This November proved to be another fruitful month for psychedelic research. Psychedelics are being tested as a treatment for more and more mental ills. As this is done, it becomes ever more evident that psychedelics work on resolving an underlying issue. And that the classification (DSM/ICD) are but mere groups of symptoms that in some ways help us make sense of how mental health disorders manifest.

The seven highlighted papers describe new testing grounds, and explanatory frameworks on how psychedelics improve our mental health. Ari Brouwer and Robin Carhart-Harris investigate this at the psychological (experienced) level and propose ‘pivotal mental state’ as a moment of plasticity in which learning can take place. Within our brains, changes that were formally the domain of serotonergic (classical) psychedelics have now also been found to be induced by MDMA.

Making this more practical is a study on MDMA, in combination with psychotherapy, for relieving anxiety. This also used to be the domain of classical psychedelics, and although the study found no significant effect, the data did suggest that a larger sample size would be able to establish this. In time, it would be very interesting to see which type of psychedelic (classical, empathogen (MDMA), or novel) will work best for whom.

An analysis of Phase II trails with MDMA shows that it works less well in the treatment of PTSD when someone has tapered off antidepressants. It would be interesting to see a further analysis of this interaction. Possibly data from other trials (with other psychedelics) could also be analysed for this purpose.

Psilocybin has been found to significantly improve depression scores in a population with major depressive disorder (MDD). This widens the net, previously cast at treatment-resistant depression (TRD), but the study below was relatively small (n=24) and open-label. Psilocybin could also help to reduce migraines and an exploratory study adds evidence to the call for allowing psilocybin for migraines and cluster headaches (also see our November News).

Do also check out our list of articles that include a reflection on psychedelic research in 2019, a critique of media coverage of retracted research, a review of ketamine in bipolar disorder, and much more.

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder

Authors: Alan K. Davis, Frederick S. Barrett, Darrick G. May, Mary P. Cosimano, Nathan D. Sepeda, Matthew W. Johnson, Patrick H. Finan & Roland R. Griffiths

Published: 4 November 2020

One-sentence summary: This randomized open-label study (n=24) found that two sessions with psilocybin (20 and 30mg/70kg) significantly improved depression scores for a population with major depressive disorder (MDD) up to 8 weeks later.

“… Results Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession 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 = 2.2; 95% CI, 1.4-3.0; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.7-3.6; P < .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 = 3.0; 95% CI, 1.9-4.0; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 3.1; 95% CI, 1.9-4.2; P < .001). In the overall sample, 16 participants (67%) 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) …”

Further analysis.

Pivotal Mental States

Authors: Ari Brouwer & Robin L. Carhart-Harris

Published: 11 November 2020

One-sentence summary: This theory-building paper introduces the ‘pivotal mental state’, a hyper-plastic state which can mediate psychological transformation.

“This paper introduces a new construct, the ‘pivotal mental state’, which is defined as a hyper-plastic state aiding rapid and deep learning that can mediate psychological transformation. We believe this new construct bears relevance to a broad range of psychological and psychiatric phenomena. We argue that pivotal mental states serve an important evolutionary function, that is, to aid psychological transformation when actual or perceived environmental pressures demand this. We cite evidence that chronic stress and neurotic traits are primers for a pivotal mental state, whereas acute stress can be a trigger. Inspired by research with serotonin 2A receptor agonist psychedelics, we highlight how activity at this particular receptor can robustly and reliably induce pivotal mental states, but we argue that the capacity for pivotal mental states is an inherent property of the human brain itself. Moreover, we hypothesize that serotonergic psychedelics hijack a system that has evolved to mediate rapid and deep learning when its need is sensed. We cite a breadth of evidences linking stress via a variety of inducers, with an upregulated serotonin 2A receptor system (e.g. upregulated availability of and/or binding to the receptor) and acute stress with 5-HT release, which we argue can activate this primed system to induce a pivotal mental state. The pivotal mental state model is multi-level, linking a specific molecular gateway (increased serotonin 2A receptor signaling) with the inception of a hyper-plastic brain and mind state, enhanced rate of associative learning and the potential mediation of a psychological transformation.“

Further analysis.

Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin

Authors: Emmanuelle A. D. Schindler, R. Andrew Sewell, Christopher H. Gottschalk, Christina Luddy, L. Taylor Flynn, Hayley Lindsey, Brian P. Pittman, Nicholas V. Cozzi & Deepak C. D’Souza

Published: 12 November 2020

One-sentence summary: This double-blind, placebo-controlled, cross-over study (n=10) finds that a medium dose of psilocybin (10mg/70kg) significantly reduced migraines (headaches) in the two weeks after dosing.

“While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT_2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, – 1.65 (95% CI: – 2.53 to – 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT_2A receptor compounds in migraine, as well as other neuropsychiatric conditions.“

MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogens

Authors: Felix Müller, Friederike Holze, Patrick Dolder, Laura Ley, Patrick Vizeli, Alain Soltermann, Matthias E. Liechti & Stefan Borgwardt

Published: 20 November 2020

One-sentence summary: This double-blind, placebo-controlled, fMRI study (n=45) found that MDMA induced similar (neuronal) changes as classical (serotonergic) psychedelics.

“It has been reported that serotonergic hallucinogens like lysergic acid diethylamide (LSD) induce decreases in functional connectivity within various resting-state networks. These alterations were seen as reflecting specific neuronal effects of hallucinogens and it was speculated that these shifts in connectivity underlie the characteristic subjective drug effects. In this study, we test the hypothesis that these alterations are not specific for hallucinogens but that they can be induced by monoaminergic stimulation using the non-hallucinogenic serotonin-norepinephrine-dopamine releasing agent 3,4-methylenedioxymethamphetamine (MDMA). In a randomized, placebo-controlled, double-blind, crossover design, 45 healthy participants underwent functional magnetic resonance imaging (fMRI) following oral administration of 125 mg MDMA. The networks under question were identified using independent component analysis (ICA) and were tested with regard to within-network connectivity. Results revealed decreased connectivity within two visual networks, the default mode network (DMN), and the sensorimotor network. These findings were almost identical to the results previously reported for hallucinogenic drugs. Therefore, our results suggest that monoaminergic substances can induce widespread changes in within-network connectivity in the absence of marked subjective drug effects. This contradicts the notion that these alterations can be regarded as specific for serotonergic hallucinogens. However, changes within the DMN might explain antidepressants effects of some of these substances.”

Further analysis.

Discontinuation of medications classified as reuptake inhibitors affects treatment response of MDMA-assisted psychotherapy

Authors: Allison A. Feduccia, Lisa Jerome, Michael C. Mithoefer & Julie Holland

Published: 21 November 2020

One-sentence summary: A pooled analysis of participants (n=50) in Phase II MDMA-trials (125mg) for PTSD found that recent tapering off SSRIs may reduce treatment response (CAPS-IV score).

“Rationale: MDMA-assisted psychotherapy is under investigation as a novel treatment for posttraumatic stress disorder (PTSD). The primary mechanism of action of MDMA involves the same reuptake transporters targeted by antidepressant medications commonly prescribed for PTSD. Objectives: Data were pooled from four phase 2 trials of MDMA-assisted psychotherapy. To explore the effect of tapering antidepressant medications, participants who had been randomized to receive active doses of MDMA (75-125 mg) were divided into two groups (taper group (n = 16) or non-taper group (n = 34)). Methods: Between-group comparisons were made for PTSD and depression symptom severity at the baseline and the primary endpoint, and for peak vital signs across two MDMA sessions. Results: Demographics, baseline PTSD, and depression severity were similar between the taper and non-taper groups. At the primary endpoint, the non-taper group (mean = 45.7, SD = 27.17) had a significantly (p = 0.009) lower CAPS-IV total scores compared to the taper group (mean = 70.3, SD = 33.60). More participants in the non-taper group (63.6%) no longer met PTSD criteria at the primary endpoint than those in the taper group (25.0%). The non-taper group (mean = 12.7, SD = 10.17) had lower depression symptom severity scores (p = 0.010) compared to the taper group (mean = 22.6, SD = 16.69). There were significant differences between groups in peak systolic blood pressure (p = 0.043) and diastolic blood pressure (p = 0.032). Conclusions: Recent exposure to antidepressant drugs that target reuptake transporters may reduce treatment response to MDMA-assisted psychotherapy.”

Further analysis.

Treatment of a Complex Personality Disorder Using Repeated Doses of LSD-A Case Report on Significant Improvements in the Absence of Acute Drug Effects

Authors: Felix Müller, Markus Mühlhauser, Friederike Holze, Undine E. Lang, Marc Walter, Matthias E. Liechti & Stefan Borgwardt

Published: 22 November 2020

One-sentence summary: This case study of a patient with mental health problems, found no acute effects of LSD (50 to 200 µg) and persistent (7 days) positive effects (dose-dependent) on depression (TRD) and suicidal ideation scores.

“A 39-year-old female patient suffering from severe, treatment-resistant depression and other symptoms associated with a complex personality disorder was admitted to our open psychiatric ward for an experimental treatment with lysergic acid diethylamide (LSD). The substance was administered in repeated weekly and ascending doses. Curiously, there were no substantial acute subjective effects of the drug despite adequate dosing, which was also confirmed by plasma drug concentration monitoring. However, the patient showed rapid and significant improvement with most notable changes in depressed mood, emotional instability, loss of energy, and suicidal ideations. Additionally, the SCL-90 questionnaire indicated significant decreases in global severity and in various psychopathological subscales. Improvements persisted for ~7 days after each administration. Due to the severe course of the illness and the resistance to previous treatment it was decided to continue this experimental approach with weekly repeated doses of LSD. The patient will be observed closely with regard to somatic and mental side effects. Two features of this case are remarkable: Firstly, administration of LSD was associated with significant improvements in various symptoms of a condition usually difficult to treat. Secondly, symptom reductions occurred in the absence of acute drug effects. Therefore, the mechanism of action seemed to deviate from the concept that improvements after administration of drugs like LSD are due to experiences during the acute drug effects. This case might indicate that LSD can induce rapid but transient beneficial effects on several psychopathological symptoms. The time course of these improvements resembled antidepressant effects seen after administration of ketamine.“

MDMA-assisted psychotherapy for treatment of anxiety and other psychological distress related to life-threatening illnesses: a randomized pilot study

Authors: Philip E. Wolfson, Julane Andries, Allison A. Feduccia, Lisa Jerome, Julie B. Wang, Emily Williams, Shannon C. Carlin, Evan Sola, Scott Hamilton, Berra Yazar-Klosinski, Amy Emerson, Michael C. Mithoefer & Rick Doblin

Published: 24 November 2020

One-sentence summary: This double-blind, placebo-controlled study (n=18) with MDMA (125mg, 2 sessions) in combination with psychotherapy found no significant difference in anxiety in a population with life-threatening illnesses.

“The success of modern medicine creates a growing population of those suffering from life-threatening illnesses (LTI) who often experience anxiety, depression, and existential distress. We present a novel approach; investigating MDMA-assisted psychotherapy for the treatment of anxiety in people with an LTI. Participants with anxiety from an LTI were randomized in a double-blind study to receive MDMA (125 mg, n = 13) or placebo (n = 5) in combination with two 8-h psychotherapy sessions. The primary outcome was change in State-Trait Anxiety Inventory (STAI) Trait scores from baseline to one month post the second experimental session. After unblinding, participants in the MDMA group had one open-label MDMA session and placebo participants crossed over to receive three open-label MDMA sessions. Additional follow-up assessments occurred six and twelve months after a participant’s last experimental session. At the primary endpoint, the MDMA group had a greater mean (SD) reduction in STAI-Trait scores, – 23.5 (13.2), indicating less anxiety, compared to placebo group, – 8.8 (14.7); results did not reach a significant group difference (p = .056). Hedges’ g between-group effect size was 1.03 (95% CI: – 5.25, 7.31). Overall, MDMA was well-tolerated in this sample. These preliminary findings can inform development of larger clinical trials to further examine MDMA-assisted psychotherapy as a novel approach to treat individuals with LTI-related anxiety.“