Psychedelic trials are getting larger and the data is still looking good. The long-term follow-up of Phase II MDMA for PTSD continues to show benefits at the one-year mark. A meta-analysis of nine placebo-controlled trials also showed strong improvements. And for the first time, ketamine was studied on a population of treatment-resistant bipolar depression.

Two studies investigate the mystical experience. One finds reliability of the MEQ30 and the other gives a narrative review of the mystical experience. Finally, we take a deeper dive into the brain and show how psychedelics increase the fractal dimension of the brain.

Long-term Follow-Up Outcomes of MDMA-assisted Psychotherapy for Treatment of PTSD: A Longitudinal Pooled Analysis of Six Phase 2 Trials

Authors: Lisa Jerome, Allison A. Feduccia, Julie B. Wang, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C. Mithoefer & Rick Doblin

Published: 4 June 2020

One sentence summary: MDMA-assisted psychotherapy showed a very large effect (d=1.58, 56% no longer met PTSD criteria) which improved at 12-months follow-up (d=0.43, 67%).

“Rationale: Posttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual’s health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD. Objectives: To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD. Methods: Participants received two to three active doses of MDMA (75-125 mg) during blinded or open-label psychotherapy sessions with additional non-drug therapy sessions. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) at baseline, 1 to 2 months after the last active MDMA session (treatment exit), and at least 12 months post final MDMA session (LTFU). A mixed-effect repeated-measures (MMRM) analysis assessed changes in CAPS-IV total severity scores. The number of participants who met PTSD diagnostic criteria was summarized at each time point. Participants completed a long-term follow-up questionnaire. Results: There was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE) = – 44.8 (2.82), p < .0001), with a Cohen’s d effect size of 1.58 (95% CI = 1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE) = – 5.2 (2.29), p < .05), with a Cohen’s d effect size of 0.23 (95% CI = 0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation. Conclusions: PTSD symptoms were reduced 1 to 2 months after MDMA-assisted psychotherapy, and symptom improvement continued at least 12 months post-treatment. Phase 3 trials are investigating this novel treatment approach in a larger sample of participants with chronic PTSD.”

Further analysis

Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan

Authors: Therasa M. Carbonaro, Matthew W. Johnson & Roland R. Griffiths

Published: 5 June 2020

One sentence summary: Psilocybin is more positively received than DMX (cough syrup) and at higher dosages (20/30mg at 70kg) had significantly greater effects.

“Rationale Although both psilocybin and dextromethorphan (DXM) produce psychedelic-like subjective effects, rates of non-medical use of psilocybin are consistently greater than DXM. Objective New data are presented from a study of psilocybin and DXM relevant to understanding the features of psilocybin subjective effects that may account for its higher rates of non-medical use. Methods Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use. Results High doses of both drugs produced similar time courses and increases in participant ratings of peak overall drug effect strength. Nine subjective effect domains are proposed to be related to the reinforcing effects of psilocybin: liking, visual effects, positive mood, insight, positive social effects, increased awareness of beauty (both visual and music), awe/amazement, meaningfulness, and mystical experience. For most ratings, (1) psilocybin and DXM both produced effects significantly greater than placebo; (2) psilocybin showed dose-related increases; 3, DXM was never significantly higher than psilocybin; (4) the two highest psilocybin doses were significantly greater than DXM. These differences were consistent with two measures of desire to take the drug condition again. Conclusions This analysis provides new information about domains of psilocybin subjective effects proposed to be related to its reinforcing effects (alternatively described as the “motivation” to use). Observed differences on these domains between psilocybin and DXM are consistent with the relative rates of non-medical use of psilocybin and DXM.“

Mystical Experiences in Retrospective Reports of First Times Using a Psychedelic in Finland

Authors: Samuli Kangaslampi, Anino Hausen & Tarina Rauteenmaa

Published: 8 June 2020

One sentence summary: Mystical experiences were captured on the MEQ30 and the questionnaire was validated with Finnish (n=288) retrospective self-reports.

“Despite their acutely inebriating and sometimes unpleasant effects, some people report positive changes in life satisfaction, well-being, or mental health after taking psychedelic drugs. One explanation may be the ability of psychedelics to trigger mystical-type experiences. We examined the validity, reliability, and factor structure of a novel Finnish translation of the Revised Mystical Experiences Questionnaire (MEQ30) among 288 people retrospectively reporting on their first time using a psychedelic. We found evidence for internal consistency reliability and preliminary evidence for criterion and discriminant validity of the Finnish MEQ30. A four-factor structure with factors for mystical qualities, positive mood, transcendence, and ineffability had the best, fair to reasonable fit to the data. MEQ30 scores and having a full mystical experience were highly associated with describing the experience as mystical, spiritual, or religious, and as personally significant, and somewhat associated with the experience being sad or difficult. Mystical experiences were especially associated with positive changes in relationships with nature and oneself and in creativity. Mystical experiences were more common with larger doses. Increasing research suggests mystical-type experiences to relate to positive changes after taking psychedelics. The Finnish MEQ30 is able to tap into relevant information about this aspect of people’s psychedelic experiences.“

Spotlight commentary: REBUS and the anarchic brain

Authors: Tehseen Noorani & Ben Alderson-Day

Published: 12 June 2020

One sentence summary: Analysis and critique on REBUS and the anarchic brain

“In ‘REBUS and the Anarchic Brain: Towards a Unified Model of the Brain Action of Psychedelics’, Carhart-Harris and Friston offer an important analysis of what the predictive processing framework has to offer our understanding of psychedelic experiences, providing an invaluable ground for psychedelic psychiatry. While applauding this, we encourage paying greater attention to contextual factors shaping extreme experiences and their sequalae, and suggest that the authors’ comparisons with certain non-psychedelic altered states may overlook more informative parallels that can be drawn elsewhere. Addressing both points will prove fruitful, ultimately, in identifying the mechanisms of action of greatest interest in psychedelic experiences.“

A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy

Authors: Jason B. Luoma, Christina Chwyl, Geoff J. Bathje, Alan K. Davis & Rafael Lancelotta

Published: 12 June 2020

One sentence summary: This 2020 meta-analysis covers 9 placebo-controlled trials (n=211) of various psychedelics and finds a significant treatment effect.

“After a two-decade hiatus in which research on psychedelics was essentially halted, placebo-controlled clinical trials of psychedelic-assisted therapy for mental health conditions have begun to be published. We identified nine randomized, placebo-controlled clinical trials of psychedelic-assisted therapy published since 1994. Studies examined psilocybin, LSD (lysergic acid diethylamide), ayahuasca (which contains a combination of N,N-dimethyltryptamine and harmala monoamine oxidase inhibitor alkaloids), and MDMA (3,4-methylenedioxymethamphetamine). We compared the standardized mean difference between the experimental and placebo control group at the primary endpoint. Results indicated a significant mean between-groups effect size of 1.21 (Hedges g), which is larger than the typical effect size found in trials of psychopharmacological or psychotherapy interventions. For the three studies that maintained a placebo control through a follow-up assessment, effects were generally maintained at follow-up. Overall, analyses support the efficacy of psychedelic-assisted therapy across four mental health conditions – post-traumatic stress disorder, anxiety/depression associated with a life-threatening illness, unipolar depression, and social anxiety among autistic adults. While study quality was high, we identify several areas for improvement regarding the conduct and reporting of trials. Larger trials with more diverse samples are needed to examine possible moderators and mediators of effects, and to establish whether effects are maintained over time.“

Further analysis

Acute Effects of MDMA on Trust, Cooperative Behaviour and Empathy: A Double-Blind, Placebo-Controlled Experiment

Authors: Anna Borissova, Bart Ferguson, Matthew B. Wall, Celia Ja Morgan, Robin L. Carhart-Harris, Mark Bolstridge, Michael Ap Bloomfield, Tim M. Williams, Amanda Feilding, Kevin Murphy, Robin J. Tyacke, David Erritzoe, Lorna Stewart, Kim Wolff, David Nutt, H. Valerie Curran & Will Lawn

Published: 15 June 2020

One sentence summary: This double-blind, placebo-controlled experiment didn’t find changes in empathy and cooperative behavior with participants on MDMA (100mg).

“Background: 3,4-Methylenedioxymethamphetamine (MDMA) is being actively researched as an adjunct to psychotherapy. It may be beneficial to trust, empathy and cooperative behaviour due to its acute prosocial effects. Aim: To test (a) the acute effects of MDMA on measures of empathy, trust and cooperative behaviour, and (b) subacute changes in mood three days after MDMA administration. Methods: Twenty-five participants (n=7 female), participated in this double-blind, repeated-measures, placebo-controlled experiment. Participants attended two acute sessions, one week apart. Each acute session was followed by a subacute session three days later. Participants received placebo (100 mg ascorbic acid) during one acute session, and MDMA (100 mg MDMA-HCl) at the other, with order counterbalanced. Participants completed the following tasks assessing prosocial behaviour: a trust investment task, a trustworthy face rating task, an empathic stories task, a public project game, a dictator game and an ultimatum game. Participants reported subjective effects. Blood was taken pre-drug, 2 and 4 hours post-drug, and tested for plasma MDMA levels. Results: MDMA acutely increased self-reported ‘closeness to others’ and ‘euphoria’ and increased plasma concentrations of MDMA. MDMA did not significantly change task-based empathy, trust or cooperative behaviour. Using Bayesian analyses, we found evidence that MDMA and placebo did not differ in their effects on empathy and cooperative behaviour. MDMA did not significantly change subacute mood and this was supported by our Bayesian analyses. Conclusion: Despite augmentation in plasma MDMA levels and subjective drug effects, we found no increase in prosocial behaviour in a laboratory setting.”

A preliminary study of adjunctive ketamine for treatment-resistant bipolar depression

Authors: Wei Zheng, Yan-Ling Zhou, Wei-Jian Liu, Cheng-Yu Wang, Yan-Ni Zhan, Xiao-Feng Lan, Bin Zhang & Yu-Ping Ning

Accepted: 22 June 2020

One sentence summary: Repeated infusion of ketamine had antidepressive and antisuicidal effects on treatment-resistant bipolar depression (TRBD) patients (n=16).

“Objectives Ketamine has shown rapid antidepressant effects in depressed patients. However, the antidepressant and antisuicidal effects of repeated ketamine infusions in patients with treatment-resistant bipolar depression (TRBD) are not known. Methods TRBD patients received six intravenous infusions of 0.5 mg/kg ketamine over 40 min on a Monday–Wednesday–Friday schedule during a 12-day period followed by a 2-week follow-up period. Depressive symptoms were measured by the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline and at each follow-up visit. Results Nineteen patients with TRBD were enrolled in the study, and 16 patients (84.2%) received all six ketamine infusions. After the first infusion, the rates of response and remission were 21.1% (95% CI: 0.9 to 21.2) and 15.8% (95% CI: 0 to 33.9), respectively, and after the sixth infusion, the rates of response and remission were 73.7% (95% CI: 51.9 to 95.5) and 63.2% (95% CI: 39.3 to 87.0), respectively. The average times for nineteen patients who responded and remitted were 9.1 and 12.5 days, respectively. There were large decreases in the scores on the MADRS and the Scale for Suicidal Ideation-part 1 within 4 h after the first infusion, and the decreases were maintained across subsequent infusions. There were no significant increases in dissociative and psychotomimetic symptoms as measured by the Clinician-Administered Dissociative States Scale (CADSS) and the Brief Psychiatric Rating Scale (BPRS)-4 items, respectively. Conclusion These pilot findings suggest the feasibility of repeated ketamine infusions at subanaesthetic doses for patients with TRBD. Future controlled studies are needed to confirm and expand these findings.”

Psilocybin occasioned mystical‐type experiences

Authors: Edward James, Thomas L. Robertshaw, Hathew Hoskins & Ben Sessa

Published: 23 June 2020

One sentence summary: A narrative review gives an overview and analysis of mystical-type experiences occasioned by psilocybin.

“Objective Research into psychedelic therapy models has shown promise for the treatment of specific psychiatric conditions. Mystical-type experiences occasioned by psilocybin have been correlated with therapeutic benefits and long-term improvements in positive mental outlook and attitudes. This article aims to provide an overview of the topic, highlight strengths and weaknesses in current research, generate novel perspectives and discussion, and consider future avenues for research. Design This narrative review was designed to summarise and assess the state of research on psilocybin occasioned mystical-type experiences and applications for the treatment of specific psychiatric conditions. Results Contemporary methods on the quantification of mystical-type experiences and their acute subjective effects are discussed. Recent studies provide some understanding of the pharmacological actions of psychedelics although the neurological similarities and differences between spontaneous and psychedelic mystical-type experiences are not well described. Applicability to modern clinical settings is assessed. Potential novel therapeutic applications include use in positive psychology interventions in healthy individuals. Conclusions Since 2006 significant advancements in understanding the therapeutic potential of psilocybin-assisted psychotherapy have been made; however, more work is required to understand the neuromechanistic processes and applicability in modern clinical settings. Despite promising results in recent studies, funding issues for clinical trials, legal concerns and socio-cultural resistance provide a counterpoint to experimental evidence.“

Further analysis will follow.

A randomized, double-blind, active placebo-controlled study of efficacy, safety, and durability of repeated vs single subanesthetic ketamine for treatment-resistant depression

Authors: Paulo R. Shiroma, Paul Thuras, Joseph Wels, C. Sophia Albott, Christopher Erbes, Susannah Tye & Kelvin O. Lim

Published: 23 June 2020

One sentence summary: Repeated ketamine wasn’t significantly more anti-depressive as a single ketamine administration.

“The strategy of repeated ketamine in open-label and saline-control studies of treatment-resistant depression suggested greater antidepressant response beyond a single ketamine. However, consensus guideline stated the lack of evidence to support frequent ketamine administration. We compared the efficacy and safety of single vs. six repeated ketamine using midazolam as active placebo. Subjects received either six ketamine or five midazolam followed by a single ketamine during 12 days followed by up to 6-month post-treatment period. The primary end point was the change from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) score at 24 h after the last infusion. Fifty-four subjects completed all six infusions. For the primary outcome measure, there was no significant difference in change of MADRS scores between six ketamine group and single ketamine group at 24 h post-last infusion. Repeated ketamine showed greater antidepressant efficacy compared to midazolam after five infusions before receiving single ketamine infusion. Remission and response favored the six ketamine after infusion 4 and 5, respectively, compared to midazolam before receiving single ketamine infusion. For those who responded, the median time-to-relapse was nominally but not statistically different (2 and 6 weeks for the single and six ketamine group, respectively). Repeated infusions were relatively well-tolerated. Repeated ketamine showed greater antidepressant efficacy to midazolam after five infusions but fell short of significance when compared to add-on single ketamine to midazolam at the end of 2 weeks. Increasing knowledge on the mechanism of ketamine should drive future studies on the optimal balance of dosing ketamine for maximum antidepressant efficacy with minimum exposure.“

Serotonergic Psychedelics LSD & Psilocybin Increase the Fractal Dimension of Cortical Brain Activity in Spatial and Temporal Domains

Authors: Thomas F. Varley, Robin L. Carhart-Harris, Leor Roseman, David K. Menon & Emmanuel A. Stamatakis

Published: 30 June 2020

One sentence summary: Psilocybin and LSD showed increased fractal dimensions in the brain, a measure similar to criticality.

“Psychedelic drugs, such as psilocybin and LSD, represent unique tools for researchers investigating the neural origins of consciousness. Currently, the most compelling theories of how psychedelics exert their effects is by increasing the complexity of brain activity and moving the system towards a critical point between order and disorder, creating more dynamic and complex patterns of neural activity. While the concept of criticality is of central importance to this theory, few of the published studies on psychedelics investigate it directly, testing instead related measures such as algorithmic complexity or Shannon entropy. We propose using the fractal dimension of functional activity in the brain as a measure of complexity since findings from physics suggest that as a system organizes towards criticality, it tends to take on a fractal structure. We tested two different measures of fractal dimension, one spatial and one temporal, using fMRI data from volunteers under the influence of both LSD and psilocybin. The first was the fractal dimension of cortical functional connectivity networks and the second was the fractal dimension of BOLD time-series. In addition to the fractal measures, we used a well-established, non-fractal measure of signal complexity and show that they behave similarly. We were able to show that both psychedelic drugs significantly increased the fractal dimension of functional connectivity networks, and that LSD significantly increased the fractal dimension of BOLD signals, with psilocybin showing a non-significant trend in the same direction. With both LSD and psilocybin, we were able to localize changes in the fractal dimension of BOLD signals to brain areas assigned to the dorsal-attenion network. These results show that psychedelic drugs increase the fractal dimension of activity in the brain and we see this as an indicator that the changes in consciousness triggered by psychedelics are associated with evolution towards a critical zone.“

Further analysis will follow.