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The increase in research surrounding psychedelics has continued into November, which saw a great number of publications. Blossom analysis has highlighted seven research papers from November 2020, which cover a range of psychedelics, indications, and disciplines.
Brouwer and Carhart-Harris provided some theoretical food for thought in the form of their paper which proposed psychedelics manifest a ‘pivotal mental state’: a hyper-plastic state which enables “rapid and deep learning that can mediate psychological transformation”.
A study by Feduccia et al suggested historic antidepressant usage may reduce the efficacy of MDMA-assisted psychotherapy. This implies that the use of SSRIs may have lasting impacts on the human brain. You can learn more about this study by reading our summary.
In terms of psilocybin, a randomised open-label study (n=24) found that 2 sessions with psilocybin significantly improved depression scores for those with major depressive disorder (Davis et al). We also covered the findings of an exploratory study from Yale, which found that a single low dose of psilocybin reduces the frequency of migraine headaches for 2 weeks (Schindler et al).
In our endeavour to provide you with the data necessary to track and analyse the emergent psychedelic sector, we’re working with Blossom Analysis to bring you a monthly research round-up.
Clicking the further analysis link will take you to a short summary of the work on Blossom’s website.
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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) …”
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.“
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-HT2A) 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-HT2A 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.”
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.”
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.“
Related Papers
(about psychedelics but possibly less influential, or are short (review/commentary) articles)
- Fast Hollow Fiber Liquid-Phase Microextraction as a Greener Alternative for the Determination of N,N-Dimethyltryptamine and Harmala Alkaloids in Human Urine (“A simple, time-saving and green alternative for the analysis of DMT and harmala alkaloids in human urine samples was developed, optimized using design of experiments, fully validated and applied to authentic samples.”)
- Practical recommendations for the management of treatment-resistant depression with esketamine nasal spray therapy: Basic science, evidence-based knowledge and expert guidance (a ‘how-to-use’ guide from experts with esketamine (the expensive one))
- Transcriptional regulation in the rat prefrontal cortex and hippocampus after a single administration of psilocybin (in rats, more evidence of the promotion of plasticity-promoting effects of psilocybin)
- Is Ketamine a Litmus Test for Capacity in Assisted Dying with Depression? (“Ketamine might serve as a type of litmus test to help clarify the influence of potentially reversible depressive symptoms on the desire for death“)
- Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects (this survey study (n=614) found relative safe practice standards, nausea and vomiting as most prevalent symptoms, and no drug-drug interactions with psychiatric medication use)
- Uncovering psychological mechanisms mediating the effects of drugs: some issues and comments using the example of psychedelic drugs (commentary on psychological mechanisms of psychedelics, and the difficulty studying this)
- Prescribing meaning: hedonistic perspectives on the therapeutic use of psychedelic-assisted meaning enhancement (student essay, complementary to the article above, argues that if meaning-making is the mechanism at work, then it should/can be ethically justified)
- Improved colour blindness symptoms associated with recreational psychedelic use: Results from the Global Drug Survey 2017 (further analysis of GDS 2017, 23 responses, possible mechanisms explained)
- Neurocognitive effects of six ketamine infusions and the association with antidepressant effects in treatment-resistant bipolar depression: a preliminary study (very specific analysis of ketamine infusions on cognitive functioning in those with TRBD)
- Ketamine: A tale of two enantiomers (review)
- Metabolic Risk Factors and Cardiovascular Safety in Ketamine Use for Treatment Resistant Depression (n=49, finds good safety and tolerability for IV ketamine in MDD and BP population)
- New agents and perspectives in the pharmacological treatment of major depressive disorder (broad review of the treatment of MDD, psychedelics (ketamine) mentioned as possible novel treatments)
- Intermittent repeated stress but not ketamine changes mice response to antidepressants (in mice, “Ketamine does not prevent stress-induced change in antidepressants’ effect.“)
- Anti-inflammatory activity of ayahuasca and its implications for the treatment of neurological and psychiatric diseases (review, not too long or controversial)
- Psilocybin-Assisted Supportive Psychotherapy in the Treatment of Major Depression—Quo Vadis? (editorial about first article of this month)
- A Proof-of-Concept Study of Subanesthetic Intravenous Ketamine Combined With Prolonged Exposure Therapy Among Veterans With Posttraumatic Stress Disorder (open-label, n=10, 7x 35mg/70kg IV-ketamine before exposure therapy)
- Happiness During Low-Dose Ketamine Infusion Predicts Treatment Response: Reexploring the Adjunctive Ketamine Study of Taiwanese Patients With Treatment-Resistant Depression (“Subjective happiness during ketamine infusion predicted the antidepressant effect of both 0.5 mg/kg and 0.2 mg/kg ketamine infusion over time.”)
- The time course of psychotic symptom side effects of ketamine in the treatment of depressive disorders: a systematic review and meta-analysis (meta-analysis, n=458, side effects (Brief Psychiatric Rating Scale) transient)
- Using classification and regression tree modelling to investigate treatment response to a single low-dose ketamine infusion: Post hoc pooled analyses of randomized placebo-controlled and open-label trials (post-hoc, n=73, younger and obese patients had the highest response rates)
- The potential use of N-methyl-3,4-methylenedioxyamphetamine (MDMA) assisted psychotherapy in the treatment of eating disorders comorbid with PTSD (hypothesis paper, still very promising)
- Advancing Elite Athlete Mental Health Treatment with Psychedelic-Assisted Psychotherapy (review, on why psychedelics may be a good treatment for athletes – a population that experiences high levels of mental health disorders)
- DARK Classics in Chemical Neuroscience: Salvinorin A (good overview of Salvinorin A, an understudied psychedelic)
- Biomedical analysis of New Psychoactive Substances (NPS) of natural origin (“… a comprehensive method to detect active compounds from different natural specimens both in biological and non-biological matrices is still lacking.“)
- Time is of the essence: Coupling sleep-wake and circadian neurobiology to the antidepressant effects of ketamine (review, interesting line of thought)
- Ketamine in Bipolar Disorder: A Review (comprehensive review, see figure 1 for all the pathways/mechanisms)
- Treatment of depression with ketamine does not change plasma levels of brain-derived neurotrophic factor or vascular endothelial growth factor
- Influence of formulation and route of administration on ketamine’s safety and tolerability: systematic review (review, not specifically about psychedelic effect, but more info on safety profile and differences between dosages/formulations/administrations)
- Long-term Amelioration of OCD Symptoms in a Patient with Chronic Consumption of Psilocybin-containing Mushrooms (case study, another data point related to psilocybin for OCD treatment)
- Entity encounters and the therapeutic effect of the psychedelic mystical experience (there may be positive/therapeutic effects resulting from ‘entity encounters’, the article proposes three ways how it mediates therapeutic effects)
- Clinically Meaningful Changes on Depressive Symptom Measures and Patient-Reported Outcomes in Patients with Treatment-Resistant Depression (defining how to measure clinical changes of treatment, esketamine & antidepressants in this case)
- Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review (review, psychedelics for substance use disorders (SUD))
- Use of subcutaneous ketamine to rapidly improve severe treatment-resistant depression in a patient with Alzheimer’s disease (case report)
- The Effects of Ketamine on Cognition in Treatment-Resistant Depression: A Systematic Review and Priority Avenues for Future Research (review, found some positive effects on cognition after ketamine treatment for TRD, no worsening of cognition)
- Persistent Tinnitus after Inhaled N,N-dimethyltryptamine (DMT) (case study, tinnitus (ringing of ears) after various ‘self-experiments’, DMT being the immediate (suspected) cause)
- Dissemination of Erroneous Research Findings and Subsequent Retraction in High-Circulation Newspapers: A Case Study of Alleged MDMA-Induced Dopaminergic Neurotoxicity in Primates (critique of media coverage and lack of it when a sensational (erroneous) article is retracted, by Brian S. Barnett & Rick Doblin)
- 2019: A year of expansion in psychedelic research, industry, and deregulation (succinct review of what changed in the psychedelic (research) landscape in 2019)
- Effects of ayahuasca on mental health and quality of life in naïve users: A longitudinal and cross-sectional study combination (two studies, first found improvements (at 6 months) for naïve Ayahuasca users after first use (n=40), second found that those who used it often compared favorably (mental health) to the former group)
- Ketamine and Serotonergic Psychedelics: Common Mechanisms Underlying the Effects of Rapid-Acting Antidepressants (review, identifies similar downstream/non-acute effects of ketamine and classical psychedelics)
- The pharmacological interaction of compounds in ayahuasca: a systematic review (review of how DMT and MAOIs in ayahuasca, it’s not currently known if the compounds are additive or synergetic)
- The Psychedelic Personality: Personality Structure and Associations in a Sample of Psychedelics Users (psychedelic users are more extraverted and risk taking)
- Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine (review of psychedelics (including ketamine and MDMA) for mental health)
- Copper and anti-anhedonic effect of ketamine in treatment-resistant depression (medical hypothesis, looking at common denominator of copper and ketamine)
