysical beliefs”⁠, Christopher Timmermann, Hannes Kettner, Chris Letheby, Leor Roseman, Fernando E. Rosas, Robin L. Carhart-Harris et al (2021-11-23; ; similar):

Can the use of psychedelic drugs induce lasting changes in metaphysical beliefs? While it is popularly believed that they can, this question has never been formally tested.

Here we exploited a large sample derived from prospective online surveying to determine whether and how beliefs concerning the nature of reality, consciousness, and free-will, change after psychedelic use.

Results: revealed statistically-significant shifts away from ‘physicalist’ or ‘materialist’ views, and towards panpsychism and fatalism⁠, post use. With the exception of fatalism, these changes endured for at least 6 months, and were positively correlated with the extent of past psychedelic-use and improved mental-health outcomes. Path modelling suggested that the belief-shifts were moderated by impressionability at baseline and mediated by perceived emotional synchrony with others during the psychedelic experience.

The observed belief-shifts post-psychedelic-use were consolidated by data from an independent controlled clinical trial.

Together, these findings imply that psychedelic-use may causally influence metaphysical beliefs—shifting them away from ‘hard materialism’. We discuss whether these apparent effects are contextually independent.

…We compared NPB scores before attending a ceremony involving psychedelic use (baseline) with NPB scores 4 weeks and 6 months after the ceremony. Pooling scores for the NPB factor, analyses revealed a statistically-significant shift away from physicalism at 4 weeks compared with baseline (t(121) = 3.66, p = 0.001, d = 0.33, 95% confidence interval [0.12, 0.39]). These changes were sustained 6 months after the ceremony (t(121) = 5.07, p < 0.0001, d = 0.46, 95% CI [0.22, 0.50]) (Figure 1a). Larger effect-sizes were found for respondents who were embarking on their first psychedelic experience (the so-called ‘psychedelic naïve’), with statistically-significant changes found at 4 weeks (t(52) = 3.85, p = 0.001, d = 0.53, 95% CI [0.21, 0.66]) and 6 months (t(52) = 5.32, p < 0.0001, d = 0.73, 95% CI [0.36, 0.80]) (Supplementary Figure 1a). Analyses of each individual item for the NPB factor revealed increases in notions of transcendentalism, mind-body dualism, and panpsychism—among others, with some changes remaining statistically-significant for 6 months (see Figure 1b-left and Supplementary Figure 1b for findings for ‘naïve’ respondents). Additionally, a statistically-significant positive correlation was found between previous psychedelic use and shifts away from the hard-materialism pole of the hard-materialism vs. hard-dualism spectrum (Figure 1b-right) at baseline (r = 0.223, p < 0.0001).

Validation with data from a controlled clinical trial: To test the validity and replicability of our findings, we included items corresponding to the NPB in a double-blind randomized controlled trial comparing a group (n = 30) receiving psilocybin therapy with another undergoing a 6-week course of escitalopram (n = 29) (See “Methods” for details of trial design).

Results replicated well across the independent studies. That is, a statistically-significant drug versus time (before treatment and 6 weeks after) interaction was observed (F(56) = 3.13, p = 0.041, one-tailed). More specifically, post-hoc tests reveal that shifts away from hard materialism were evident in the psilocybin group only (Z = 2.28, p = 0.02, d = 0.45). The escitalopram group showed no changes in NPB (Z = 0.24, p = 0.33, d = 0.2). (Figure 5a). Importantly, consistent with the above-reported findings of a relationship between belief shifts and positive mental health outcomes, statistically-significantly greater shifts away from hard materialistic beliefs (the NPB factor) were found for those patients who showed a clinically meaningful response to psilocybin only (response is defined as at least 50% reduction in depression scores from baseline to week 6), versus those who showed a response to escitalopram (Z = 1.74, p = 0.041, g = 0.56, 90% CI [−0.17, 1.26]) (Figure 5b). Finally, we found that the belief-shifts in the psilocybin condition were largely correlated with positive endorsement of an unifying spiritual principle (measured at the same timepoints as metaphysical beliefs; see “Supplementary Methods” for the items used), indicating that changes in metaphysical beliefs are related to changes in spiritual beliefs, and are specific to the action of psychedelics versus a conventional antidepressant drug (Figure 5c).

Figure 5: Consistent shifts away from physicalism after psilocybin therapy for depression: (a) statistically-significant shifts away from hard physicalism were only seen for psilocybin and not the escitalopram condition at the 6 week endpoint versus baseline (Bonferroni-corrected; p-values and Cohen’s d effect-sizes shown). (b) Greater belief-shifts in the predicted direction were found for treatment responders in the psilocybin condition versus responders in the escitalopram group (p value and Hedges’ g effect size shown). (c) Shift in non-physicalist beliefs were statistically-significantly associated with increases in ‘Spiritual Universality’ (STS scale) at the 6-week endpoint versus baseline, and this was specific for the psilocybin group (ie. it was not seen in the escitalopram group).

“Adults Who Microdose Psychedelics Report Health Related Motivations and Lower Levels of Anxiety and Depression Compared to Non-microdosers”, Rootman et al 2021

“Adults who microdose psychedelics report health related motivations and lower levels of anxiety and depression compared to non-microdosers”⁠, Joseph M. Rootman, Pamela Kryskow, Kalin Harvey, Paul Stamets, Eesmyal Santos-Brault, Kim P. C. Kuypers et al (2021-11-18; ⁠, ; backlinks; similar):

The use of psychedelic substances at sub-sensorium microdoses⁠, has gained popular academic interest for reported positive effects on wellness and cognition.

The present study describes microdosing practices, motivations and mental health among a sample of self-selected microdosers (n = 4,050) and non-microdosers (n = 4,653) via a mobile application.

Psilocybin was the most commonly used microdose substances in our sample (85%) and we identified diverse microdose practices with regard to dosage, frequency, and the practice of stacking which involves combining psilocybin with non-psychedelic substances such as Lion’s Mane mushrooms⁠, chocolate⁠, and niacin⁠. Microdosers were generally similar to non-microdosing controls with regard to demographics, but were more likely to report a history of mental health concerns. Among individuals reporting mental health concerns, microdosers exhibited lower levels of depression, anxiety, and stress across gender. Health and wellness-related motives were the most prominent motives across microdosers in general, and were more prominent among females and among individuals who reported mental health concerns.

Our results indicate health and wellness motives and perceived mental health benefits among microdosers, and highlight the need for further research into the mental health consequences of microdosing including studies with rigorous longitudinal designs.

[Keywords: addiction, ADHD⁠, anxiety, Autism spectrum disorders, Bipolar disorder, Depression, human behaviour, Obsessive Compulsive Disorder, Post-Traumatic Stress Disorder, psychiatric disorders, psychology, psychosis, Schizophrenia]

Design and participants: We collected cross-sectional data between November 2019 and July 2020 from self-selected respondents recruited via media related to psychedelic use such as podcasts and online psychedelic research conference presentations. Participants were directed to the Microdose.me website⁠. The website directed participants to install the Quantified Citizen (QC) application32 to their Apple mobile device. The QC application was only available on Apple iOS devices at the time of study; as such, participants were limited to iPhone users. The application hosted the study and participants completed questionnaires and assessments entirely within the application. To encourage participation, users were explicitly not asked to submit any personally identifiable information and use of the application was designed to be completely anonymous. All participants endorsed being 18 years of age or older and capable of responding to an English survey. Nonetheless, given the anonymous nature of the study design, these inclusion criteria could not be verified beyond participant self-report. All participants provided informed consent prior to study initiation. Data are drawn from the baseline and supplementary questionnaires from a longitudinal study of microdosing and mental health and consisted of a maximal total of 123 questions, organized hierarchically such that many items were contingent on prior responses.

“Largest Psilocybin Trial Finds the Psychedelic Is Effective in Treating Serious Depression”, Goldhill 2021

“Largest psilocybin trial finds the psychedelic is effective in treating serious depression”⁠, Olivia Goldhill (2021-11-09; ; similar):

Eagerly awaited results of the largest-ever study of psilocybin were announced Tuesday, with Compass Pathways revealing the psychedelic drug was highly efficacious as a therapy for treatment-resistant depression⁠. Still, the company’s stock price dropped 16.4% by the close of trading, perhaps because of safety concerns among investors.

The Phase 2b study is the largest randomized, controlled, double-blind trial of psilocybin, the psychedelic compound in magic mushrooms. The company said it found that patients who were given the highest dose, 25 milligrams, had a statistically-significant decrease in depressive symptoms compared to those given 1 milligram, which is such a low dose it functions as a placebo.

Overall, 29.1% of patients in the highest-dose group were in remission 3 weeks after treatment, compared to 7.6% of those in the control group, and more than a quarter of the patients in the 25-milligram arm were still in remission 3 months after treatment. Those who received the highest dose also experienced an average reduction on a measure of clinical depression (the Montgomery-Asberg Depression Rating Scale) that was 6.6 points greater than those who took 1 milligram. Other patients were given a 10-milligram dose, but there was not a statistically-significant impact for those patients compared with the 1-milligram arm.

“Psilocybin Therapy Increases Cognitive and Neural Flexibility in Patients With Major Depressive Disorder”, Doss et al 2021

“Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder”⁠, Manoj K. Doss, Michal Považan, Monica D. Rosenberg, Nathan D. Sepeda, Alan K. Davis, Patrick H. Finan et al (2021-11-08; ; similar):

Psilocybin has shown promise for the treatment of mood disorders, which are often accompanied by cognitive dysfunction including cognitive rigidity. Recent studies have proposed neuropsychoplastogenic effects as mechanisms underlying the enduring therapeutic effects of psilocybin.

In an open-label study of 24 patients with major depressive disorder⁠, we tested the enduring effects of psilocybin therapy on cognitive flexibility (perseverative errors on a set-shifting task), neural flexibility (dynamics of functional connectivity or dFC via functional magnetic resonance imaging), and neurometabolite concentrations (via magnetic resonance spectroscopy) in brain regions supporting cognitive flexibility and implicated in acute psilocybin effects (eg. the anterior cingulate cortex⁠, or ACC).

Psilocybin therapy increased cognitive flexibility for at least 4 weeks post-treatment, though these improvements were not correlated with the previously reported antidepressant effects. One week after psilocybin therapy, glutamate and N-acetylaspartate concentrations were decreased in the ACC, and dFC was increased between the ACC and the posterior cingulate cortex (PCC). Surprisingly, greater increases in dFC between the ACC and PCC were associated with less improvement in cognitive flexibility after psilocybin therapy. Connectome-based predictive modeling demonstrated that baseline dFC emanating from the ACC predicted improvements in cognitive flexibility. In these models, greater baseline dFC was associated with better baseline cognitive flexibility but less improvement in cognitive flexibility.

These findings suggest a nuanced relationship between cognitive and neural flexibility. Whereas some enduring increases in neural dynamics may allow for shifting out of a maladaptively rigid state, larger persisting increases in neural dynamics may be of less benefit to psilocybin therapy.

“Wastewater Analysis for Psychoactive Substances at Music Festivals across New South Wales, Australia in 2019–2020”, Jonathan et al 2021

2021-brett.pdf: “Wastewater analysis for psychoactive substances at music festivals across New South Wales, Australia in 2019–2020”⁠, Brett Jonathan, Siefried Krista J., Healey Amy, Harrod Mary Ellen, Franklin Erica, Barratt Monica J. et al (2021-09-20; ; similar):

Introduction: Implementation of wastewater surveillance at music festivals has been limited to date. We aimed to use wastewater analysis and a self-report survey to determine the range of psychoactive substances being used during a music festival season in New South Wales, Australia⁠.

Methods: We sampled 6 single-day music festivals requiring a music festival license in New South Wales from March 2019 to March 2020; between 15% and 100% of portaloos (temporary, un-fixed toilet facilities) were sampled at each festival. Samples were screened for 98 psychoactive substances and/​or their metabolites with results qualitatively expressed as detection frequencies for each substance at each festival and across all festivals. We compared these data with the results of surveys of self-reported drug use at 4 of the 6 festivals.

Results: Festival attendance ranged from 6,200 to 14,975 people. Amphetamine⁠, cocaine⁠, ketamine⁠, methylone⁠, MDMA⁠, MDA⁠, alprazolam⁠, diazepam⁠, etizolam⁠, oxazepam and temazepam were found in almost all samples from all festivals. Ethylone⁠, mephedrone and methcathinone were also found in over 50% of festivals. Acetyl norfentanyl (a fentanyl metabolite) and n-ethylpentylone were found at 2⁄6 and 1⁄6 festivals. No festival survey participant reported intentionally taking cathinones.

Discussion: The detection frequency for cathinones was higher than expected relative to recent other data sources and this may represent adulteration or substitution. Similarly, the appearance of etizolam may be related to the use of counterfeit alprazolam. The detection of highly toxic substances such as n-ethylpentylone and norfentanyl may warrant public health alerts.

Conclusion: If provided close to real time, wastewater analysis at festivals could be complemented with information sources such as drug checking, on-site surveys, medical presentations and intelligence from peer networks to feed into early warning systems, public health alerts and peer-based harm reduction education during the festival season.

[Keywords: Festivals, drugs, wastewater, novel psychoactive substances]

“Psychedelic Drugs and Atheism: Debunking the Myths”, Glausser 2021

“Psychedelic Drugs and Atheism: Debunking the Myths”⁠, Wayne Glausser (2021-08-08; similar):

Two recent surveys [Griffiths et al 2019⁠, Davis et al 2020]. of people who took psychedelic drugs and reported “God experience encounters”, along with successful clinical trials using psychedelic therapy for depression, have given rise to public misconceptions about psychedelics and atheism. Specifically, 3 inferences have been drawn:

  1. that the psychedelic experience tends to dissolve atheist convictions;
  2. that atheist convictions, once dissolved, are replaced with traditional monotheist beliefs; and
  3. that atheism and depression somehow correlate as afflictions for which psychedelic drugs offer relief.

This paper argues, based on analysis of the studies and trials along with relevant supplemental evidence, that each of these popular inferences is substantially misleading. Survey data do not indicate that most psychedelic atheists have cleanly cut ties with their former convictions, and there is strong evidence that they have not traded atheism for traditional monotheism. Both personal testimony and the effectiveness of microdose clinical trials serve to complicate any notion that a psychedelic drug alleviates symptoms of depression by “curing” atheism.

The paper then extends its focus to argue that the broader field of neurotheology includes elements that contribute to these popular misconceptions.

[Keywords: psychedelic drugs, atheism, monotheism, pantheism, depression, neurotheology]

…The first and most obvious weakness in popular inferences about psychedelics and theistic belief has to do with the selective criterion for participation in the studies. The first study surveyed only individuals who self-reported something that felt like a God experience encounter. The DMT study asked for those who had experienced an entity encounter, which might seem a more neutral term—but the authors elicited descriptions of the entity with categories very similar to those used in the first study. Given that the people surveyed constituted a special subset of psychedelic users—those who experienced something that felt like an encounter with a godlike entity—it is notable and somewhat surprising that as many as 534 of them continued to identify as atheist afterwards.

One of the co-authors of the 2019 study made this very point about the specially selected survey group, in order to fend off a bioethicist’s complaint. The bioethicist had cited the 2019 data about atheists and worried that the medical profession, ideally “neutral and agnostic” on religious matters, might violate that neutrality if psychedelic therapy should become a mainstream option (Jacobs 2020). Co-author Matthew Johnson countered that “belief change of a religious type”, such as the reduction in the percentage of atheists reported in his study, “would be massively inflated in this sample” (Johnson 2020).

However, there are other weaknesses besides the obvious problem of a selective survey population. Even with analysis of just this special subset of psychedelic users, popular inferences do not stand up to scrutiny. Survey data clearly do not support the second of the inferences, the supposed conversion of atheists to traditional monotheism. Among the total psychedelic participants in the multi-drug study, “Identification as monotheist statistically-significantly decreased and identification as Other statistically-significantly increased from before to after the experience” (Griffiths et al 2019). “Other” for the survey signified neither monotheist nor atheist. In this survey, in fact, the vast majority—85%—chose “Other” as their religious affiliation after a psychedelic drug occasioned a God experience encounter. If the psychedelic experience was tempting people away from the atheist label, it certainly did not move them into the camp of traditional monotheism.

It is reasonable to assume, then, that all or nearly all of those who identified as atheist before their psychedelic encounters either continued to identify as atheist or chose to identify neither as atheist nor monotheist. Contrary to the popular misconception, their psychedelic experience did not convert them from atheism to belief in a traditional God. There remains the question of what the shift from atheist to Other signifies. Does it mean that the psychedelic experience, at least within this selective group, dissolved atheist convictions?

Careful analysis of the 2 surveys suggests a more complex result. In the first study, a key question asked participants to choose the “best descriptor of that which was encountered”: “God (the God of your understanding)”, “Ultimate Reality”, “Higher Power”, or “An Aspect or emissary of God (eg. an angel)” (Griffiths et al 2019). Data for the psychedelic group—the full group, not just those who had identified as atheist—indicated that a majority, 55%, chose “Ultimate Reality” as the best descriptor. Despite the fact that the survey was framed with the term “God experience encounter”, the descriptor “God” finished in third place, the choice of only 18%. Given that only 18% of the entire psychedelic group chose God, it is likely that the atheist subset, only one-fifth of the group, chose God in very small numbers, if at all.

In the DMT survey, where the before and after numbers for atheism were similar, the study was framed with the more neutral term “entity encounter experience”. This study also offered a question about God and Ultimate Reality, but in a form that made it unhelpful for comparison with the first study. The DMT group was asked whether they “identified as believing in Ultimate Reality, Higher Power, God, or Universal Divinity” (Davis et al 2020). The authors made note of a large increase in these numbers: 36% answered yes before the experience, 58% afterwards. Because the 4 entity descriptors were merged into a single category, there can be no differentiating analysis of their separate implications. Interestingly, however, the authors—all of whom worked on the 2019 study—borrowed the first 3 descriptors from the earlier survey, but changed the order of listing. This time, they arranged them in order of popularity from those earlier results, with Ultimate Reality listed first, and God now third.

The descriptor Ultimate Reality took clear priority over God in the first study, and although ambiguous survey construction clouded results in the second, Ultimate Reality led the cluster of available descriptors. The number of atheists dropped from 21% to 8% in the first study and from 28% to 10% in the second. If we posit that nearly all of those who swerved away from atheism chose to identify as Other, and most of them encountered an entity best described as Ultimate Reality, is a religious position so defined fundamentally incompatible with atheism? This is the crucial question for evaluating the first popular inference, about psychedelic experience dissolving atheist conviction.

“Psilocybin Induces Rapid and Persistent Growth of Dendritic Spines in Frontal Cortex in Vivo”, Shao et al 2021

“Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo”⁠, Ling-Xiao Shao, Clara Liao, Ian Gregg, Pasha A. Davoudian, Neil K. Savalia, Kristina Delagarza, Alex C. Kwan et al (2021-06-02; similar):

Psilocybin is a serotonergic psychedelic with untapped therapeutic potential. There are hints that the use of psychedelics can produce neural adaptations, although the extent and time scale of the impact in a mammalian brain are unknown. In this study, we used chronic two-photon microscopy to image longitudinally the apical dendritic spines of layer 5 pyramidal neurons in the mouse medial frontal cortex. We found that a single dose of psilocybin led to ~10% increases in spine size and density, driven by an elevated spine formation rate. The structural remodeling occurred quickly within 24 hours and was persistent 1 month later. Psilocybin also ameliorated stress-related behavioral deficit and elevated excitatory neurotransmission. Overall, the results demonstrate that psilocybin-evoked synaptic rewiring in the cortex is fast and enduring, potentially providing a structural trace for long-term integration of experiences and lasting beneficial actions.

“Leroy’s Elusive Little People: A Systematic Review on Lilliputian Hallucinations”, Blom 2021

“Leroy’s elusive little people: A systematic review on lilliputian hallucinations”⁠, Jan Dirk Blom (2021-06; ; similar):

  • Lilliputian hallucinations are not as harmless as traditionally assumed.
  • Their etiology is diverse, with CNS pathology accounting for a third of the cases.
  • Therefore, in most cases auxiliary investigations are advisable.
  • Treatment is directed at the underlying cause.
  • A failure of size constancy may explain part of the underlying mechanism.

Lilliputian hallucinations concern hallucinated human, animal or fantasy entities of minute size. Having been famously described by the French psychiatrist Raoul Leroy in 1909, who wrote from personal experience, to date they are mentioned almost routinely in textbooks of psychiatry, albeit with little in-depth knowledge.

I therefore systematically reviewed 145 case reports and case series comprising 226 case descriptions, concluding that lilliputian hallucinations are visual (61%) or multimodal (39%) in nature. In 97% of the cases, they are perceived as grounded in the actual environment, thus indicating involvement of higher-level regions of the perceptual network subserving the fusion of sensory and hallucinatory content. Perceptual release and deafferentiation [“loss of peripheral afferent input, believed to lead under many circumstances to central hyperirritability or excitatory states”] are the most likely underlying mechanisms. Etiology is extremely diverse, with schizophrenia spectrum disorder, alcohol use disorder and loss of vision accounting for 50% of the cases and neurological disease for 36%. Recovery was obtained in 62% of the cases, whereas 18% of the cases ended in chronicity and 8% in death.

Recommendations are made for clinical practice and future research.

[Keywords: Alcohol hallucinosis, Charles Bonnet syndrome, entity experience, intoxication, multimodal hallucination, psychedelics, size constancy]

“What Happens When You Ask Questions to the DMT Entities?”, Josikinz & algekalipso 2021

“What Happens When You Ask Questions to the DMT Entities?”⁠, Josikinz, algekalipso (2021-05-14; ; backlinks; similar):

Josikinz recently posted a wonderful video on Youtube titled “Psychedelic Entities—broken down and described”⁠. I really appreciate the use of high-quality psychedelic replication art throughout the video in order to illustrate what they are talking about. I recommend watching the whole video; below an excerpt that discusses what happens when you try to ask these entities questions (starting at 10:53):

Personal Commentary: …a substantial potion of the people who encounter them will go as far as to assert that these experiences are not simply fabrications of the mind, but rather beings from another world that exist independently of the human brain. This is a viewpoint that was originally popularized in mainstream culture by the likes of Terence McKenna, who famously theorized that the machine elves he encountered under the influence of DMT were either extraterrestrial in nature, interdimensional beings from a higher plane of existence, time-traveling humans from the future, or an ecology of souls that apparently includes both our ancestors and those who are yet to be born. As far as I can tell, the most common reasonings behind this viewpoint are that the experience of encountering these entities is often interpreted as feeling more realistic and well-defined than that of any sober experience the person has ever had. Alongside this, there is often a sense that the encounter itself is so incomprehensibly complex and other-worldly that there is simply no possible way that the human brain could generate such an experience on its own.

In regards to this particular notion, it is then sometimes asserted that consciousness must be an antenna of sorts that receives either all or some of its subjective experiences from that of an unknown interdimensional source. Furthermore, the source of this received input is sometimes said to be adjustable depending on the person’s brain state. With substances such as psychedelics simply “tuning” our consciousness into the analogous equivalent of a different radio station or TV channel. This is an idea that was once again further popularized by Terence McKenna, who is famously quoted as saying: “I don’t believe that consciousness is generated in the brain anymore than TV programs are made inside my TV. The box is too small.”

…In my personal opinion, if autonomous entities were truly something that exists beyond the human mind, I think there would likely be a single verifiable case of them conveying information to a person that they did not already know or could not have come to the conclusion of within that moment. This would also likely be testable to some degree, which has led myself and my close friends to casually experiment with asking DMT entities a variety of questions over the years [emphasis mine]. These questions have included math problems, metaphysical questions, philosophical questions, and queries pertaining to the general nature of beings inhabiting their particular world. However, each attempt at doing so has resulted in the entities simply ignoring the question, arrogantly scoffing at the absurdity of us asking them such a trivial thing, or replying with vague ambiguous wording that the person’s own mind could have easily come up with. This has even been the case when the entities are presenting themselves as vastly more complex, knowledgeable, and powerful than the humans that they are interacting with.

“Psychedelic-inspired Drug Discovery Using an Engineered Biosensor”, Dong et al 2021

2021-dong.pdf: “Psychedelic-inspired drug discovery using an engineered biosensor”⁠, Chunyang Dong, Calvin Ly, Lee E. Dunlap, Maxemiliano V. Vargas, Junqing Sun, In-Wook Hwang, Arya Azinfar et al (2021-05-13; ; backlinks; similar):

  • Engineered psychLight—a genetically encoded 5-HT sensor based on the 5-HT2AR
  • PsychLight can measure 5-HT dynamics in behaving mice
  • A psychLight-based cellular imaging platform predicts hallucinogenic potential
  • Identified a non-hallucinogenic psychedelic analog with antidepressant properties

Ligands can induce G protein-coupled receptors (GPCRs) to adopt a myriad of conformations, many of which play critical roles in determining the activation of specific signaling cascades associated with distinct functional and behavioral consequences. For example, the 5-hydroxytryptamine 2A receptor (5-HT2AR) is the target of classic hallucinogens, atypical antipsychotics, and psychoplastogens. However, currently available methods are inadequate for directly assessing 5-HT2AR conformation both in vitro and in vivo.

Here, we developed psychLight, a genetically encoded fluorescent sensor based on the 5-HT2AR structure. PsychLight detects behaviorally relevant serotonin release and correctly predicts the hallucinogenic behavioral effects of structurally similar 5-HT2AR ligands. We further used psychLight to identify a non-hallucinogenic psychedelic analog, which produced rapid-onset and long-lasting antidepressant-like effects after a single administration.

The advent of psychLight will enable in vivo detection of serotonin dynamics, early identification of designer drugs of abuse, and the development of 5-HT2AR-dependent non-hallucinogenic therapeutics.

[Keywords: genetically encoded indicators, serotonin, serotonin receptors, psychedelic, hallucinogen, depression]

“MDMA-assisted Therapy for Severe PTSD: a Randomized, Double-blind, Placebo-controlled Phase 3 Study”, Mitchell et al 2021

“MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study”⁠, Jennifer M. Mitchell, Michael Bogenschutz, Alia Lilienstein, Charlotte Harrison, Sarah Kleiman, Kelly Parker-Guilbert et al (2021-05-10; ; similar):

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective.

We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with 3 preparatory and 9 integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study.

MDMA was found to induce statistically-significant and robust attenuation in CAPS-5 score compared with placebo (p < 0.0001, d = 0.91) and to statistically-significantly decrease the SDS total score (p = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities.

We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

“A 'Trip' to the Intensive Care Unit: An Intravenous Injection of Psilocybin”, Giancola et al 2021

2021-giancola.pdf: “A 'Trip' to the Intensive Care Unit: An Intravenous Injection of Psilocybin”⁠, Nicholas B. Giancola, Clayton J. Korson, Jason P. Caplan, Curtis A. McKnight (2021-05-01; similar):

Here, we describe a case of a 30-year-old man who injected psilocybin intravenously resulting in an extended stay in the intensive care unit because of multiple-system organ failure.

…History gathered from his family was remarkable for recent non-adherence with his prescribed psychotropics (risperidone and valproate) and subsequent cycling between depressive and manic states. He had reportedly been researching ways to self-treat his opioid dependence and depression.

In his reading, he encountered reports of therapeutic effects of microdosing lysergic acid diethylamide and hallucinogenic psilocybin mushrooms prompting him to inject what he had named “mushroom tea”–psilocybin mushrooms boiled down in water. He then “filtered” this substance by drawing it through a cotton swab before directly injecting the solution intravenously. Over the next several days, he developed lethargy, jaundice, diarrhea, nausea, and hematemesis before he was found by his family and taken to the emergency department.

…He was then transferred to the intensive care unit for evidence of multi-organ failure…His hospital course was further complicated by septic shock and acute respiratory failure requiring intubation on hospital day 2…Cultures confirmed both bacterial (ultimately cultured as Brevibacillus) and fungal infections (ultimately cultured and DNA identified by a specialist laboratory as Psilocybe cubensis—i.e., the species of mushroom he had injected was now growing from his blood).

“Trial of Psilocybin versus Escitalopram for Depression”, Carhart-Harris et al 2021

2021-carhartharris.pdf: “Trial of Psilocybin versus Escitalopram for Depression”⁠, Robin Carhart-Harris, Bruna Giribaldi, Rosalind Watts, Michelle Baker-Jones, Ashleigh Murphy-Beiner, Roberta Murphy et al (2021-04-15; ; backlinks; similar):

Background: psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.

Methods: In a phase 2, double-blind, randomized controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram⁠, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive 2 separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or 2 separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.

Results: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group.

The mean (±SE) changes in the scores from baseline to week 6 were −8.0±1.0 points in the psilocybin group and −6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], −5.0 to 0.9) (p = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, −3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54).

Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons⁠. The incidence of adverse events was similar in the trial groups.

Conclusions: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a statistically-significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants.

(Funded by the Alexander Mosley Charitable Trust and Imperial College London’s Centre for Psychedelic Research; ClinicalTrials.gov number, NCT03429075⁠.)

“Citizen Science: Asking Questions of Psychedelic Microdosing”, Cameron 2021

“Citizen Science: Asking questions of psychedelic microdosing”⁠, Lindsay P. Cameron (2021-03-02; ; backlinks; similar):

A citizen science approach to research has shown that the improvements in mood and cognition associated with psychedelic microdosing are likely due to a placebo effect⁠.

…Now, in eLife, Balász Szigeti (Imperial College) and colleagues report how they have taken a citizen science approach to enroll 191 participants in a trial, and then used a clever experimental protocol to blind these participants to the experimental conditions (Szigeti et al 2021). Participants were split into 3 groups and took doses for 4 weeks: the first group microdosed, the second group took only placebo, and the last group had 2 weeks of microdoses and 2 weeks of placebo (Figure 1)…Surveys were given to participants at the start of the study, at multiple points during the investigation, and afterwards to measure a wide range of psychological outcomes including creativity, emotional state, mood, energy, well-being, mindfulness, openness, neuroticism and paranoia. Critically, their method enabled a placebo-controlled study, with a large sample size and realistic drug-use practices (albeit with drug samples that vary in purity and dose). This is the largest placebo-controlled microdosing study to date.

While Szigeti et al confirm anecdotal reports that microdosing improves mood and cognitive functions, there was no statistically-significant difference between the microdosing group and the placebo-treated group. This suggests that effects associated with psychedelic microdosing can be explained by the placebo effect. Consistent with this, participants scored statistically-significantly higher on the surveys when they believed they had taken a microdose.

So, does the dose of a psychedelic compound have to be strong enough to cause hallucinations in order to have a therapeutic effect? The results of Szigeti et al suggest that the answer to this question is yes.

“Self-blinding Citizen Science to Explore Psychedelic Microdosing”, Szigeti et al 2021

“Self-blinding citizen science to explore psychedelic microdosing”⁠, Balázs Szigeti, Laura Kartner, Allan Blemings, Fernando Rosas, Amanda Feilding, David J. Nutt, Robin L. Carhart-Harris et al (2021-03-02; ; backlinks; similar):

[commentary] Microdosing is the practice of regularly using low doses of psychedelic drugs. Anecdotal reports suggest that microdosing enhances well-being and cognition; however, such accounts are potentially biased by the placebo effect.

This study used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision. The study was completed by 191 participants, making it the largest placebo-controlled trial on psychedelics to-date.

All psychological outcomes improved statistically-significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no statistically-significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but statistically-significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind.

The findings suggest that anecdotal benefits of microdosing can be explained by the placebo effect.

Figure 4: Each panel shows the adjusted mean estimate of the change from baseline and the 95% CI for the accumulative outcomes. Top horizontal bars represent the over time comparisons for each group (from baseline to post-regime [week 5] and from baseline to follow-up). Symbols on top of bars show the statistical-significance for the PL [4 weeks placebo]/​HH [2 weeks placebo, 2 weeks microdose]/​MD [4 weeks microdose] groups, respectively (eg. change from baseline to post-regime in well-being was statistically-significant for the MD group, but not statistically-significant for the other two groups, see legend). There was no statistically-significant between-groups difference at any timepoint for any scale. Sample size was 240/​191/​159 at the pre-test, post-regime and 4 weeks follow-up timepoints, respectively. See Supplementary files 4, 5, and 6 for the unadjusted descriptive statistics, adjusted mean differences (and their statistical-significance) associated with both over time and between group comparisons and model parameters, respectively.

…It is worth noting that the current study was designed to protect blinding integrity by including placebos for the microdose group as well, administering the microdose capsules on different days of the week and by including the half-half group. The 3-arm design can be seen as a strength in this regard, adding ambiguity and thus strengthening blinding. Illustrative of the integrity of the blind, we received several emails from participants in the PL group who were in disbelief after opening their unused envelopes containing unused capsules after the conclusion of the study:

  • “I counted the number of cut blotters I had in the left overs: they are 8…so you must be right… Which is incredible […] Some days during the test were really, really focused and colours more vivid. This sensation was really new to me”.
  • “I have just checked the remaining envelopes and it appears that I was indeed taking placebos throughout the trial. I’m quite astonished […] It seems I was able to generate a powerful ‘altered consciousness’ experience based only the expectation around the possibility of a microdose”.
  • “An empty pill with strong belief/​intentions makes nearly everything. You put spirituality into an empty pill here…wow!”

eLife digest: Psychedelic psychotherapy, therapy enhanced with psychedelic drugs such as LSD or psilocybin (the active ingredient of ‘magic mushrooms’), has been suggested to improve psychological well-being. For this reason, trials on psychedelic therapy for the treatment of depression, addiction and other conditions are ongoing. Recently, ‘microdosing’—a way of administering psychedelics that involves taking about 10% of a recreational dose 2 or 3× per week—has gained popularity. Unlike taking large doses of psychedelics, microdosing does not induce hallucinations, but anecdotal reports suggest that it yields similar benefits as psychedelic therapy.

A key feature of modern medicine are ‘placebo control’ studies that compare two groups of patients: one that takes a drug and another that takes inactive pills, known as placebos. Crucially, neither group knows whether they are taking drug or placebo. This control ensures that observed effects are due to the drug itself and not to unrelated psychological causes. For example, in trials of mood medicines, participants often expect to feel happier, which in itself improves their mood even when taking a placebo. This is known as the placebo effect.

Restrictive drug policies make placebo-controlled studies on psychedelics difficult and expensive, in particular for microdosing, which involves taking psychedelics over a longer time period. To overcome this problem, Szigeti et al 2021 developed a new citizen-science approach, where microdosers implemented their own placebo control based on online instructions. The advantages are the low cost and the ability to recruit participants globally. The experiment was completed by 191 microdosers, making it the largest placebo-controlled study on psychedelics to-date, for a fraction of the cost of an equivalent clinical study.

The trial examined whether psychedelic microdosing can improve cognitive function and psychological well-being. The team found that microdosing statistically-significantly increased a number of psychological measures, such as well-being and life satisfaction. However, participants taking placebo also improved: there were no statistically-significant differences between the two groups. The findings confirmed positive anecdotes about microdosing improving people’s moods, but at the same time show that taking empty capsules, knowing they might be microdoses, have the same benefits. This result suggests that the observed benefits are not caused by the microdose, but rather by psychological expectations.

The study’s innovative ‘do-it-yourself’ approach to placebo control may serve as a template for future citizen science studies on other popular phenomena where positive expectations and social factors could play a role, such as cannabidiol (CBD) oils, nootropics and nutrition.

“The Acute Antisuicidal Effects of Single-dose Intravenous Ketamine and Intranasal Esketamine in Individuals With Major Depression and Bipolar Disorders: A Systematic Review and Meta-analysis”, Xiong et al 2021

2021-xiong.pdf: “The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis”⁠, Jiaqi Xiong, Orly Lipsitz, David Chen-Li, Joshua D. Rosenblat, Nelson B. Rodrigues, Isabelle Carvalho et al (2021-02-01; ; similar):

  • Single-dose intravenous ketamine/​intranasal esketamine has rapid and robust acute effects in reducing suicidal ideation (SI).
  • Future high-quality research on the anti-SI efficacy of alternative administration routes and formulations of ketamine is needed.
  • Dosage, routes of administration, and formulations are factors to be considered for optimizing SI treatment using ketamine.

The efficacy of ketamine in reducing suicidal ideation (SI) has been previously reported. We aimed to evaluate acute anti-SI effects of single-dose ketamine in different formulations/​routes of administration by pooling results from randomized controlled trials (RCTs). A systematic search was conducted on Cochrane, Embase⁠, MEDLINE⁠, and PubMed from inception to July 1st, 2020. Studies were selected based on pre-determined eligibility criteria. Effect sizes of different formulations/​routes at various time points were computed using random-effects models⁠. With data from nine eligible RCTs (n = 197), the pooled effect size for anti-SI effects at the 24-h time point was 1.035 (n = 6, CI: 0.793 to 1.277, p < 0.001) for intravenous (IV) racemic ketamine and 1.309 (n = 1, CI: 0.857 to 1.761, p < 0.001) for intranasal (IN) esketamine. An additional five RCTs were available for qualitative analysis. RCTs were identified for oral/​sublingual ketamine for depression, however, none of these trials reported anti-SI effects preventing quantitative analysis for these routes of delivery. No RCTs for intramuscular (IM) ketamine were identified. The findings suggest that single-dose IV ketamine/​IN esketamine is associated with robust reductions in suicidal thoughts at 2-h, 4-h, and 24-h post-intervention. In addition, future studies on IM/​oral/​sublingual ketamine and comparative studies are warranted to evaluate the anti-SI efficacy of distinct formulations and routes of administration.

[Keywords: glutamate, NMDA, suicidal ideation (SI), mood disorders]

“Positive Expectations Predict Improved Mental-health Outcomes Linked to Psychedelic Microdosing”, Kaertner et al 2021

“Positive expectations predict improved mental-health outcomes linked to psychedelic microdosing”⁠, L. S. Kaertner, M. B. Steinborn, H. Kettner, M. J. Spriggs, L. Roseman, T. Buchborn, M. Balaet, C. Timmermann et al (2021-01-21; ; backlinks; similar):

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 4-week test period. 81 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 substantial 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.

…Due to the pragmatic challenges of doing so via an online observational study, the present study did not include a placebo control condition. We did, however, employ a prospective, naturalistic design that included baseline sampling of expectations about possible outcomes from the impending microdosing. Well-being, state anxiety and depressive symptom scores were measured weekly on five occasions (pre-dosing at baseline to week 4 of the microdosing regimen) in order to track time-dependent changes. Neuroticism⁠/​emotional stability was measured pre-dosing at baseline and post-dosing at week 4 only. It was predicted that well-being and emotional stability would be increased, and that depression and anxiety scores would be decreased, at the key-endpoint (4 weeks) compared with baseline. Capitalising on the nature of the prospective design, we also predicted that baseline positive expectations about microdosing would be related to any subsequent improvements in well-being, depressive symptoms and anxiety scores. Finally, exploratory analyses were performed to assess pre-post changes in a range of secondary psychological outcomes of interest.

Expectancy effect on main outcome change scores: One-tailed partial correlations using Pearson coefficient were employed in order to investigate the effects of baseline expectations on endpoint change scores (endpoint—baseline) for the primary outcome variables (well-being, depressive symptoms and anxiety), whilst controlling for the corresponding baseline scores. In line with our main hypothesis, expectations for well-being improvement were statistically-significantly associated with change scores in well-being (r = 0.275 [d = −0.57], p = 0.007), depressive symptoms (r = −0.263 [d = −0.54], p = 0.009) and anxiety (r = −0.220 [d = −0.45], p = 0.025). These results indicate that baseline expectations were predictive of mental health change at the study endpoint.

“A Non-hallucinogenic Psychedelic Analogue With Therapeutic Potential”, Cameron et al 2021

“A non-hallucinogenic psychedelic analogue with therapeutic potential”⁠, Lindsay P. Cameron, Robert J. Tombari, Ju Lu, Alexander J. Pell, Zefan Q. Hurley, Yann Ehinger, Maxemiliano V. Vargas et al (2021; ; backlinks; similar):

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias.

Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog—a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step.

In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol-seeking and heroin-seeking behaviour, and produce antidepressant-like effects.

This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

“Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial”, Davis et al 2021

“Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial”⁠, Alan K. Davis, Frederick S. Barrett, Darrick G. May, Mary P. Cosimano, Nathan D. Sepeda, Matthew W. Johnson et al (2021; similar):

Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.

Objective: To investigate the effect of psilocybin therapy in patients with MDD.

Design, Setting, and Participants: This randomized, waiting list-controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).

Interventions: Two psilocybin sessions (session 1: 20 mg/​70 kg; session 2: 30 mg/​70 kg) were given (administered in opaque gelatin capsules with ~100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.

Main Outcomes and Measures: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).

Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 post-session assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically-significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4–3.5; p < 0.001) and week 8 (Cohen d = 2.6; 95% CI, 1.5–3.7; p < 0.001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8–3.5; p < 0.001), which remained statistically-significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5–3.0; p < 0.001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically-significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).

Conclusions and Relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.

Trial Registration: ClinicalTrials.gov Identifier: NCT03181529.

“Psychedelic Drugs: Neurobiology and Potential for Treatment of Psychiatric Disorders”, Vollenweider & Preller 2020

2020-vollenweider.pdf: “Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders”⁠, Franz X. Vollenweider, Katrin H. Preller (2020-09-14; similar):

Renewed interest in the use of psychedelics in the treatment of psychiatric disorders warrants a better understanding of the neurobiological mechanisms underlying the effects of these substances.

After a hiatus of about 50 years, state-of-the art studies have recently begun to close important knowledge gaps by elucidating the mechanisms of action of psychedelics with regard to their effects on receptor subsystems, systems-level brain activity and connectivity, and cognitive and emotional processing. In addition, functional studies have shown that changes in self-experience, emotional processing and social cognition may contribute to the potential therapeutic effects of psychedelics.

These discoveries provide a scientific road map for the investigation and application of psychedelic substances in psychiatry.

“Obscure and Unknown: Deliriants of the Edgewood Arsenal Human Experiments”, space_crustacean 2020

“Obscure and Unknown: Deliriants of the Edgewood Arsenal Human Experiments”⁠, space_crustacean (2020-06-08; ; backlinks; similar):

The Edgewood Arsenal Human Experiments were a series of classified studies conducted by the U.S. Army at the Edgewood Arsenal in Maryland between 1955 and 1975. A wide variety of chemical weapon applications and protections were tested, including the use of psychoactive agents. Unlike MKUltra, which was tested on many people without their consent, the Edgewood Arsenal Experiments were tested on volunteer army personnel. They were not however, prepared for the horrors they would be exposed to. The psychoactive compounds tested in these experiments include a variety of familiar chemicals like LSD, PCP, and various synthetic cannabinoids. Of particular interest however, are anticholinergics that were tested, better known as deliriants, a class of chemicals notorious for inducing hallucinations through a psychosis-like state, where the user has difficulty distinguishing hallucinations from reality.

Some of the deliriants that were tested will be detailed below. Almost all of the information on them comes from a series of summary reports on the experiments published by the National Academy of Medicine from 1982–1985, along with a detailed Memoir by one of the lead scientists behind the project Dr. James S. Ketchum. All of them except BZ were invented for the purpose of being studied and are only known by a codename “EA” (For Edgewood Arsenal) followed by 4 numbers. We will specifically look at BZ, EA-3443⁠, EA-3580⁠, EA-3834⁠, and EA-3167⁠. The effects of these extremely potent drugs are remarkable and terrifying.

…EA-3167 was most notable for its extreme duration, unlike that of any other psychoactive known of any class. Incapacitating effects could last anywhere from 5–10 days, which could sometimes present as a full 3 day long peak of vivid hallucinations, along with drawn out confusion, amnesia, and inhibition of speech and cognition4. Some subjects would not fully recover for almost 20 days4. After two weeks the symptoms experienced by subjects included:

“included increased irritability; mild impairment of memory, judgment, or abstraction; mental sluggishness with occasional confusion; nervousness; and tenseness.”1

Even 6 months later, a few of the subjects exposed to higher doses demonstrated:

“significant increases in the scores on the hypochondriasis, depression, hysteria, psychasthenia, schizophrenia, and mania scales”

Subjects would often have to be exposed to drawn out and extreme cumulative doses of physostigmine (which can be toxic itself at high doses) to stave off lasting delirium4.

…The potency of EA-3167 was in the range of other deliriants studied when given intramuscularly, 4.1 μg/​kg (254 μg in an average person)1. The power of this chemical is astounding-around a quarter of a milligram is enough to induce a 10 day marathon of incapacitated delirium, with at least 3 days of full blown delirious hallucinations. That such a compound can exist and that it is even possible to affect the human mind in that way is utterly terrifying.

“Survey of Entity Encounter Experiences Occasioned by Inhaled N,N-dimethyltryptamine: Phenomenology, Interpretation, and Enduring Effects”, Davis et al 2020

2020-davis.pdf: “Survey of entity encounter experiences occasioned by inhaled N,N-dimethyltryptamine: Phenomenology, interpretation, and enduring effects”⁠, Alan K. Davis, John M. Clifton, Eric G. Weaver, Ethan S. Hurwitz, Matthew W. Johnson, Roland R. Griffiths et al (2020-04-28; ⁠, ; backlinks; similar):

Background: Experiences of having an encounter with seemingly autonomous entities are sometimes reported after inhaling N,N-dimethyltryptamine⁠.

Aim: The study characterized the subjective phenomena, interpretation, and persisting changes that people attribute to N,N-dimethyltryptamine-occasioned entity encounter experiences.

Methods: 2,561 individuals (mean age 32 years; 77% male) completed an online survey about their single most memorable entity encounter after taking N,N-dimethyltryptamine.

Results: Respondents reported the primary senses involved in the encounter were visual and extrasensory (eg. telepathic). The most common descriptive labels for the entity were being, guide, spirit, alien, and helper. Although 41% of respondents reported fear during the encounter, the most prominent emotions both in the respondent and attributed to the entity were love, kindness, and joy. Most respondents endorsed that the entity had the attributes of being conscious, intelligent, and benevolent, existed in some real but different dimension of reality, and continued to exist after the encounter. Respondents endorsed receiving a message (69%) or a prediction about the future (19%) from the experience. More than half of those who identified as atheist before the experience no longer identified as atheist afterwards. The experiences were rated as among the most meaningful, spiritual, and psychologically insightful lifetime experiences, with persisting positive changes in life satisfaction, purpose, and meaning attributed to the experiences.

Conclusion: N,N-dimethyltryptamine-occasioned entity encounter experiences have many similarities to non-drug entity encounter experiences such as those described in religious, alien abduction, and near-death contexts. Aspects of the experience and its interpretation produced profound and enduring ontological changes in worldview.

“Psychedelic Psychiatry’s Brave New World”, Nutt et al 2020

“Psychedelic Psychiatry’s Brave New World”⁠, David Nutt, David Erritzoe, Robin Carhart-Harris (2020-04-02; ; backlinks; similar):

After a legally mandated, decades-long global arrest of research on psychedelic drugs, investigation of psychedelics in the context of psychiatric disorders is yielding exciting results.

Outcomes of neuroscience and clinical research into 5-Hydroxytryptamine 2A (5-HT2A) receptor agonists, such as psilocybin⁠, show promise for addressing a range of serious disorders, including depression and addiction.

“Tripping on Nothing: Placebo Psychedelics and Contextual Factors”, Olson et al 2020

2020-olson.pdf: “Tripping on nothing: placebo psychedelics and contextual factors”⁠, Jay A. Olson, Léah Suissa-Rocheleau, Michael Lifshitz, Amir Raz, Samuel P. L. Veissière (2020-03-07; backlinks; similar):

Rationale: Is it possible to have a psychedelic experience from a placebo alone? Most psychedelic studies find few effects in the placebo control group, yet these effects may have been obscured by the study design, setting, or analysis decisions.

Objective: We examined individual variation in placebo effects in a naturalistic environment resembling a typical psychedelic party.

Methods: 33 students completed a single-arm study ostensibly examining how a psychedelic drug affects creativity. The 4-h study took place in a group setting with music, paintings, coloured lights, and visual projections. Participants consumed a placebo that we described as a drug resembling psilocybin, which is found in psychedelic mushrooms. To boost expectations, confederates subtly acted out the stated effects of the drug and participants were led to believe that there was no placebo control group. The participants later completed the 5-Dimensional Altered States of Consciousness Rating Scale, which measures changes in conscious experience.

Results: There was considerable individual variation in the placebo effects; many participants reported no changes while others showed effects with magnitudes typically associated with moderate or high doses of psilocybin. In addition, the majority (61%) of participants verbally reported some effect of the drug. Several stated that they saw the paintings on the walls “move” or “reshape” themselves, others felt “heavy…as if gravity [had] a stronger hold”, and one had a “come down” before another “wave” hit her.

Conclusion: Understanding how context and expectations promote psychedelic-like effects, even without the drug, will help researchers to isolate drug effects and clinicians to maximise their therapeutic potential.

…In the second sample, before the debriefing, we asked participants to guess whether they had taken a psychedelic, a placebo, or whether they were uncertain. Overall, 35% reported being certain they had taken a placebo, 12% were certain that they had taken a psychedelic, and the rest (53%) were uncertain. In the first sample, we did not ask this question, but the same number of people spontaneously reported being certain that they had taken a psychedelic drug. During the debriefing, when we revealed the placebo nature of the study, many participants appeared shocked. Several gasped and started laughing. One stated, “It’s very funny!”, and another replied, “It’s sad!” One of the participants who had sat with a group near the paintings throughout the study asked, “So we were all sober and just watching these paintings for 45 minutes‽”

[“This is a remarkable study, and probably the most elaborate placebo ever reported. But how well did the trick work? The authors say that after they revealed the truth, some of the participants expressed shock. However, 35% of them said they were”certain” they had taken a placebo when quizzed just before the debriefing. Only 12% were “certain” that they’d taken a real psychedelic drug, which suggests that the deception was only partially successful.

Some of the participants did report very strong effects on a questionnaire of ‘psychedelic effects’. However, I noticed that the effects reported tended to be the more abstract kind, such as “insight” and “bliss”. In terms of actual hallucinogenic effects like ‘complex imagery’ and ‘elementary imagery’ (ie. seeing things), no participants reported effects equal to even a low dose of LSD, let alone a stronger dose. See the rather confusing Figure 2 for details.” —Neuroskeptic]

“Long-term Follow-up of Psilocybin-assisted Psychotherapy for Psychiatric and Existential Distress in Patients With Life-threatening Cancer”, Agin-Liebes et al 2020

2020-aginliebes.pdf: “Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer”⁠, Gabrielle I. Agin-Liebes, Tara Malone, Matthew M. Yalch, Sarah E. Mennenga, K. Linnae Ponté, Jeffrey Guss et al (2020-01-09; ; similar):

Background: A recently published randomized controlled trial compared single-dose psilocybin with single-dose niacin in conjunction with psychotherapy in participants with cancer-related psychiatric distress. Results suggested that psilocybin-assisted psychotherapy facilitated improvements in psychiatric and existential distress, quality of life, and spiritual well-being up to seven weeks prior to the crossover. At the 6.5-month follow-up, after the crossover, 60–80% of participants continued to meet criteria for clinically-significant antidepressant or anxiolytic responses.

Methods: The present study is a long-term within-subjects follow-up analysis of self-reported symptomatology involving a subset of participants that completed the parent trial. All 16 participants who were still alive were contacted, and 15 participants agreed to participate at an average of 3.2 and 4.5 years following psilocybin administration.

Results: Reductions in anxiety, depression, hopelessness, demoralization, and death anxiety were sustained at the first and second follow-ups. Within-group effect sizes were large. At the second (4.5 year) follow-up ~60–80% of participants met criteria for clinically-significant antidepressant or anxiolytic responses. Participants overwhelmingly (71–100%) attributed positive life changes to the psilocybin-assisted therapy experience and rated it among the most personally meaningful and spiritually important experiences of their lives.

Conclusion: These findings suggest that psilocybin-assisted psychotherapy holds promise in promoting long-term relief from cancer-related psychiatric distress. Limited conclusions, however, can be drawn regarding the efficacy of this therapy due to the crossover design of the parent study. Nonetheless, the present study adds to the emerging literature base suggesting that psilocybin-facilitated therapy may enhance the psychological, emotional, and spiritual well-being of patients with life-threatening cancer.

“What Intellectual Progress Did I Make In The 2010s?”, Alexander 2020

“What Intellectual Progress Did I Make In The 2010s?”⁠, Scott Alexander (2020-01-08; similar):

[Scott Alexander look back on how his ideas/​beliefs evolved over the past decade of blogging at Jackdaws/​LessWrong⁠/​SlateStarCodex. Primary topics:

  1. Bayesian predictive coding as an unified theory of brain perception, control, behavior, and psychiatric disorders as bad priors/​updates

    • Psychedelics use as modifying brain priors⁠, explaining how psychedelics affect and sometimes benefit their users
    • trauma/​attachment disorder
  2. Philosophy of mental disease

  3. efficacy of SSRIs

  4. Genetics of psychiatric disorders, especially autism/​transsexuals: ???

  5. Willpower: also predictive coding???

  6. Diet/​weight loss: setpoints, somehow

  7. Existential risk: dissolving the Great Filter, raising AI risk awareness

  8. Secular stagnation: progress is slowing, perhaps because human populations aren’t growing exponentially

    • Baumol’s cost disease as core cause of economic stagnation and political backlash
  9. The Replication Crisis: even worse than he thought

  10. Psychological effects:

    • Placebo effect: much more powerless than he thought
    • Birth order effects: much more powerful than he thought
  11. Utilitarianism: still confused, but more towards rule-utilitarianism

  12. Politics: social media turbocharging tribalism/​outgroup-bias

  13. Ideology of liberalism and SJWism

  14. Coordination problems as core problem of politics

  15. Enlightenment: not actually that great, possibly wireheading]

“Metabolic Engineering of Saccharomyces Cerevisiae for the de Novo Production of Psilocybin and Related Tryptamine Derivatives”, Milne et al 2020

“Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives”⁠, N Milne, P. Thomsen, N. Mølgaard Knudsen, P. Rubaszka, M. Kristensen, I. Borodina (2020; ; similar):

Psilocybin is a tryptamine-derived psychoactive alkaloid found mainly in the fungal genus Psilocybe, among others, and is the active ingredient in so-called “magic mushrooms”. Although its notoriety originates from its psychotropic properties and popular use as a recreational drug, clinical trials have recently recognized psilocybin as a promising candidate for the treatment of various psychological and neurological afflictions. In this work, we demonstrate the de novo biosynthetic production of psilocybin and related tryptamine derivatives in Saccharomyces cerevisiae by expression of a heterologous biosynthesis pathway sourced from Psilocybe cubensis. Additionally, we achieve improved product titers by supplementing the pathway with a novel cytochrome P450 reductase from P. cubensis. Further rational engineering resulted in a final production strain producing 627 ± 140 mg/​L of psilocybin and 580 ± 276 mg/​L of the dephosphorylated degradation product psilocin in triplicate controlled fed-batch fermentations in minimal synthetic media. Pathway intermediates baeocystin, nor norbaeocystin as well the dephosphorylated baeocystin degradation product norpsilocin were also detected in strains engineered for psilocybin production. We also demonstrate the biosynthetic production of natural tryptamine derivative aeruginascin as well as the production of a new-to-nature tryptamine derivative N-acetyl-4-hydroxytryptamine. These results lay the foundation for the biotechnological production of psilocybin in a controlled environment for pharmaceutical applications, and provide a starting point for the biosynthetic production of other tryptamine derivatives of therapeutic relevance.

“Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Low Dose Lysergic Acid Diethylamide (LSD) in Healthy Older Volunteers”, Family et al 2020

“Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers”⁠, Neiloufar Family, Emeline L. Maillet, Luke T. J Williams, Erwin Krediet, Robin L. Carhart-Harris, Tim M. Williams et al (2020; similar):

Null: Research has shown that psychedelics, such as lysergic acid diethylamide (LSD), have profound anti-inflammatory properties mediated by 5-HT2A receptor signaling, supporting their evaluation as a therapeutic for neuroinflammation associated with neurodegenerative disease.

Objective: This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of orally repeated administration of 5 μg, 10 μg, and 20 μg LSD in older healthy individuals. In the current paper, we present safety, tolerability, pharmacokinetics, and pharmacodynamic measures that relate to safety, tolerability, and dose response.

Methods: This was a phase 1 double-blind, placebo-controlled, randomized study. Volunteers were randomly assigned to 1 of 4 dose groups (5 μg, 10 μg, 20 μg LSD, and placebo), and received their assigned dose on six occasions (ie. every 4 days).

Results: Forty-eight older healthy volunteers (mean age = 62.9 years) received placebo (n = 12), 5 μg (n = 12), 10 μg (n = 12), or 20 μg (n = 12) LSD. LSD plasma levels were undetectable for the 5 μg group and peak blood plasma levels for the 10 μg and 20 μg groups occurred at 30 min. LSD was well tolerated, and the frequency of adverse events was no higher than for placebo. Assessments of cognition, balance, and proprioception revealed no impairment.

Conclusions: Our results suggest safety and tolerability of orally administered 5 μg, 10 μg, and 20 μg LSD every fourth day over a 21-day period and support further clinical development of LSD for the treatment and prevention of Alzheimer’s disease (AD).

“Logarithmic Scales of Pleasure and Pain: Rating, Ranking, and Comparing Peak Experiences Suggest the Existence of Long Tails for Bliss and Suffering”, Computing 2019

“Logarithmic Scales of Pleasure and Pain: Rating, Ranking, and Comparing Peak Experiences Suggest the Existence of Long Tails for Bliss and Suffering”⁠, Qualia Computing (2019-08-10; similar):

Based on: the characteristic distribution of neural activity, personal accounts of intense pleasure and pain, the way various pain scales have been described by their creators, and the results of a pilot study we conducted which ranks, rates, and compares the hedonic quality of extreme experiences, we suggest that the best way to interpret pleasure and pain scales is by thinking of them as logarithmic compressions of what is truly a long-tail. The most intense pains are orders of magnitude more awful than mild pains (and symmetrically for pleasure).

This should inform the way we prioritize altruistic interventions and plan for a better future. Since the bulk of suffering is concentrated in a small percentage of experiences, focusing our efforts on preventing cases of intense suffering likely dominates most utilitarian calculations.

An important pragmatic takeaway from this article is that if one is trying to select an effective career path, as a heuristic it would be good to take into account how one’s efforts would cash out in the prevention of extreme suffering (see: ‘Hell-Index’), rather than just QALYs and wellness indices that ignore the long-tail. Of particular note as promising Effective Altruist careers, we would highlight working directly to develop remedies for specific, extremely painful experiences. Finding scalable treatments for migraines, kidney stones, childbirth, cluster headaches, CRPS, and fibromyalgia may be extremely high-impact (cf. ‘Treating Cluster Headaches and Migraines Using N,N-DMT and Other Tryptamines’, ‘Using Ibogaine to Create Friendlier Opioids’, and ‘Frequency Specific Microcurrent for Kidney-Stone Pain’). More research efforts into identifying and quantifying intense suffering currently unaddressed would also be extremely helpful. Finally, if the positive valence scale also has a long-tail, focusing one’s career in developing bliss technologies may pay-off in surprisingly good ways (whereby you may stumble on methods to generate high-valence healing experiences which are orders of magnitude better than you thought were possible).

[Keywords: consciousness research, Effective Altruism, ethics, Hedonic Tone, meaning, psychedelic, sex, spirituality, valence]

“Decreased Directed Functional Connectivity in the Psychedelic State”, Barnett et al 2019

“Decreased Directed Functional Connectivity in the Psychedelic State”⁠, Lionel Barnett, Suresh D. Muthukumaraswamy, Robin L. Carhart-Harris, Anil K. Seth (2019-07-16; ; similar):

Neuroimaging studies of the psychedelic state offer an unique window onto the neural basis of conscious perception and selfhood. Despite well understood pharmacological mechanisms of action, the large-scale changes in neural dynamics induced by psychedelic compounds remain poorly understood. Using source-localized, steady-state MEG recordings, we describe changes in functional connectivity following the controlled administration of LSD, psilocybin and low-dose ketamine, as well as, for comparison, the (non-psychedelic) anticonvulsant drug tiagabine. We compare both undirected and directed measures of functional connectivity between placebo and drug conditions. We observe a general decrease in directed functional connectivity for all three psychedelics, as measured by Granger causality, throughout the brain. These data support the view that the psychedelic state involves a breakdown in patterns of functional organisation or information flow in the brain. In the case of LSD, the decrease in directed functional connectivity is coupled with an increase in undirected functional connectivity, which we measure using correlation and coherence. This surprising opposite movement of directed and undirected measures is of more general interest for functional connectivity analyses, which we interpret using analytical modelling. Overall, our results uncover the neural dynamics of information flow in the psychedelic state, and highlight the importance of comparing multiple measures of functional connectivity when analysing time-resolved neuroimaging data.

“Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers”, Bershad et al 2019

“Acute Subjective and Behavioral Effects of Microdoses of Lysergic Acid Diethylamide in Healthy Human Volunteers”⁠, Anya K. Bershad, Scott T. Schepers, Michael P. Bremmer, Royce Lee, Harriet de Wit (2019; ; backlinks; similar):

Background: Numerous anecdotal reports suggest that repeated use of very low doses of lysergic acid diethylamide (LSD), known as microdosing, improves mood and cognitive function. These effects are consistent both with the known actions of LSD on serotonin receptors and with limited evidence that higher doses of LSD (100–200 μg) positively bias emotion processing. Yet, the effects of such sub-threshold doses of LSD have not been tested in a controlled laboratory setting. As a first step, we examined the effects of single very low doses of LSD (0–26 μg) on mood and behavior in healthy volunteers under double-blind conditions.

Methods: Healthy young adults (n = 20) attended 4 laboratory sessions during which they received 0 (placebo), 6.5, 13, or 26 μg of LSD in randomized order at 1-week intervals. During expected peak drug effect, they completed mood questionnaires and behavioral tasks assessing emotion processing and cognition. Cardiovascular measures and body temperature were also assessed.

Results: LSD produced dose-related subjective effects across the 3 doses (6.5, 13, and 26 μg). At the highest dose, the drug also increased ratings of vigor and slightly decreased positivity ratings of images with positive emotional content. Other mood measures, cognition, and physiological measures were unaffected.

Conclusions: Single microdoses of LSD produced orderly dose-related subjective effects in healthy volunteers. These findings indicate that a threshold dose of 13 μg of LSD might be used safely in an investigation of repeated administrations. It remains to be determined whether the drug improves mood or cognition in individuals with symptoms of depression.

“Survey of Subjective 'God Encounter Experiences': Comparisons among Naturally Occurring Experiences and Those Occasioned by the Classic Psychedelics Psilocybin, LSD, Ayahuasca, or DMT”, Rol et al 2019

“Survey of subjective 'God encounter experiences': Comparisons among naturally occurring experiences and those occasioned by the classic psychedelics psilocybin, LSD, ayahuasca, or DMT”⁠, Rol, R. Griffiths, Ethan S. Hurwitz, Alan K. Davis, Matthew W. Johnson, Robert Jesse (2019; ; backlinks; similar):

Naturally occurring and psychedelic drug-occasioned experiences interpreted as personal encounters with God are well described but have not been systematically compared.

In this study, five groups of individuals participated in an online survey with detailed questions characterizing the subjective phenomena, interpretation, and persisting changes attributed to their single most memorable God encounter experience (n = 809 Non-Drug, 1,184 psilocybin, 1,251 lysergic acid diethylamide (LSD), 435 ayahuasca, and 606 N,N-dimethyltryptamine (DMT)). Analyses of differences in experiences were adjusted statistically for demographic differences between groups.

The Non-Drug Group was most likely to choose “God” as the best descriptor of that which was encountered while the psychedelic groups were most likely to choose “Ultimate Reality.” Although there were some other differences between non-drug and the combined psychedelic group, as well as between the four psychedelic groups, the similarities among these groups were most striking.

Most participants reported vivid memories of the encounter experience, which frequently involved communication with something having the attributes of being conscious, benevolent, intelligent, sacred, eternal, and all-knowing. The encounter experience fulfilled a priori criteria for being a complete mystical experience in ~half of the participants. More than two-thirds of those who identified as atheist before the experience no longer identified as atheist afterwards. These experiences were rated as among the most personally meaningful and spiritually important lifetime experiences, with moderate to strong persisting positive changes in life satisfaction, purpose, and meaning attributed to these experiences. Among the four groups of psychedelic users, the psilocybin and LSD groups were most similar and the ayahuasca group tended to have the highest rates of endorsing positive features and enduring consequences of the experience.

Future exploration of predisposing factors and phenomenological and neural correlates of such experiences may provide new insights into religious and spiritual beliefs that have been integral to shaping human culture since time immemorial.

“A Systematic Study of Microdosing Psychedelics”, Polito & Stevenson 2018

“A systematic study of microdosing psychedelics”⁠, Vince Polito, Richard J. Stevenson (2018-12-10; ⁠, ; backlinks; similar):

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.

“Exploring the Effect of Microdosing Psychedelics on Creativity in an Open-label Natural Setting”, Prochazkova et al 2018

“Exploring the effect of microdosing psychedelics on creativity in an open-label natural setting”⁠, Luisa Prochazkova, Dominique P. Lippelt, Lorenza S. Colzato, Martin Kuchar, Zsuzsika Sjoerds, Bernhard Hommel et al (2018-08-11; ; backlinks; similar):

Introduction

Recently popular sub-perceptual doses of psychedelic substances such as truffles, referred to as microdosing, allegedly have multiple beneficial effects including creativity and problem solving performance, potentially through targeting serotonergic 5-HT2A receptors and promoting cognitive flexibility, crucial to creative thinking. Nevertheless, enhancing effects of microdosing remain anecdotal, and in the absence of quantitative research on microdosing psychedelics it is impossible to draw definitive conclusions on that matter. Here, our main aim was to quantitatively explore the cognitive-enhancing potential of microdosing psychedelics in healthy adults.

Methods: During a microdosing event organized by the Dutch Psychedelic Society, we examined the effects of psychedelic truffles (which were later analyzed to quantify active psychedelic alkaloids) on two creativity-related problem-solving tasks: the Picture Concept Task assessing convergent thinking, and the Alternative Uses Task assessing divergent thinking. A short version of the Ravens Progressive Matrices task assessed potential changes in fluid intelligence. We tested once before taking a microdose and once while the effects were manifested.

Results: We found that both convergent and divergent thinking performance was improved after a non-blinded microdose, whereas fluid intelligence was unaffected.

Conclusion: While this study provides quantitative support for the cognitive enhancing properties of microdosing psychedelics, future research has to confirm these preliminary findings in more rigorous placebo-controlled study designs. Based on these preliminary results we speculate that psychedelics might affect cognitive meta-control policies by optimizing the balance between cognitive persistence and flexibility. We hope this study will motivate future microdosing studies with more controlled designs to test this hypothesis.

“Discovery of Psychoactive Plant and Mushroom Alkaloids in Behavior-modifying Fungal Cicada Pathogens”, Boyce et al 2018

“Discovery of psychoactive plant and mushroom alkaloids in behavior-modifying fungal cicada pathogens”⁠, Greg R. Boyce, Emile Gluck-Thaler, Jason C. Slot, Jason E. Stajich, William J. Davis, Tim Y. James, John R. Cooley et al (2018-07-30; similar):

Entomopathogenic fungi routinely kill their hosts before releasing infectious conidia, but select species keep their hosts alive while sporulating to enhance spore dispersal. Recent expression and metabolomics studies involving “host-killing” entomopathogens have helped unravel infection processes and host responses, yet the mechanisms underlying “active host transmission” in insects with Entomophthoralean fungal infections are completely unexplored. Here we report the discovery, through global and targeted metabolomics supported by metagenomics and proteomics, of the plant amphetamine, cathinone, in Massospora cicadina-infected periodical cicadas, and the mushroom tryptamine, psilocybin, in M. platypediae-infected and M. levispora-infected annual cicadas. The neurogenic activities of these alkaloids provide a hypothetical framework for a chemically induced extended phenotype of Massospora that alters cicada behavior by increasing endurance and suppressing feeding prior to death.

“Convergent Evolution of Psilocybin Biosynthesis by Psychedelic Mushrooms”, Awan et al 2018

“Convergent evolution of psilocybin biosynthesis by psychedelic mushrooms”⁠, Ali R. Awan, Jaclyn M. Winter, Daniel Turner, William M. Shaw, Laura M. Suz, Alexander J. Bradshaw, Tom Ellis et al (2018-07-27; similar):

Psilocybin is a psychoactive compound with clinical applications produced by dozens of mushroom species1. There has been a longstanding interest in psilocybin research with regard to treatment for addiction2, depression3, and end-of-life suffering4. However, until recently very little was known about psilocybin biosynthesis and its ecological role. Here we confirm and refine recent findings5 about the genes underpinning psilocybin biosynthesis, discover that there is more than one psilocybin biosynthesis cluster in mushrooms, and we provide the first data directly addressing psilocybin’s ecological role. By analysing independent genome assemblies for the hallucinogenic mushrooms Psilocybe cyanescens and Pluteus salicinus we recapture the recently discovered psilocybin biosynthesis cluster5,6 and show that a transcription factor previously implicated in its regulation is actually not part of the cluster. Further, we show that the mushroom Inocybe corydalina produces psilocybin but does not contain the established biosynthetic cluster, and we present an alternative cluster. Finally, a meta-transcriptome analysis of wild-collected mushrooms provides evidence for intra-mushroom insect gene expression of flies whose larvae grow inside Psilocybe cyanescens. These larvae were successfully reared into adults. Our results show that psilocybin does not confer complete protection against insect mycophagy, and the hypothesis that it is produced as an adaptive defense compound may need to be reconsidered.

“Psilocybin With Psychological Support for Treatment-resistant Depression: Six-month Follow-up”, Carhart-Harris et al 2018

“Psilocybin with psychological support for treatment-resistant depression: six-month follow-up”⁠, R L. Carhart-Harris, M. Bolstridge, C. M J. Day, J. Rucker, R. Watts, D. E Erritzoe, M. Kaelen, B. Giribaldi et al (2018; ; backlinks; similar):

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 statistically-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.

“Serotonin and Brain Function: a Tale of Two Receptors”, Carhart-Harris & Nutt 2017

2017-carharttharris.pdf: “Serotonin and brain function: a tale of two receptors”⁠, R. L. Carhart-Harris, D. J. Nutt (2017-08-31; ; backlinks; similar):

Previous attempts to identify an 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 (ie. tolerating a source of stress) is mediated by postsynaptic 5-HT1AR signalling and characterised by stress moderation. Conversely, we argue that active coping (ie. 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.

“Results of an International Drug Testing Service for Cryptomarket Users”, Caudevilla 2016b

2016-caudevilla-2.pdf: “Results of an international drug testing service for cryptomarket users”⁠, Fernando Caudevilla (2016-09-01; ⁠, ⁠, ; backlinks):

Introduction: User surveys indicate that expectations of higher drug purity are a key reason for cryptomarket use. In 2014–2015, Spain’s NGO Energy Control conducted a 1-year pilot project to provide a testing service to cryptomarket drug users using the Transnational European Drug Information (TEDI) guidelines. In this paper, we present content and purity data from the trial.

Methods: 219 samples were analyzed by gas chromatography associated with mass spectrometry (GC⁠/​MS). Users were asked to report what substance they allegedly purchased.

Results: 40 different advertised substances were reported, although 77.6% were common recreational drugs (cocaine, MDMA, amphetamines, LSD, ketamine, cannabis). In 200 samples (91.3%), the main result of analysis matched the advertised substance. Where the advertised compound was detected, purity levels (m ± SD) were: cocaine 71.6 ± 19.4%; MDMA (crystal) 88.3 ± 1.4%; MDMA (pills) 133.3 ± 38.4 mg; Amphetamine (speed) 51.3 ± 33.9%; LSD 123.6 ± 40.5 μg; Cannabis resin THC: 16.5 ± 7.5% CBD: 3.4 ± 1.5%; Ketamine 71.3 ± 38.4%. 39.8% of cocaine samples contained the adulterant levamisole (11.6 ± 8%). No adulterants were found in MDMA and LSD samples.

Discussion: The largest collection of test results from drug samples delivered from cryptomarkets are reported in this study. Most substances contained the advertised ingredient and most samples were of high purity. The representativeness of these results is unknown.

[Keywords: cryptomarkets, drug markets, purity, adulterants, drug checking, drug trend monitoring]

[See also Arce 2020⁠.]

Table 1: Advertised substance and purities in samples from International Drug Testing Service (March 2014–March 2015).

“Purity, Adulteration and Price of Drugs Bought Online versus Offline in the Netherlands”, Gouwe et al 2016

2016-gouwe.pdf: “Purity, adulteration and price of drugs bought online versus offline in the Netherlands”⁠, Daan Gouwe, Tibor M. Brunt, Margriet Laar, Peggy Pol (2016-01-01; ; backlinks)

“Rapid and Sustained Symptom Reduction following Psilocybin Treatment for Anxiety and Depression in Patients With Life-threatening Cancer: a Randomized Controlled Trial”, Ross et al 2016

“Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial”⁠, Stephen Ross, Anthony Bossis, Jeffrey Guss, Gabrielle Agin-Liebes, Tara Malone, Barry Cohen, Sarah E. Mennenga et al (2016; ; backlinks; similar):

Background: Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.

Methods: In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/​kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.

Results: Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (~60–80% of participants continued with clinically-significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.

Conclusions: In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.

Trial Registration: ClinicalTrials.gov Identifier: NCT00957359.

“Hunting and Hallucinogens: The Use of Psychoactive and Other Plants to Improve the Hunting Ability of Dogs”, Bennett & Alarcón 2015

2015-bennett.pdf: “Hunting and hallucinogens: The use of psychoactive and other plants to improve the hunting ability of dogs”⁠, Bradley C. Bennett, Rocío Alarcón (2015-01-01; )

“Psychedelics and Mental Health: A Population Study”, Krebs & Johansen 2013

“Psychedelics and Mental Health: A Population Study”⁠, Teri S. Krebs, Pål-Ørjan Johansen (2013-04-11; ; backlinks; similar):

Background:

The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive. Clinical studies do not suggest that psychedelics cause long-term mental health problems. Psychedelics have been used in the Americas for thousands of years. Over 30 million people currently living in the US have used LSD, psilocybin, or mescaline.

Objective:

To evaluate the association between the lifetime use of psychedelics and current mental health in the adult population.

Method:

Data drawn from years 2001 to 2004 of the National Survey on Drug Use and Health consisted of 130,152 respondents, randomly selected to be representative of the adult population in the United States. Standardized screening measures for past year mental health included serious psychological distress (K6 scale), mental health treatment (inpatient, outpatient, medication, needed but did not receive), symptoms of eight psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, post-traumatic stress disorder, and non-affective psychosis), and seven specific symptoms of non-affective psychosis. We calculated weighted odds ratios by multivariate logistic regression controlling for a range of sociodemographic variables, use of illicit drugs, risk taking behavior, and exposure to traumatic events.

Results:

21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no statistically-significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.

Conclusion:

We did not find use of psychedelics to be an independent risk factor for mental health problems.

“Clusters of Individual Experiences Form a Continuum of Persistent Non-Symbolic Experiences [PNSE] in Adults”, Martin 2013

“Clusters of Individual Experiences form a Continuum of Persistent Non-Symbolic Experiences [PNSE] in Adults”⁠, Jeffery A. Martin (2013; ; backlinks; similar):

Persistent forms of nondual awareness, enlightenment, mystical experience, and so forth (Persistent Non-Symbolic Experience) have been reported since antiquity. Though sporadic research has been performed on them, the research reported here represents the initial report from the first larger scale cognitive psychology study of this population.

Method: Assessment of the subjective experience of fifty adult participants reporting persistent non-symbolic experience was undertaken using 6–12 hour semi-structured interviews and evaluated using thematic analysis. Additional assessment was performed using psychometric measures, physiological measurement, and experimentation.

Results: Five core, consistent categories of change were uncovered: sense-of-self, cognition, emotion, perception, and memory. Participants’ reports formed clusters in which the types of change in each of these categories were consistent. Multiple clusters were uncovered that formed a range of possible experiences. The variety of these experiences and their underlying categories may inform the debate between constructivist, common core, and participatory theorists.

…Over the course of a week, his father died followed very rapidly by his sister. He was also going through a major issue with one of his children. Over dinner I asked him about his internal state, which he reported as deeply peaceful and positive despite everything that was happening. Having known that the participant was bringing his longtime girlfriend, I’d taken an associate researcher with me to the meeting to independently collect the observations from her. My fellow researcher isolated the participant’s girlfriend at the bar and interviewed her about any signs of stress that the participant might be exhibiting. I casually asked the same questions to the participant as we continued our dinner conversation. Their answers couldn’t have been more different. While the participant reported no stress, his partner had been observing many telltale signs: he wasn’t sleeping well, his appetite was off, his mood was noticeably different, his muscles were much tenser than normal, his sex drive was reduced, his health was suffering, and so forth…It was not uncommon for participants to state that they had gained increased bodily awareness upon their transition into PNSE. I arranged and observed private yoga sessions with a series of participants as part of a larger inquiry into their bodily awareness. During these sessions it became clear that participants believed they were far more aware of their body than they actually were…Many participants discussed the thought, just after their transition to PNSE, that they would have to go to work and explain the difference in themselves to co-workers. They went on to describe a puzzled drive home after a full day of work when no one seemed to notice anything different about them. Quite a few chose to never discuss the change that had occurred in them with their families and friends and stated that no one seemed to notice much of a difference.

There was also a progressively decreasing sense of agency. In the final stage, Location 4, he reports: “These participants reported having no sense of agency or any ability to make a decision. It felt as if life was simply unfolding and they were watching the process happen. Severe memory deficits were common in these participants, including the inability to recall scheduled events that were not regular and ongoing.” And yet, almost all of the subjects reported it as a positive experience. The subjects, at whatever point they were in the scale, were often completely certain about the nature of the experience: “PNSE was often accompanied by a tremendous sense of certainty that participants were experiencing a ‘deeper’ or ‘more true’ reality. As time passed, this often increased in strength.” They also tended to be dogmatic about their PNSE being the real thing (whichever location they were at) and descriptions of other people’s different PNSEs as not the real thing. Another way to say “completely certain” is “unable to doubt”.

“A Philosopher Defends Religion [review of Plantinga, Where the Conflict Really Lies]”, Nagel 2012

2012-09-27-nagel.txt: “A Philosopher Defends Religion [review of Plantinga, Where the Conflict Really Lies]”⁠, Thomas Nagel (2012-09-27; ⁠, ; backlinks; similar):

The gulf in outlook between atheists and adherents of the monotheistic religions is profound. We are fortunate to live under a constitutional system and a code of manners that by and large keep it from disturbing the social peace; usually the parties ignore each other. But sometimes the conflict surfaces and heats up into a public debate. The present is such a time.

…In his absorbing new book, Where the Conflict Really Lies, Alvin Plantinga, a distinguished analytic philosopher known for his contributions to metaphysics and theory of knowledge as well as to the philosophy of religion, turns this alleged opposition on its head. His overall claim is that “there is superficial conflict but deep concord between science and theistic religion, but superficial concord and deep conflict between science and naturalism.” By naturalism he means the view that the world describable by the natural sciences is all that exists, and that there is no such person as God, or anything like God. Plantinga’s religion is the real thing, not just an intellectual deism that gives God nothing to do in the world. He himself is an evangelical Protestant, but he conducts his argument with respect to a version of Christianity that is the “rough intersection of the great Christian creeds”—ranging from the Apostle’s Creed to the Anglican Thirty-Nine Articles—according to which God is a person who not only created and maintains the universe and its laws, but also intervenes specially in the world, with the miracles related in the Bible and in other ways. It is of great interest to be presented with a lucid and sophisticated account of how someone who holds these beliefs understands them to harmonize with and indeed to provide crucial support for the methods and results of the natural sciences…Faith, according to Plantinga, is another basic way of forming beliefs, distinct from but not in competition with reason, perception, memory, and the others. However, it is

a wholly different kettle of fish: according to the Christian tradition (including both Thomas Aquinas and John Calvin), faith is a special gift from God, not part of our ordinary epistemic equipment. Faith is a source of belief, a source that goes beyond the faculties included in reason.

God endows human beings with a sensus divinitatis that ordinarily leads them to believe in him. (In atheists the sensus divinitatis is either blocked or not functioning properly.)2 In addition, God acts in the world more selectively by “enabling Christians to see the truth of the central teachings of the Gospel.”

If all this is true, then by Plantinga’s standard of reliability and proper function, faith is a kind of cause that provides a warrant for theistic belief, even though it is a gift, and not an universal human faculty. (Plantinga recognizes that rational arguments have also been offered for the existence of God, but he thinks it is not necessary to rely on these, any more than it is necessary to rely on rational proofs of the existence of the external world to know just by looking that there is beer in the refrigerator.) It is illuminating to have the starkness of the opposition between Plantinga’s theism and the secular outlook so clearly explained. My instinctively atheistic perspective implies that if I ever found myself flooded with the conviction that what the Nicene Creed says is true, the most likely explanation would be that I was losing my mind, not that I was being granted the gift of faith. From Plantinga’s point of view, by contrast, I suffer from a kind of spiritual blindness from which I am unwilling to be cured. This is a huge epistemological gulf, and it cannot be overcome by the cooperative employment of the cognitive faculties that we share, as is the hope with scientific disagreements…The interest of this book, especially for secular readers, is its presentation from the inside of the point of view of a philosophically subtle and scientifically informed theist—an outlook with which many of them will not be familiar. Plantinga writes clearly and accessibly, and sometimes acidly—in response to aggressive critics of religion like Dawkins and Daniel Dennett. His comprehensive stand is a valuable contribution to this debate.

“Dual N-Back Meta-Analysis”, Branwen 2012

DNB-meta-analysis: “Dual n-Back Meta-Analysis”⁠, Gwern Branwen (2012-05-20; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

Does DNB increase IQ? What factors affect the studies? Probably not: gains are driven by studies with weakest methodology like apathetic control groups.

I meta-analyze the >19 studies up to 2016 which measure IQ after an n-back intervention, finding (over all studies) a net gain (medium-sized) on the post-training IQ tests.

The size of this increase on IQ test score correlates highly with the methodological concern of whether a study used active or passive control groups⁠. This indicates that the medium effect size is due to methodological problems and that n-back training does not increase subjects’ underlying fluid intelligence but the gains are due to the motivational effect of passive control groups (who did not train on anything) not trying as hard as the n-back-trained experimental groups on the post-tests. The remaining studies using active control groups find a small positive effect (but this may be due to matrix-test-specific training, undetected publication bias, smaller motivational effects, etc.)

I also investigate several other n-back claims, criticisms, and indicators of bias, finding:

“One Man’s Modus Ponens”, Branwen 2012

Modus: “One Man’s Modus Ponens”⁠, Gwern Branwen (2012-05-01; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

One man’s modus ponens is another man’s modus tollens is a saying in Western philosophy encapsulating a common response to a logical proof which generalizes the reductio ad absurdum and consists of rejecting a premise based on an implied conclusion. I explain it in more detail, provide examples, and a Bayesian gloss.

A logically-valid argument which takes the form of a modus ponens may be interpreted in several ways; a major one is to interpret it as a kind of reductio ad absurdum, where by ‘proving’ a conclusion believed to be false, one might instead take it as a modus tollens which proves that one of the premises is false. This “Moorean shift” is aphorized as the snowclone⁠, “One man’s modus ponens is another man’s modus tollens”.

The Moorean shift is a powerful counter-argument which has been deployed against many skeptical & metaphysical claims in philosophy, where often the conclusion is extremely unlikely and little evidence can be provided for the premises used in the proofs; and it is relevant to many other debates, particularly methodological ones.

“Silk Road 1: Theory & Practice”, Branwen 2011

Silk-Road: “Silk Road 1: Theory & Practice”⁠, Gwern Branwen (2011-07-11; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

History, background, visiting, ordering, using, & analyzing the drug market Silk Road 1

The cypherpunk movement laid the ideological roots of Bitcoin and the online drug market Silk Road; balancing previous emphasis on cryptography, I emphasize the non-cryptographic market aspects of Silk Road which is rooted in cypherpunk economic reasoning, and give a fully detailed account of how a buyer might use market information to rationally buy, and finish by discussing strengths and weaknesses of Silk Road, and what future developments are predicted by cypherpunk ideas.

“Mystical Experiences Occasioned by the Hallucinogen Psilocybin Lead to Increases in the Personality Domain of Openness”, MacLean et al 2011

“Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness”⁠, Katherine A. MacLean, Matthew W. Johnson, Rol, R. Griffiths (2011; ; backlinks):

A large body of evidence, including longitudinal analyses of personality change, suggests that core personality traits are predominantly stable after age 30. To our knowledge, no study has demonstrated changes in personality in healthy adults after an experimentally manipulated discrete event. Intriguingly, double-blind controlled studies have shown that the classic hallucinogen psilocybin occasions personally and spiritually significant mystical experiences that predict long-term changes in behaviors, attitudes and values. In the present report we assessed the effect of psilocybin on changes in the five broad domains of personality—Neuroticism, Extroversion, Openness, Agreeableness⁠, and Conscientiousness⁠. Consistent with participant claims of hallucinogen-occasioned increases in aesthetic appreciation, imagination, and creativity, we found statistically-significant increases in Openness following a high-dose psilocybin session. In participants who had mystical experiences during their psilocybin session, Openness remained significantly higher than baseline more than 1 year after the session. The findings suggest a specific role for psilocybin and mystical-type experiences in adult personality change.

“Zeo Sleep Self-experiments”, Branwen 2010

Zeo: “Zeo sleep self-experiments”⁠, Gwern Branwen (2010-12-28; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

EEG recordings of sleep and my experiments with things affecting sleep quality or durations: melatonin, potassium, vitamin D etc

I discuss my beliefs about Quantified Self⁠, and demonstrate with a series of single-subject design self-experiments using a Zeo. A Zeo records sleep via EEG; I have made many measurements and performed many experiments. This is what I have learned so far:

  1. the Zeo headband is wearable long-term
  2. melatonin improves my sleep
  3. one-legged standing does little
  4. Vitamin D at night damages my sleep & Vitamin D in morning does not affect my sleep
  5. potassium (over the day but not so much the morning) damages my sleep and does not improve my mood/​productivity
  6. small quantities of alcohol appear to make little difference to my sleep quality
  7. I may be better off changing my sleep timing by waking up somewhat earlier & going to bed somewhat earlier
  8. lithium orotate does not affect my sleep
  9. Redshift causes me to go to bed earlier
  10. ZMA: inconclusive results slightly suggestive of benefits

“The Replication Crisis: Flaws in Mainstream Science”, Branwen 2010

Replication: “The Replication Crisis: Flaws in Mainstream Science”⁠, Gwern Branwen (2010-10-27; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

2013 discussion of how systemic biases in science, particularly medicine and psychology, have resulted in a research literature filled with false positives and exaggerated effects, called ‘the Replication Crisis’.

Long-standing problems in standard scientific methodology have exploded as the “Replication Crisis”: the discovery that many results in fields as diverse as psychology, economics, medicine, biology, and sociology are in fact false or quantitatively highly inaccurately measured. I cover here a handful of the issues and publications on this large, important, and rapidly developing topic up to about 2013, at which point the Replication Crisis became too large a topic to cover more than cursorily. (A compilation of some additional links are provided for post-2013 developments.)

The crisis is caused by methods & publishing procedures which interpret random noise as important results, far too small datasets, selective analysis by an analyst trying to reach expected/​desired results, publication bias, poor implementation of existing best-practices, nontrivial levels of research fraud, software errors, philosophical beliefs among researchers that false positives are acceptable, neglect of known confounding like genetics, and skewed incentives (financial & professional) to publish ‘hot’ results.

Thus, any individual piece of research typically establishes little. Scientific validation comes not from small p-values, but from discovering a regular feature of the world which disinterested third parties can discover with straightforward research done independently on new data with new procedures—replication.

“Nootropics”, Branwen 2010

Nootropics: “Nootropics”⁠, Gwern Branwen (2010-01-02; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar)

“Dual N-Back FAQ”, Branwen 2009

DNB-FAQ: “Dual n-Back FAQ”⁠, Gwern Branwen (2009-03-25; ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

A compendium of DNB, WM⁠, IQ information up to 2015.

Between 2008 and 2011, I collected a number of anecdotal reports about the effects of n-backing; there are many other anecdotes out there, but the following are a good representation—for what they’re worth.

“Spaced Repetition for Efficient Learning”, Branwen 2009

Spaced-repetition: “Spaced Repetition for Efficient Learning”⁠, Gwern Branwen (2009-03-11; ⁠, ⁠, ⁠, ⁠, ⁠, ; backlinks; similar):

Efficient memorization using the spacing effect: literature review of widespread applicability, tips on use & what it’s good for.

Spaced repetition is a centuries-old psychological technique for efficient memorization & practice of skills where instead of attempting to memorize by ‘cramming’, memorization can be done far more efficiently by instead spacing out each review, with increasing durations as one learns the item, with the scheduling done by software. Because of the greater efficiency of its slow but steady approach, spaced repetition can scale to memorizing hundreds of thousands of items (while crammed items are almost immediately forgotten) and is especially useful for foreign languages & medical studies.

I review what this technique is useful for, some of the large research literature on it and the testing effect (up to ~2013, primarily), the available software tools and use patterns, and miscellaneous ideas & observations on it.

“The Bayesian Brain: the Role of Uncertainty in Neural Coding and Computation”, Knill & Pouget 2004

2004-knill.pdf: “The Bayesian brain: the role of uncertainty in neural coding and computation”⁠, David C. Knill, Alexandre Pouget (2004-12; ⁠, ; backlinks; similar):

To use sensory information efficiently to make judgments and guide action in the world, the brain must represent and use information about uncertainty in its computations for perception and action. Bayesian methods have proven successful in building computational theories for perception and sensorimotor control, and psychophysics is providing a growing body of evidence that human perceptual computations are ‘Bayes’ optimal’. This leads to the ‘Bayesian coding hypothesis’: that the brain represents sensory information probabilistically, in the form of probability distributions. Several computational schemes have recently been proposed for how this might be achieved in populations of neurons. Neurophysiological data on the hypothesis, however, is almost non-existent. A major challenge for neuroscientists is to test these ideas experimentally, and so determine whether and how neurons code information about sensory uncertainty.

“Serotonin and Hallucinogens”, Aghajanian & Marek 1999

1999-aghajanian.pdf: “Serotonin and Hallucinogens”⁠, G. K. Aghajanian, G. J. Marek (1999-08-01; backlinks; similar):

This brief review traces the serotonin (5-HT) hypothesis of the action of hallucinogenic drugs from the early 1950s to the present day.

There is now converging evidence from biochemical, electrophysiological, and behavioral studies that the two major classes of psychedelic hallucinogens, the indoleamines (eg. LSD) and the phenethylamines (eg. mescaline), have a common site of action as partial agonists at 5-HT2A and other 5-HT2 receptors in the central nervous system. The noradrenergic locus coeruleus and the cerebral cortex are among the regions where hallucinogens have prominent effects through their actions upon a 5-HT2A receptors.

Recently, we have observed a novel effect of hallucinogens—a 5-HT2A receptor-mediated enhancement of nonsynchronous, late components of glutamatergic excitatory postsynaptic potentials at apical dendrites of layer V cortical pyramidal cells.

We propose that an effect of hallucinogens upon glutamatergic transmission in the cerebral cortex may be responsible for the higher-level cognitive, perceptual, and affective distortions produced by these drugs.

“FY1995 Federal Sentencing Statistics by State, District and Circuit”, Commission 1994

1994-doj-sentencing.pdf: “FY1995 Federal Sentencing Statistics by State, District and Circuit”⁠, U. S. Sentencing Commission (1994-01-01; ; backlinks)

“LSD-induced Effects in Elephants: Comparisons With Musth Behavior”, Siegel 1984b

1984-siegel-2.pdf: “LSD-induced effects in elephants: Comparisons with musth behavior”⁠, Ronald K. Siegel (1984-07-01; similar):

Musth is a condition observed in male Asiatic elephants and is characterized by aggression and temporal gland secretions. A classic and controversial 1962 study attempted to induce a musth syndrome in an elephant via treatment with LSD. Two elephants in the present study survived dosages of LSD (0.003–0.10 mg/​kg) and exhibited changes in the frequency and/​or duration of several behaviors as scored according to a quantitative observational system. LSD increased aggression and inappropriate behaviors such as ataxia. Results are discussed in terms of musth and drug-induced perceptual-motor dysfunction.

…Treatment with the low dosage of LSD produced dramatic changes in behavior within 10–20 min. The female showed a small increase in rock/​sway time and slightly increased ear flapping and exploration. Perhaps the most interesting change was the increased inappropriate behavior marked by leaning with closed eyes and slightly ataxic gait. Vocalizations decreased but changed to short squeaks or chirping, which may indicate pleasure or conflict. The male showed similar, albeit more intense, behaviors, as well as head shaking and several aggressive displays.

The high dosage of LSD produced an initial aggressive display by the female, marked by trumpets and snorts, vocalizations that indicate extreme arousal. This was followed by increasing ataxia, with spread forelegs and hindlegs, and eventually by the animal’s falling onto its side. It remained down for ~60 min and exhibited shallow respirations and some tremors, but when nudged by handlers, arose slowly and eventually regained an upright posture. Activity remained quiescent for the remainder of the session. The high dosage also produced an aggressive display in the male elephant, which repeatedly trumpeted and snorted while charging the observer. This was quickly followed by leaning with closed eyes and ataxia. Periodically, this inappropriate behavior was interrupted by aggressive displays or dustbathing. During all LSD sessions, both elephants refused feeding and most drinking. However, during the high-dosage session, the male bathed with the hay but did not eat it.

…Within 24 h following LSD treatments, both elephants returned to normal baseline behaviors, including feeding and drinking. Examination of the temporal glands revealed no evidence of discharging…The female displayed some aggression during the high-dose session, but the accompanying vocalizations suggest that this was more alarm and panic to the sudden onset of perceptual-motor symptoms than it was a threat.

“Religious Behavior in Animals and Man: Drug-Induced Effects”, Siegel 1977

1977-siegel.pdf: “Religious Behavior in Animals and Man: Drug-Induced Effects”⁠, Ronald K. Siegel (1977-06; similar):

This paper attempts to develop an experimental analysis of drug-induced religious behavior. The first part discusses drugs and religious behavior in man and includes sections on anthropological, contemporary, and experimental perspectives. The second part reviews analogous natural and drug-induced animal behaviors which are seen to be structurally similar to human religious activities. The functional similarities are examined in the third section which analyses religion in terms of operant behavior concepts and findings. It is concluded that the behavioral, albeit not necessarily the experiential, aspects of drug-induced religious behavior can be studied in the animal model.

“An Ethologic Search for Self-Administration of Hallucinogens”, Siegel 1973

1973-siegel.pdf: “An Ethologic Search for Self-Administration of Hallucinogens”⁠, Ronald K. Siegel (1973; similar):

It is well-known that Homo sapiens voluntarily learns to self-administer psychoactive drugs without additional reinforcement. The primary societal use of these self-administrations is social (Blum et al 1969), while the motivation to repeatedly self-administer is considered a major factor in human drug abuse (cf. Weeks, 1971). Among the many drugs used in this way by man are the hallucinogens. Indeed, it is a traditional, albeit tacit, assumption of psychopharmacological thinking that Homo sapiens is the only species that will self-administer hallucinogens without additional rewards.

Table 2: Ethologic Examples of Self-Administration of Various Types of Drugs

Conclusions: The ethologic search has found that Homo sapiens is not alone in the self-administration of hallucinogens. Either by accident or design, numerous infrahuman species also self-administer these drugs. Table 2 shows some ethologic examples of the self-administration of various types of drugs as described in this paper. The drug types and their naturally occurring substances are listed together with the animals which self-administer them, pattern of self-administration as discussed in this paper, animals which self-administer the same or similar substances in the laboratory, and the human use of these substances. Of the 14 drugs listed in Table 2, four are hallucinogens and four others are known to have hallucinogenic effects in man. Many of the examples cited here need further controlled psychopharmacological study in order to identify the biological, environmental, and pharmacological variables which reinforce and maintain self-administration. Nonetheless, it is clear that the consequences of such administrations dramatically affect the social behavior of these animals. Whether “sick”, “ill”, “intoxicated”, “poisoned”, “hypersensitive”, “genetically guided”, “narcotized”, or “addicted”, hallucinogen-treated animals tend to isolate themselves from social groups.

“Psychedelic-Induced Social Behavior in Mice: A Preliminary Report”, Siegel & Poole 1969

1969-siegel.pdf: “Psychedelic-Induced Social Behavior in Mice: A Preliminary Report”⁠, Ronald K. Siegel, Jean Poole (1969-12-01; ; similar):

When large populations of mice were treated with LSD (2mcg/​kg to 30mcg/​kg), bufotenine (5mg/​kg to 30mg/​kg), a cannabis sativa extract (50mg/​kg to 100mg/​kg), or tetrahydrocannabinol (2mg/​kg to 10mg/​kg), there was a dramatic change in social behavior. Such treatment produced a statistically-significant reduction in aggression, group aggregation, and temporary disruptions of social hierarchies. Hallucinogenic-treated mice placed in normal untreated colonies were hypersensitive to auditory and tactile stimulation and aggregated in small groups apart from the rest of the population. Treatment with saline or BOL-148 produced no statistically-significant changes in behavior.

…When strangers were introduced into the drugged colonies, they were relatively ignored by the inhabitants. This was true whether the strangers were introduced in a drugged or undrugged state. If the strangers were undrugged, however, they moved about the colony investigating mice and inducing squealing and flight behavior in the inhabitants. And, if the strangers were dominant mice to begin with, they would often establish dominance over the entire colony, exploiting the food supplies and territories of the inhabitants.

“Lysergic Acid Diethylamide (LSD-25): Xv. the Effects Produced By Substitution of a Tap Water Placebo”, Abramson et al 1955

1955-abramson.pdf: “Lysergic Acid Diethylamide (LSD-25): Xv. the Effects Produced By Substitution of a Tap Water Placebo”⁠, H. A. Abramson, M. E. Jarvik, A. Levine, M. R. Kaufman, M. W. Hirsch (1955; ⁠, ; backlinks; similar):

The purpose of this paper is to study the responses given to a questionnaire by subjects who received a tap water ‘placebo’ instead of lysergic acid diethylamide (LSD-25), and to relate the number of responses to other variables. These variables are: body weight, number of responses on a health questionnaire, arithmetic test scores, scores on the Wechsler-Bellevue Intelligence Scale, and Rorschach test responses.

Figure 4 shows for each question the percentage and number of subjects out of 28 who gave a positive response at least once during the 0.5, 2.5, and 4.5-hour intervals. The questions appear in the figure in the order of decreasing percentages of response to them. The time of the response and the magnitude are disregarded in this tabulation. The question receiving the greatest percentage response was (Subject 24), “Are your palms moist?” As many as 60.7% reported this symptom. Half of the subjects reported headache (Subject 13), fatigue (Subject 44), and drowsiness (Subject 45). About 36% reported anxiety (Subject 47). Illness (Subject 1), and dizziness (Subject 15) were reported by 28.6 per cent of the group and 25% indicated a dream-like feeling (Subject 46), increased appetite (Subject 6), unsteadiness (Subject 16), a hot feeling (Subject 22), heaviness of hands and feet (Subject 30), and weakness (Subject 43). There were 19 questions which received positive responses from between 10 and 22 per cent of the subjects. Less than 10% of the group (or no more than two subjects) responded positively to the remaining questions, but each question received a positive response from at least one subject.

…The findings point out that a substance such as tap water, which is generally considered chemically and pharmacologically inactive, is capable of eliciting certain responses from certain subjects who believe they have received lysergic acid diethylamide. These observations emphasize once more the need for placebo controls in studies investigating the effects of drugs; without them changes which are produced merely by the situation and not by the drug are frequently falsely attributed to the action of the drug…Most subjects who respond to a placebo tend to do so most markedly during the first 0.5 hour after receiving the substance. At this time their anticipation of, and anxiety about, the effects of LSD-25 are probably greatest. Gradually the effects wear off, as the anticipation wears off. Individual differences exist in the time of peak effect, but this is the most common finding. The questions which elicited the greatest percentage response from the group were those related to anxiety (moist palms and feeling anxious) or to phenomena which commonly occur without the presence of any foreign agent (drowsiness, fatigue, and headache). The remaining questions received random responses. The fact that there is a wide range in the number of positive responses made to the questionnaire is of major interest.

An Essay On The Psychology Of Invention In The Mathematical Field”, Hadamard 1945

An Essay On The Psychology Of Invention In The Mathematical Field⁠, Jacques Hadamard (1945; ⁠, ; backlinks; similar):

[Relevant to an essay of mine on mathematical errorHadamard’s book is one of the classics in the area of mathematical discovery, mentioned along with Poincaré’s lecture⁠.

With due allowance for style and age, Hadamard ably describes and defends the basic model of ‘work, incubation⁠, illumination, verification’, with reference to his own discoveries, his many famous acquaintances, Poincaré’s lecture, and a very interesting survey of mathematicians. In fact, it’s a little depressing that we don’t seem to have gone much beyond that in the half-century since this was published back in 1945 or so. While at least we no longer need his defense of the unconscious as a meaningful part of cognition, much of the rest is depressingly familiar—for example, his acute observations on mental imagery & people who solely think in words, and mention of Francis Galton’s survey (little-known outside of psychology), could be usefully read by many who commit the typical mind fallacy⁠.

If Hadamard comes to no hard and fast conclusions, but merely raises many interesting points and criticizes a number of theories, we can hardly hold that against him, as we can do little better and so it becomes our failing to followup, not his.]

“Volumetric Liquid Dosing”, Wiki 2022

“Volumetric liquid dosing”⁠, Psychonaut Wiki (; backlinks; similar):

Volumetric dosing is the process of dissolving a compound in a liquid to make it easier to measure. In the interest of harm reduction, it is important to use volumetric dosing with certain compounds that are too potent to measure with traditional weighing scales. This technique makes it possible to use a cheap $39.5$30.02013 scale and still measure accurately to a few milligrams.

Many psychoactive substances, including benzodiazepines and certain psychedelics, are active at less than a single milligram. Such small quantities cannot be accurately measured with common digital scales, so the drug must instead be dosed volumetrically by weighing out larger amounts of the compound and dissolving it in a calculated volume of a suitable liquid.

William Leonard Pickard

Wikipedia

Psychedelics in problem-solving experiment

Wikipedia

Psychedelic therapy

Wikipedia

Psychedelic microdosing

Wikipedia

Psychedelic drug

Wikipedia

Psilocybin mushroom

Wikipedia

Psilocybe cubensis

Wikipedia

Pineapple Fund

Wikipedia

PiHKAL

Wikipedia

Nutmeg § Effects

Wikipedia

N,N-Dimethyltryptamine

Wikipedia

MDMA

Wikipedia

Lysergic acid diethylamide

Wikipedia

Ketamine

Wikipedia

Ibogaine

Wikipedia

Hallucinogenic fish

Wikipedia

Erowid

Wikipedia

EA-3834

Wikipedia

EA-3580

Wikipedia

EA-3443

Wikipedia

EA-3167

Wikipedia

Datura § Toxicity

Wikipedia

Ayahuasca

Wikipedia

Alexander Shulgin

Wikipedia

Miscellaneous