October was possibly the most active month this year for psychedelic research. Although none of the research might have made the big splash that a big double-blind trail does, these are all building blocks that further the psychedelic field.

Research this month took a look inside our brains and how DMT and Salvinorin A acutely changed it. The DMT-activity can be likened to how your brain normally reacts to visual stimuli. The research on Salvinorin A shows that this psychedelic works via very different pathways than others. A simulation of the brain also showed how (and where) entropy increases under psychedelics.

Many reviews were published of which we’ve highlighted three. The first looks at how microdosing is experienced by over 3000 people. The study finds that expectations and reality don’t always match. Both positive and negative outcomes from microdosing were common (and diverse). An interview study on Norwegian psychedelic users may provide more context on how people deal with (macrodose) bad trips.

The second review investigates the literature on psychedelics as potential treatments for autoimmune conditions. Whilst there is definitely promise, this is in the very early stages.

The third review investigates the long-term (one year) outcomes of psychedelic-assisted therapy. The effect size on therapeutic outcomes is large, that on personality traits not so. This review also ties into the cost-effectiveness analysis that MAPS has done in which they argue that it’s more cost-effective than current treatments.

Two studies from Switzerland enlighten us further on the acute effects of LSD and its combination with MDMA. Surprisingly the effects at different dosages haven’t been fully investigated/described in this detailed manner before. The study on LSD finds 100 micrograms to be the best dosage that they tested.

Another paper that we’ve highlighted finds that oral or IV ketamine is as effective as electroconvulsive therapy (ECT) for depression (MDD) and suicidal ideation (measured up to three weeks later). Ayahuasca has also shown significant decreases in both measures in an analysis of data of an earlier study.

In the ‘related papers’ section you will find many more papers on ketamine and other topics.

The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain

Authors: Manoj K. Doss, Darrick G. May, Matthew W. Johnson, John M. Clifton, Sidnee L. Hedrick, Thomas E. Prisinzano, Roland R. Griffiths & Frederick S. Barrett

Published: 2 October 2020

One-sentence summary: Although the psychedelic Salvinorin A works via very different pathways in the brain, it elicited similar effects (lower activity DMN) as other psychedelics.

“Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.”

Further analysis.

Potential safety, benefits, and influence of the placebo effect in microdosing psychedelic drugs: A systematic review

Authors: Genís Ona & José C. Bouso

Published: 5 October 2020

One-sentence summary: Microdosing psychedelics (LSD & psilocybin) is experienced both positively and negatively by participants (n=3619) in this systematic review of mostly observational studies.

“Microdosing psychedelic drugs-that is, taking sub-behavioral doses of lysergic acid diethylamide (LSD) or psilocybin-is a growing practice in Western societies. Taken mainly for creative or mood-enhancing purposes, thousands of users are increasingly being exposed to (micro)doses of psychedelic drugs. In this systematic review, we searched the available evidence from human studies, focusing our results in terms of three main axes: efficacy, safety, and the influence of the placebo effect in microdosing practices. While the available evidence has some strengths (e.g. large sample sizes, robust methodologies) there are also remarkable limitations (e.g. gender bias, heterogeneity of dosing schedules and drugs used). Highly contradictory results have been found, showing both the benefits and detriments of microdosing in terms of mood, creative processes, and energy, among other regards. This review provides a general overview of the methods and approaches used, which could be useful for improving future studies.”

Further analysis.

Psychedelics as a Novel Approach to Treating Autoimmune Conditions

Authors: Caitlin Thompson & Attila Szabo

Published: 7 October 2020

One-sentence summary: This literature review argues that psychedelics may attenuate/resolve autoimmunity through various mechanisms.

“With a rise in the incidence of autoimmune diseases (AiD), health care providers continue to seek out more efficacious treatment approaches for the AD patient population. Classic serotonergic psychedelics have recently been gaining public and professional interest as novel interventions to a number of mental health afflictions. Psychedelics have also been shown to be able to modulate immune functions, however, while there has been great interest to researching into their psychotherapeutic applications, there has so far been very little exploration into the potential to treat inflammatory and immune-related diseases with these compounds. A handful of studies from a variety of fields suggest that psychedelics do indeed have effects in the body that may attenuate the outcome of AD. This literature review explores existing evidence that psychedelic compounds may offer a potential novel application in the treatment of pathologies related to autoimmunity. We propose that psychedelics hold the potential to attenuate or even resolve autoimmunity by targeting psychosomatic origins, maladaptive chronic stress responses, inflammatory pathways, immune modulation and enteric microbiome populations.”

Further analysis.

Acute subjective effects in LSD- and MDMA-assisted psychotherapy

Authors: Yasmin Schmid, Peter Gasser, Peter Oehen, Matthias E. Liechti

Published: 8 October 2020

One-sentence summary: This open-label study (n=18) of group-therapy with LSD and MDMA aimed to describe the characteristics, treatment indicators, and acute effects on patients.

“Background Lysergic acid diethylamide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA) were used in psychotherapy in the 1960s–1980s, and are currently being re-investigated as treatments for several psychiatric disorders. In Switzerland, limited medical use of these substances is possible in patients not responding to other treatments (compassionate use). Methods This study aimed to describe patient characteristics, treatment indications, and acute alterations of mind in patients receiving LSD (100–200 µg) and/or MDMA (100–175 mg) within the Swiss compassionate use programme from 2014–2018. Acute effects were assessed using the 5 Dimensions of Altered States of Consciousness scale and the Mystical Experience Questionnaire, and compared with those in healthy volunteers administered with LSD or MDMA and patients treated alone with LSD in clinical trials. Results Eighteen patients (including 12 women and six men, aged 29–77 years) were treated in group settings. Indications mostly included posttraumatic stress disorder and major depression. Generally, a drug-assisted session was conducted every 3.5 months after 3–10 psychotherapy sessions. LSD induced pronounced alterations of consciousness on the 5 Dimensions of Altered States of Consciousness scale, and mystical-type experiences with increases in all scales on the Mystical Experience Questionnaire. Effects were largely comparable between patients in the compassionate use programme and patients or healthy subjects treated alone in a research setting. Conclusion LSD and MDMA are currently used medically in Switzerland mainly in patients with posttraumatic stress disorder and depression in group settings, producing similar acute responses as in research subjects. The data may serve as a basis for further controlled studies of substance-assisted psychotherapy.“

Further analysis.

Post-acute psychological effects of classical serotonergic psychedelics: A systematic review and meta-analysis

Authors: Simon B. Goldberg, Benjamin Shechet, Christopher R. Nicholas, Chi Wing Ng, Geetanjali Deole, Zhuofan Chen & Charles L. Raison

Published/in press: 12 October 2020

One-sentence summary: This review and meta-analysis of long-term effects of psychedelics finds a large effect (Hedges’ g ≈ 1) on various outcomes, but also notes various biases as issues in current research.

“Background: Scientific interest in the therapeutic effects of classical psychedelics has increased in the past two decades. The psychological effects of these substances outside the period of acute intoxication have not been fully characterized. This study aimed to: (1) quantify the effects of psilocybin, ayahuasca, and LSD on psychological outcomes in the post-acute period; (2) test moderators of these effects; and (3) evaluate adverse effects and risk of bias. Methods: We conducted a systematic review and meta-analysis of experimental studies (single-group pre-post or randomized controlled trials) that involved administration of psilocybin, ayahuasca, or LSD to clinical or non-clinical samples and assessed psychological outcomes ≥24 hours postadministration. Effects were summarized by study design, timepoint, and outcome domain. Results: A total of 34 studies (24 unique samples, n = 549, mean longest follow-up = 55.34 weeks) were included. Classical psychedelics showed significant within-group pre-post and between-group placebo-controlled effects on a range of outcomes including targeted symptoms within psychiatric samples, negative and positive affect-related measures, social outcomes, and existential/spiritual outcomes, with large between-group effect in these domains (Hedges’ gs = 0.84 to 1.08). Moderator tests suggest some effects may be larger in clinical samples. Evidence of effects on big five personality traits and mindfulness was weak. There was no evidence of post-acute adverse effects. Conclusions: High risk of bias in several domains, heterogeneity across studies, and indications of publication bias for some models highlight the need for careful, large-scale, placebo-controlled randomized trials.”

DMT alters cortical travelling waves

Authors: Andrea Alamia, Christopher Timmermann, Rufin VanRullen & Robin L. Carhart-Harris

Published: 12 October 2020

One-sentence summary: This EEG study (n=13) finds that DMT elicited similar brain activation (cortical travelling waves) as visual stimulation does.

“Psychedelic drugs are potent modulators of conscious states and therefore powerful tools for investigating their neurobiology. N,N, Dimethyltryptamine (DMT) can rapidly induce an extremely immersive state of consciousness characterized by vivid and elaborate visual imagery. Here, we investigated the electrophysiological correlates of the DMT induced altered state from a pool of participants receiving DMT and (separately) placebo (saline) while instructed to keep their eyes closed. Consistent with our hypotheses, results revealed a spatio-temporal pattern of cortical activation (i.e., travelling waves) similar to that elicited by visual stimulation. Moreover, the typical top-down alpha-band rhythms of closed-eyes rest were significantly decreased, while the bottom-up forward wave was significantly increased. These results support a recent model proposing that psychedelics reduce the ‘precision-weighting of priors’, thus altering the balance of top-down versus bottom-up information passing. The robust hypothesis-confirming nature of these findings imply the discovery of an important mechanistic principle underpinning psychedelic-induced altered states.”

Further analysis.

The cost-effectiveness of MDMA-assisted psychotherapy for the treatment of chronic, treatment-resistant PTSD

Authors: Elliot Marseille, James G. Kahn, Berra Yazar-Klosinski, Rick Doblin

Published: 14 October 2020

One-sentence summary: This study (2020) on the costs (and benefits) of MDMA-assisted therapy for PTSD finds it to be more cost-effective than other treatments.

“Background Chronic posttraumatic stress disorder (PTSD) is a disabling condition that generates considerable morbidity, mortality, and both medical and indirect social costs. Treatment options are limited. A novel therapy using 3,4-methylenedioxymethamphetamine (MDMA) has shown efficacy in six phase 2 trials. Its cost-effectiveness is unknown. Methods and findings To assess the cost-effectiveness of MDMA-assisted psychotherapy (MAP) from the health care payer’s perspective, we constructed a decision-analytic Markov model to portray the costs and health benefits of treating patients with chronic, severe, or extreme, treatment-resistant PTSD with MAP. In six double-blind phase 2 trials, MAP consisted of a mean of 2.5 90-minute trauma-focused psychotherapy sessions before two 8-hour sessions with MDMA (mean dose of 125 mg), followed by a mean of 3.5 integration sessions for each active session. The control group received an inactive placebo or 25–40 mg. of MDMA, and otherwise followed the same regimen. Our model calculates net medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Efficacy was based on the pooled results of six randomized controlled phase 2 trials with 105 subjects; and a four-year follow-up of 19 subjects. Other inputs were based on published literature and on assumptions when data were unavailable. We modeled results over a 30-year analytic horizon and conducted extensive sensitivity analyses. Our model calculates expected medical costs, mortality, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Future costs and QALYs were discounted at 3% per year. For 1,000 individuals, MAP generates discounted net savings of $103.2 million over 30 years while accruing 5,553 discounted QALYs, compared to continued standard of care. MAP breaks even on cost at 3.1 years while delivering 918 QALYs. Making the conservative assumption that benefits cease after one year, MAP would accrue net costs of $7.6 million while generating 288 QALYS, or $26,427 per QALY gained. Conclusion MAP provided to patients with severe or extreme, chronic PTSD appears to be cost-saving while delivering substantial clinical benefit. Third-party payers are likely to save money within three years by covering this form of therapy.”

Further analysis.

Comparison of Rapid Antidepressant and Antisuicidal Effects of Intramuscular Ketamine, Oral Ketamine, and Electroconvulsive Therapy in Patients With Major Depressive Disorder

Authors: Dorna Kheirabadi, Gholam R. Kheirabadi, Zahra Mirlohi, Mohammad J. Tarrahi & Amir Norbaksh

Published: 14 October 2020

One-sentence summary: This pilot study (n=45) found that oral and IV ketamine was as effective as electroconvulsive therapy (ECT) for depression (MDD) and suicidal ideation, and was rated more positively by participants.

“Purpose/Background This study was devised to compare the antidepressant and antisuicidal effects of oral and intramuscular (IM) ketamine versus electroconvulsive therapy (ECT). Methods/Procedures In our pilot study, 45 patients with major depressive disorder [MDD] (based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria) in the age range of 18 to 70 years who were determined suitable candidates for ECT got randomly divided into 3 equal groups. Each group received one of these treatment modalities: 0.5 mg/kg of IM ketamine; 1 mg/kg of oral ketamine; and ECT in 6 to 9 sessions during 3 weeks. Depression and suicidal ideation scores were recorded using the Hamilton Depression Rating Scale and the Beck Scale for Suicidal Ideation, respectively, at baseline, 24 hours, 1 week, 2 weeks, and 3 weeks within the intervention. The measurements were repeated 1 week and 1 month after the end of the intervention as well. Vital signs and adverse effects were noted. Finally, satisfaction levels of patients for each method were recorded and compared between groups. Findings/Results The Hamilton Depression Rating Scale and the Beck Scale for Suicidal Ideation scores significantly improved in all groups compared with baseline with no significant differences between the 3 groups. The adverse effects for ketamine-consuming groups such as dissociative symptoms were brief and transient, whereas memory loss for the ECT group remained up to 1 month in some patients. Ketamine-receiving groups preferred it more than ECT. Implications/Conclusions Oral and IM ketamine probably have equal antidepressant in addition to more antisuicidal effects compared with ECT but had less cognitive adverse effects and higher preference by patients. Thereby, ketamine can be an alternative method in the treatment of patients with severe and/or suicidal MDD.”

Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects

Authors: Friederike Holze, Patrick Vizeli, Laura Ley, Felix Müller, Patrick Dolder, Melanie Stocker, Urs Duthaler, Nimmy Varghese, Anne Eckert, Stefan Borgwardt & Matthias E. Liechti

Published: 15 October 2020

One-sentence summary: This double-blind placebo-controlled, randomized, cross-over study (n=16) investigated the subjective effects of LSD (from 0-200µg).

“Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25–200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose–response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.”

Further analysis.

Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences

Authors: Liridona Gashi, Sveinung Sandberg & Willy Pedersen

Published (online first): 17 October 2020

One-sentence summary: This interview study (n=50) of Norwegian psychedelic users found that narrative techniques helped them deal with/recontextualize ‘bad’ trips.

“Background We study the significance of stories about bad trips among users of psychedelics. Drawing on narrative theory, we describe the characteristics of such stories and explore the work they do. Methods In-depth qualitative interviews with 50 Norwegian users of psychedelics. Results Almost all participants had frightening experiences when using psychedelics and many described these as bad trips. The key feature of a bad trip was a feeling of losing oneself or going crazy, or ego dissolution. Most users said that these experiences could be avoided by following certain rules, based on tacit knowledge in the subcultures of users. Possessing such knowledge was part of symbolic boundary work that distinguished between drug culture insiders and outsiders. Some also rejected the validity of the term bad trip altogether, arguing that such experiences reflected the lack of such competence. Finally, and most importantly, most participants argued that unpleasant experiences during bad trips had been beneficial and had sometimes given them deep existential and life-altering insights. Conclusion Bad trip experiences are common among users of psychedelics. Such experiences are often transformed into valuable experiences through storytelling. Bad trip narratives may be a potent coping mechanism for users of psychedelics in non-controlled environments, enabling them to make sense of frightening experiences and integrate these into their life stories. Such narrative sense-making, or narrative work, facilitates the continued use of psychedelics, even after unpleasant experiences with the drugs.”

Further analysis.

Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study

Authors: Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder, Eef L. Theunissen, Friederike Holze, Matthias E. Liechti, Amanda Feilding, Johannes G. Ramaekers & Kim P. C. Kuypers

Published: 17 October 2020

One-sentence summary: This fourth publication on the administration of a low/micro (5, 10, or 20 µg) dose of LSD found enhanced attention, slower information processing, more positive mood, increased anxiety and confusion (again, the results are small and quite ambiguous).

“There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.”

Further analysis.

A mechanistic model of the neural entropy increase elicited by psychedelic drugs

Authors: Ruben Herzog, Pedro A. M. Mediano, Fernando E. Rosas, Robin L. Carhart-Harris, Yonatan Sanz Perl, Enzo Tagliazucchi & Rodrigo Cofre

Published: 17 October 2020

One-sentence summary: This whole-brain simulation study (DMF model) reproduced increased entropy under psychedelics, but also found this to be different (higher/lower) in various parts of the brain, this was correlated with the connections between brain regions, not serotonin (5-HT2a) receptor density.

“Psychedelic drugs, including lysergic acid diethylamide (LSD) and other agonists of the serotonin 2A receptor (5HT2A-R), induce drastic changes in subjective experience, and provide a unique opportunity to study the neurobiological basis of consciousness. One of the most notable neurophysiological signatures of psychedelics, increased entropy in spontaneous neural activity, is thought to be of relevance to the psychedelic experience, encoding both acute alterations in consciousness and mediating long-term effects. However, no clear mechanistic explanation for this ’entropic’ phenomenon has been put forward so far. We sought to do this here by building upon a recent whole-brain model of serotonergic neuromodulation, to study the entropic effects of 5HT2A-R activation. Our results reproduce the overall entropy increase observed in previous experiments in vivo, providing the first model-based explanation for this phenomenon. We also found that entropy changes were not uniform across the brain: entropy increased in some regions and decreased in others, suggesting a topographical reconfiguration mediated by 5HT2A-R activation. Interestingly, at the whole-brain level, this reconfiguration was not well explained by 5HT2A-R density, but related closely to the topological properties of the brain’s anatomical connectivity. These results help us understand the mechanisms underlying the psychedelic state and, more generally, the pharmacological modulation of whole-brain activity.”

Further analysis.

Rapid and sustained decreases in suicidality following a single dose of ayahuasca among individuals with recurrent major depressive disorder: results from an open-label trial

Authors: Richard J. Zeifman, Nikhita Singhal, Rafael G. Dos Santos, Rafael F. Sanches, Flávia de Lima Osório, Jaime E. C. Hallak & Cory R. Weissman

Published: 29 October 2020

One-sentence summary: This analysis of an earlier open-label study (n=15) on Ayahuasca (one session), found significant (Hedges’ g = 1.75) and sustained decreases in suicidality in people with depression (MDD).

“Rationale: Suicidality is a major public health concern with limited treatment options. Accordingly, there is a need for innovative interventions for suicidality. Preliminary evidence indicates that treatment with the psychedelic ayahuasca may lead to decreases in depressive symptoms among individuals with major depressive disorder (MDD). However, there remains limited understanding of whether ayahuasca also leads to reductions in suicidality. Objective: To examine the acute and post-acute effect of ayahuasca on suicidality among individuals with MDD. Methods: We conducted a secondary analysis of an open-label trial in which individuals with recurrent MDD received a single dose of ayahuasca (N = 17). Suicidality was assessed at baseline; during the intervention; and 1, 7, 14, and 21 days after the intervention. Results: Among individuals with suicidality at baseline (n = 15), there were significant acute (i.e., 40, 80, 140, and 180 min after administration) and post-acute (1, 7, 14, and 21 days after administration) decreases in suicidality following administration of ayahuasca. Post-acute effect sizes for decreases in suicidality were large (Hedges’ g = 1.31-1.75), with the largest effect size 21 days after the intervention (g = 1.75). Conclusions: When administered in the appropriate context, ayahuasca may lead to rapid and sustained reductions in suicidality among individuals with MDD. Randomized, double-blind studies with larger sample sizes are needed to confirm this early finding.“

Further analysis.